Applied Evidence

You are asked to perform a preoperative evaluation of a 6-year-old boy who is due to have a tonsillectomy. The family history reveals that his father had an episode that sounds like malignant hyperthermia (MH). Also, a paternal uncle experienced a high fever and almost died after undergoing anesthesia. The boy’s parents tell you they took the boy to a pediatrician, who did a “blood test” for MH. They hand you a written report of an enzyme-linked immunosorbent assay, which tested negative for an allergy to succinylcholine.

Has this child been adequately screened for MH?

If you answered No, you are correct. The review that follows explains why.

The “disease of anesthesia”

MH is a pharmacogenetic disease process that occurs when predisposed individuals are exposed to certain triggering agents—specifically, anesthetics. Succinylcholine and all potent inhalational anesthetic agents have been implicated (TABLE 1). Most episodes occur in the intraoperative period.

MH is a familial disease and follows an autosomal dominant pattern, but with incomplete penetrance. Surprisingly, the disease was not described until 1961, when Denborough et al reported a string of anesthetic-related deaths in a family.^1,2 A similar condition was described in pigs in 1966.³ This condition, porcine stress syndrome, was noted during research in which pigs had received succinylcholine. This syndrome has become the animal model for the study of MH.^4,5

Over time, this condition came to be known as malignant hyperthermia because a rapid rise in temperature was a common feature in all reported cases. Additional possible signs and symptoms include skin mottling, arrhythmias, elevated creatine kinase (CK), and rhabdomyolysis, among others (TABLE 2).

Associated conditions. MH may occur with any condition requiring intervention with anesthesia. It was once believed that strabismus and MH were linked, but this assumption was based on a statistical error related to an increased number of surgical procedures in children with strabismus. Currently, a propensity toward MH seems associated only with rare myopathic conditions such as central core disease, hypokalemic periodic paralysis, Evans myopathy, and King-Denborough syndrome.⁶ Precise genetic mapping will determine what, if any, relationship there is between these processes and MH.

TABLE 1
Triggering and nontriggering anesthetic agents

Triggering agents	Nontriggering agents
Succinylcholine (most common)	Barbiturates
Desflurane	Benzodiazepines
Halothane	Ketamine
Isoflurane	Local anesthetics
Sevoflurane	Nitrous oxide
	Nondepolarizing muscle relaxants
	Opioids
	Propofol
Adapted from: Barash PG, et al, eds. Clinical Anesthesia. 6th ed. Philadelphia, Pa: Lippincott Williams & Wilkins; 2009.

TABLE 2
Signs and symptoms of malignant hyperthermia

Arrhythmias
Coagulopathy
Elevated creatine kinase
Elevated temperature
Hypercarbia
Hyperkalemia
Increased oxygen consumption
Masseter muscle spasm
Metabolic acidosis
Muscle rigidity
Rhabdomyolysis
Skin mottling
Tachycardia
Tachypnea
Adapted from: Barash PG, et al, eds. Clinical Anesthesia. 6th ed. Philadelphia, Pa: Lippincott Williams & Wilkins; 2009.

Awake triggering: Similar disorder without anesthesia
Since 1980 there have been several reports of “awake triggering” in genetically predisposed individuals, whereby stressful conditions alone unrelated to general anesthesia cause MH.^7-10 Often, the presenting condition has been heat-stroke, but other symptoms are also common, such as rhabdomyolysis, increased CK, muscle pain, and cardiovascular collapse.¹¹ Relatives of those with a history of MH have also exhibited chronic muscle pain or chronic CK elevation. All of these people, when tested, have had a positive reaction to the caffeine-halothane contracture test (CHCT), which is the gold standard for confirming MH.¹²

The Malignant Hyperthermia Association of the United States (MHAUS) lists signs and symptoms that accompany awake triggering on its Web site, www.mhaus.org. They include heat sensitivity, night sweats, cramping, mottled skin, low-grade fever, and excessive sweating.

Should such findings—especially elevated CK and rhabdomyolysis—come to your attention by a patient’s report or during physical examination, consider further workup for MH.

How MH develops
MH occurs because of a defect in the ryanodine receptor, RYR1. This receptor is responsible for intracellular calcium release by its mediation of the sarcoplasmic reticulum. RYR1 is found in all skeletal muscle.¹³ During an episode of MH, exposure to the triggering agent causes intracellular calcium release by the sarcoplasmic reticulum and sustained skeletal muscle contractions and rigidity. Increased oxygen consumption occurs, and this hypermetabolic state leads to hypercarbia, severe metabolic acidosis, tachycardia, arrhythmias, hyperkalemia, and elevated temperature. Rhabdomyolysis and elevations in CK also occur because of skeletal muscle breakdown.

How to treat this medical emergency

 

Only rapid, specific treatment can save a patient with MH from death. Before investigators discovered that dantrolene sodium is an effective treatment for MH, >70% of patients who developed the disease died.¹² Mortality has since dropped to ≤15%.¹⁴ With a presumptive diagnosis of MH, dantrolene should be prepared and given immediately. The drug inhibits the release of calcium from the sarcoplasmic reticulum of skeletal muscle by limiting the activation of RYR1.

Successful resuscitation of patients with MH hinges on the following:

Making a prompt diagnosis. While most episodes of MH occur shortly after induction of anesthesia or during the intraoperative course, nearly 2% of MH cases occur postoperatively¹⁵—some as long as 12 hours after exposure to the presumed trigger.

Immediately discontinuing triggering anesthetics and starting dantrolene. The patient should be kept anesthetized using nontriggering agents (TABLE 1), and surgery should be concluded as quickly as possible.

Preparation of dantrolene is a tedious process because of its poor water solubility. One to 2 minutes are needed for the preparation to solubilize. Initial treatment with dantrolene is 2.5 mg/kg administered intravenously (via peripheral or central line). This dose (or up to 10 mg/kg) can be repeated every 5 to 10 minutes until major symptoms such as hypercarbia, arrhythmias, hyperpyrexia, and metabolic acidosis abate. Thereafter, dantrolene is continued at 2.5 mg/kg every 4 hours for 24 hours.

Cooling the patient. A patient should be cooled using ice packs, gastric lavage with ice water, cold intravenous fluid, or ice water lavage at the surgical site. Active cooling should stop when the patient’s temperature reaches 100°F (so as not to cause hypothermia). Cooling should not, however, prevent or slow the administration of dantrolene.

Treating acidosis, arrhythmias, electrolyte disturbances, coagulopathy, excess myoglobin, and acute renal failure. Arrhythmias should not be treated with calcium channel blockers.

Monitoring patients in the ICU for potential adverse effects of dantrolene that can include sedation and muscle weakness. Mechanical ventilation may be needed. (The malignant hyperthermia hotline [800-644-9737] at MHAUS is available 24 hours a day to assist clinicians with questions regarding diagnosis and treatment.)

Keeping patients safe by properly testing them
The CHCT is 97% sensitive and 78% specific for MH.¹⁶ It is an invasive procedure, requiring the patient to undergo anesthesia. The test costs more than $5,000, which most insurance companies will cover.¹⁷

The CHCT is performed only on fresh muscle, and only 5 centers in North America perform the test. The number of centers is kept to a minimum to maintain high procedural quality. The biopsy specimen is taken from the vastus lateralis. Because of the size of the specimen required to perform the test, a child weighing <20 kg or <5 years of age is usually not tested but simply presumed to be MH susceptible.¹⁸

Counseling patients and their families
Make sure affected individuals and family members know the life-threatening implications of this condition; that it is familial and that its onset does not always occur with a first exposure to anesthesia, but sometimes with a subsequent exposure. Explain that MH is not an “allergy to anesthesia” or an “allergy to succinylcholine.” Patients can undergo anesthesia safely in the future if performed with a nontriggering agent and associated technique. Anesthesiologists today are well trained to manage these patients with minimum risk.

Counsel first-degree relatives of MH patients about undergoing the CHCT. Molecular genetic testing, which requires a blood draw but is less sensitive than the CHCT, may be another option. If an MH patient was diagnosed using this blood test, relatives may opt to be tested this way, as well. If genetic test results for relatives are positive, these individuals are presumed to have MH and should be treated as such, saving them the expense and risk of undergoing muscle biopsy. If genetic test results are negative, the CHCT should be considered or patients should be presumed to be MH susceptible.

 

Why is testing of relatives needed if a nontriggering anesthetic can be administered? Nontriggering anesthetic agents are not routinely used in surgery, and problems can arise in, say, emergency situations when MH susceptibility in a patient is unknown to the surgical team. Testing enables patients to learn their status and to obtain a medical alert bracelet.

What about the child in the opening scenario?
It is evident that the child in the scenario at the beginning of this article was not adequately screened for MH. Given that the child is >5 years of age, he should undergo the CHCT. You would be wise to presume that his first-degree relatives are also susceptible until proven otherwise by the CHCT. With children not meeting the age or weight requirement for CHCT, make sure the family understands the potential severity of MH and immediately inform the surgeon and anesthesiologist of the family history so appropriate precautions, including arrangements for nontriggering anesthetics, can be put into place.

CORRESPONDENCE
Gregory L. Rose, MD, Department of Anesthesia, University of Kentucky College of Medicine, 800 Rose Street, Lexington, KY 40536; [email protected]

You are asked to perform a preoperative evaluation of a 6-year-old boy who is due to have a tonsillectomy. The family history reveals that his father had an episode that sounds like malignant hyperthermia (MH). Also, a paternal uncle experienced a high fever and almost died after undergoing anesthesia. The boy’s parents tell you they took the boy to a pediatrician, who did a “blood test” for MH. They hand you a written report of an enzyme-linked immunosorbent assay, which tested negative for an allergy to succinylcholine.

Has this child been adequately screened for MH?

If you answered No, you are correct. The review that follows explains why.

The “disease of anesthesia”

MH is a pharmacogenetic disease process that occurs when predisposed individuals are exposed to certain triggering agents—specifically, anesthetics. Succinylcholine and all potent inhalational anesthetic agents have been implicated (TABLE 1). Most episodes occur in the intraoperative period.

MH is a familial disease and follows an autosomal dominant pattern, but with incomplete penetrance. Surprisingly, the disease was not described until 1961, when Denborough et al reported a string of anesthetic-related deaths in a family.^1,2 A similar condition was described in pigs in 1966.³ This condition, porcine stress syndrome, was noted during research in which pigs had received succinylcholine. This syndrome has become the animal model for the study of MH.^4,5

Over time, this condition came to be known as malignant hyperthermia because a rapid rise in temperature was a common feature in all reported cases. Additional possible signs and symptoms include skin mottling, arrhythmias, elevated creatine kinase (CK), and rhabdomyolysis, among others (TABLE 2).

Associated conditions. MH may occur with any condition requiring intervention with anesthesia. It was once believed that strabismus and MH were linked, but this assumption was based on a statistical error related to an increased number of surgical procedures in children with strabismus. Currently, a propensity toward MH seems associated only with rare myopathic conditions such as central core disease, hypokalemic periodic paralysis, Evans myopathy, and King-Denborough syndrome.⁶ Precise genetic mapping will determine what, if any, relationship there is between these processes and MH.

TABLE 1
Triggering and nontriggering anesthetic agents

Triggering agents	Nontriggering agents
Succinylcholine (most common)	Barbiturates
Desflurane	Benzodiazepines
Halothane	Ketamine
Isoflurane	Local anesthetics
Sevoflurane	Nitrous oxide
	Nondepolarizing muscle relaxants
	Opioids
	Propofol
Adapted from: Barash PG, et al, eds. Clinical Anesthesia. 6th ed. Philadelphia, Pa: Lippincott Williams & Wilkins; 2009.

TABLE 2
Signs and symptoms of malignant hyperthermia

Arrhythmias
Coagulopathy
Elevated creatine kinase
Elevated temperature
Hypercarbia
Hyperkalemia
Increased oxygen consumption
Masseter muscle spasm
Metabolic acidosis
Muscle rigidity
Rhabdomyolysis
Skin mottling
Tachycardia
Tachypnea
Adapted from: Barash PG, et al, eds. Clinical Anesthesia. 6th ed. Philadelphia, Pa: Lippincott Williams & Wilkins; 2009.

Awake triggering: Similar disorder without anesthesia
Since 1980 there have been several reports of “awake triggering” in genetically predisposed individuals, whereby stressful conditions alone unrelated to general anesthesia cause MH.^7-10 Often, the presenting condition has been heat-stroke, but other symptoms are also common, such as rhabdomyolysis, increased CK, muscle pain, and cardiovascular collapse.¹¹ Relatives of those with a history of MH have also exhibited chronic muscle pain or chronic CK elevation. All of these people, when tested, have had a positive reaction to the caffeine-halothane contracture test (CHCT), which is the gold standard for confirming MH.¹²

The Malignant Hyperthermia Association of the United States (MHAUS) lists signs and symptoms that accompany awake triggering on its Web site, www.mhaus.org. They include heat sensitivity, night sweats, cramping, mottled skin, low-grade fever, and excessive sweating.

Should such findings—especially elevated CK and rhabdomyolysis—come to your attention by a patient’s report or during physical examination, consider further workup for MH.

How MH develops
MH occurs because of a defect in the ryanodine receptor, RYR1. This receptor is responsible for intracellular calcium release by its mediation of the sarcoplasmic reticulum. RYR1 is found in all skeletal muscle.¹³ During an episode of MH, exposure to the triggering agent causes intracellular calcium release by the sarcoplasmic reticulum and sustained skeletal muscle contractions and rigidity. Increased oxygen consumption occurs, and this hypermetabolic state leads to hypercarbia, severe metabolic acidosis, tachycardia, arrhythmias, hyperkalemia, and elevated temperature. Rhabdomyolysis and elevations in CK also occur because of skeletal muscle breakdown.

How to treat this medical emergency

 

Only rapid, specific treatment can save a patient with MH from death. Before investigators discovered that dantrolene sodium is an effective treatment for MH, >70% of patients who developed the disease died.¹² Mortality has since dropped to ≤15%.¹⁴ With a presumptive diagnosis of MH, dantrolene should be prepared and given immediately. The drug inhibits the release of calcium from the sarcoplasmic reticulum of skeletal muscle by limiting the activation of RYR1.

Successful resuscitation of patients with MH hinges on the following:

Making a prompt diagnosis. While most episodes of MH occur shortly after induction of anesthesia or during the intraoperative course, nearly 2% of MH cases occur postoperatively¹⁵—some as long as 12 hours after exposure to the presumed trigger.

Immediately discontinuing triggering anesthetics and starting dantrolene. The patient should be kept anesthetized using nontriggering agents (TABLE 1), and surgery should be concluded as quickly as possible.

Preparation of dantrolene is a tedious process because of its poor water solubility. One to 2 minutes are needed for the preparation to solubilize. Initial treatment with dantrolene is 2.5 mg/kg administered intravenously (via peripheral or central line). This dose (or up to 10 mg/kg) can be repeated every 5 to 10 minutes until major symptoms such as hypercarbia, arrhythmias, hyperpyrexia, and metabolic acidosis abate. Thereafter, dantrolene is continued at 2.5 mg/kg every 4 hours for 24 hours.

Cooling the patient. A patient should be cooled using ice packs, gastric lavage with ice water, cold intravenous fluid, or ice water lavage at the surgical site. Active cooling should stop when the patient’s temperature reaches 100°F (so as not to cause hypothermia). Cooling should not, however, prevent or slow the administration of dantrolene.

Treating acidosis, arrhythmias, electrolyte disturbances, coagulopathy, excess myoglobin, and acute renal failure. Arrhythmias should not be treated with calcium channel blockers.

Monitoring patients in the ICU for potential adverse effects of dantrolene that can include sedation and muscle weakness. Mechanical ventilation may be needed. (The malignant hyperthermia hotline [800-644-9737] at MHAUS is available 24 hours a day to assist clinicians with questions regarding diagnosis and treatment.)

Keeping patients safe by properly testing them
The CHCT is 97% sensitive and 78% specific for MH.¹⁶ It is an invasive procedure, requiring the patient to undergo anesthesia. The test costs more than $5,000, which most insurance companies will cover.¹⁷

The CHCT is performed only on fresh muscle, and only 5 centers in North America perform the test. The number of centers is kept to a minimum to maintain high procedural quality. The biopsy specimen is taken from the vastus lateralis. Because of the size of the specimen required to perform the test, a child weighing <20 kg or <5 years of age is usually not tested but simply presumed to be MH susceptible.¹⁸

Counseling patients and their families
Make sure affected individuals and family members know the life-threatening implications of this condition; that it is familial and that its onset does not always occur with a first exposure to anesthesia, but sometimes with a subsequent exposure. Explain that MH is not an “allergy to anesthesia” or an “allergy to succinylcholine.” Patients can undergo anesthesia safely in the future if performed with a nontriggering agent and associated technique. Anesthesiologists today are well trained to manage these patients with minimum risk.

Counsel first-degree relatives of MH patients about undergoing the CHCT. Molecular genetic testing, which requires a blood draw but is less sensitive than the CHCT, may be another option. If an MH patient was diagnosed using this blood test, relatives may opt to be tested this way, as well. If genetic test results for relatives are positive, these individuals are presumed to have MH and should be treated as such, saving them the expense and risk of undergoing muscle biopsy. If genetic test results are negative, the CHCT should be considered or patients should be presumed to be MH susceptible.

 

Why is testing of relatives needed if a nontriggering anesthetic can be administered? Nontriggering anesthetic agents are not routinely used in surgery, and problems can arise in, say, emergency situations when MH susceptibility in a patient is unknown to the surgical team. Testing enables patients to learn their status and to obtain a medical alert bracelet.

What about the child in the opening scenario?
It is evident that the child in the scenario at the beginning of this article was not adequately screened for MH. Given that the child is >5 years of age, he should undergo the CHCT. You would be wise to presume that his first-degree relatives are also susceptible until proven otherwise by the CHCT. With children not meeting the age or weight requirement for CHCT, make sure the family understands the potential severity of MH and immediately inform the surgeon and anesthesiologist of the family history so appropriate precautions, including arrangements for nontriggering anesthetics, can be put into place.

CORRESPONDENCE
Gregory L. Rose, MD, Department of Anesthesia, University of Kentucky College of Medicine, 800 Rose Street, Lexington, KY 40536; [email protected]

You are asked to perform a preoperative evaluation of a 6-year-old boy who is due to have a tonsillectomy. The family history reveals that his father had an episode that sounds like malignant hyperthermia (MH). Also, a paternal uncle experienced a high fever and almost died after undergoing anesthesia. The boy’s parents tell you they took the boy to a pediatrician, who did a “blood test” for MH. They hand you a written report of an enzyme-linked immunosorbent assay, which tested negative for an allergy to succinylcholine.

Has this child been adequately screened for MH?

If you answered No, you are correct. The review that follows explains why.

The “disease of anesthesia”

MH is a pharmacogenetic disease process that occurs when predisposed individuals are exposed to certain triggering agents—specifically, anesthetics. Succinylcholine and all potent inhalational anesthetic agents have been implicated (TABLE 1). Most episodes occur in the intraoperative period.

MH is a familial disease and follows an autosomal dominant pattern, but with incomplete penetrance. Surprisingly, the disease was not described until 1961, when Denborough et al reported a string of anesthetic-related deaths in a family.^1,2 A similar condition was described in pigs in 1966.³ This condition, porcine stress syndrome, was noted during research in which pigs had received succinylcholine. This syndrome has become the animal model for the study of MH.^4,5

Over time, this condition came to be known as malignant hyperthermia because a rapid rise in temperature was a common feature in all reported cases. Additional possible signs and symptoms include skin mottling, arrhythmias, elevated creatine kinase (CK), and rhabdomyolysis, among others (TABLE 2).

Associated conditions. MH may occur with any condition requiring intervention with anesthesia. It was once believed that strabismus and MH were linked, but this assumption was based on a statistical error related to an increased number of surgical procedures in children with strabismus. Currently, a propensity toward MH seems associated only with rare myopathic conditions such as central core disease, hypokalemic periodic paralysis, Evans myopathy, and King-Denborough syndrome.⁶ Precise genetic mapping will determine what, if any, relationship there is between these processes and MH.

TABLE 1
Triggering and nontriggering anesthetic agents

Triggering agents	Nontriggering agents
Succinylcholine (most common)	Barbiturates
Desflurane	Benzodiazepines
Halothane	Ketamine
Isoflurane	Local anesthetics
Sevoflurane	Nitrous oxide
	Nondepolarizing muscle relaxants
	Opioids
	Propofol
Adapted from: Barash PG, et al, eds. Clinical Anesthesia. 6th ed. Philadelphia, Pa: Lippincott Williams & Wilkins; 2009.

TABLE 2
Signs and symptoms of malignant hyperthermia

Arrhythmias
Coagulopathy
Elevated creatine kinase
Elevated temperature
Hypercarbia
Hyperkalemia
Increased oxygen consumption
Masseter muscle spasm
Metabolic acidosis
Muscle rigidity
Rhabdomyolysis
Skin mottling
Tachycardia
Tachypnea
Adapted from: Barash PG, et al, eds. Clinical Anesthesia. 6th ed. Philadelphia, Pa: Lippincott Williams & Wilkins; 2009.

Awake triggering: Similar disorder without anesthesia
Since 1980 there have been several reports of “awake triggering” in genetically predisposed individuals, whereby stressful conditions alone unrelated to general anesthesia cause MH.^7-10 Often, the presenting condition has been heat-stroke, but other symptoms are also common, such as rhabdomyolysis, increased CK, muscle pain, and cardiovascular collapse.¹¹ Relatives of those with a history of MH have also exhibited chronic muscle pain or chronic CK elevation. All of these people, when tested, have had a positive reaction to the caffeine-halothane contracture test (CHCT), which is the gold standard for confirming MH.¹²

The Malignant Hyperthermia Association of the United States (MHAUS) lists signs and symptoms that accompany awake triggering on its Web site, www.mhaus.org. They include heat sensitivity, night sweats, cramping, mottled skin, low-grade fever, and excessive sweating.

Should such findings—especially elevated CK and rhabdomyolysis—come to your attention by a patient’s report or during physical examination, consider further workup for MH.

How MH develops
MH occurs because of a defect in the ryanodine receptor, RYR1. This receptor is responsible for intracellular calcium release by its mediation of the sarcoplasmic reticulum. RYR1 is found in all skeletal muscle.¹³ During an episode of MH, exposure to the triggering agent causes intracellular calcium release by the sarcoplasmic reticulum and sustained skeletal muscle contractions and rigidity. Increased oxygen consumption occurs, and this hypermetabolic state leads to hypercarbia, severe metabolic acidosis, tachycardia, arrhythmias, hyperkalemia, and elevated temperature. Rhabdomyolysis and elevations in CK also occur because of skeletal muscle breakdown.

How to treat this medical emergency

 

Only rapid, specific treatment can save a patient with MH from death. Before investigators discovered that dantrolene sodium is an effective treatment for MH, >70% of patients who developed the disease died.¹² Mortality has since dropped to ≤15%.¹⁴ With a presumptive diagnosis of MH, dantrolene should be prepared and given immediately. The drug inhibits the release of calcium from the sarcoplasmic reticulum of skeletal muscle by limiting the activation of RYR1.

Successful resuscitation of patients with MH hinges on the following:

Making a prompt diagnosis. While most episodes of MH occur shortly after induction of anesthesia or during the intraoperative course, nearly 2% of MH cases occur postoperatively¹⁵—some as long as 12 hours after exposure to the presumed trigger.

Immediately discontinuing triggering anesthetics and starting dantrolene. The patient should be kept anesthetized using nontriggering agents (TABLE 1), and surgery should be concluded as quickly as possible.

Preparation of dantrolene is a tedious process because of its poor water solubility. One to 2 minutes are needed for the preparation to solubilize. Initial treatment with dantrolene is 2.5 mg/kg administered intravenously (via peripheral or central line). This dose (or up to 10 mg/kg) can be repeated every 5 to 10 minutes until major symptoms such as hypercarbia, arrhythmias, hyperpyrexia, and metabolic acidosis abate. Thereafter, dantrolene is continued at 2.5 mg/kg every 4 hours for 24 hours.

Cooling the patient. A patient should be cooled using ice packs, gastric lavage with ice water, cold intravenous fluid, or ice water lavage at the surgical site. Active cooling should stop when the patient’s temperature reaches 100°F (so as not to cause hypothermia). Cooling should not, however, prevent or slow the administration of dantrolene.

Treating acidosis, arrhythmias, electrolyte disturbances, coagulopathy, excess myoglobin, and acute renal failure. Arrhythmias should not be treated with calcium channel blockers.

Monitoring patients in the ICU for potential adverse effects of dantrolene that can include sedation and muscle weakness. Mechanical ventilation may be needed. (The malignant hyperthermia hotline [800-644-9737] at MHAUS is available 24 hours a day to assist clinicians with questions regarding diagnosis and treatment.)

Keeping patients safe by properly testing them
The CHCT is 97% sensitive and 78% specific for MH.¹⁶ It is an invasive procedure, requiring the patient to undergo anesthesia. The test costs more than $5,000, which most insurance companies will cover.¹⁷

The CHCT is performed only on fresh muscle, and only 5 centers in North America perform the test. The number of centers is kept to a minimum to maintain high procedural quality. The biopsy specimen is taken from the vastus lateralis. Because of the size of the specimen required to perform the test, a child weighing <20 kg or <5 years of age is usually not tested but simply presumed to be MH susceptible.¹⁸

Counseling patients and their families
Make sure affected individuals and family members know the life-threatening implications of this condition; that it is familial and that its onset does not always occur with a first exposure to anesthesia, but sometimes with a subsequent exposure. Explain that MH is not an “allergy to anesthesia” or an “allergy to succinylcholine.” Patients can undergo anesthesia safely in the future if performed with a nontriggering agent and associated technique. Anesthesiologists today are well trained to manage these patients with minimum risk.

Counsel first-degree relatives of MH patients about undergoing the CHCT. Molecular genetic testing, which requires a blood draw but is less sensitive than the CHCT, may be another option. If an MH patient was diagnosed using this blood test, relatives may opt to be tested this way, as well. If genetic test results for relatives are positive, these individuals are presumed to have MH and should be treated as such, saving them the expense and risk of undergoing muscle biopsy. If genetic test results are negative, the CHCT should be considered or patients should be presumed to be MH susceptible.

 

Why is testing of relatives needed if a nontriggering anesthetic can be administered? Nontriggering anesthetic agents are not routinely used in surgery, and problems can arise in, say, emergency situations when MH susceptibility in a patient is unknown to the surgical team. Testing enables patients to learn their status and to obtain a medical alert bracelet.

What about the child in the opening scenario?
It is evident that the child in the scenario at the beginning of this article was not adequately screened for MH. Given that the child is >5 years of age, he should undergo the CHCT. You would be wise to presume that his first-degree relatives are also susceptible until proven otherwise by the CHCT. With children not meeting the age or weight requirement for CHCT, make sure the family understands the potential severity of MH and immediately inform the surgeon and anesthesiologist of the family history so appropriate precautions, including arrangements for nontriggering anesthetics, can be put into place.

CORRESPONDENCE
Gregory L. Rose, MD, Department of Anesthesia, University of Kentucky College of Medicine, 800 Rose Street, Lexington, KY 40536; [email protected]

An estimated 10 million US residents, most of them women over the age of 50, suffer from osteoporosis, and another 33 million have low bone mass.¹ Together, they incur more than 2 million osteoporotic fractures annually.^1,2 In addition to the high cost of a single osteoporotic fracture in terms of morbidity, mortality, and health care spending, individuals who sustain one such fracture are at high risk for another. That risk can be greatly reduced with appropriate treatment.

Bisphosphonates, which act on osteoclasts to inhibit bone resorption, are first-line therapy for prevention of osteoporotic fractures. Four bisphosphonates—alendronate, ibandronate, risedronate, and zoledronic acid—are approved by the US Food and Drug Administration (FDA) for the treatment of postmenopausal osteoporosis.

While menopause itself increases a woman’s risk for osteoporotic fracture, questions remain about when to initiate preventive therapy, which patients are candidates for bisphosphonates, and whether bisphosphonates are effective for primary as well as secondary prevention. This overview from the Cochrane Musculoskeletal Group (CMSG) addresses those questions.

To help you provide optimal treatment for postmenopausal patients, we present the findings of recently conducted systematic reviews of 2 bisphosphonates—alendronate and risedronate—from the Cochrane Database of Systematic Reviews,^3,4 in context with the available evidence on the efficacy of ibandronate and zoledronic acid. Cochrane reviews of ibandronate and zoledronic acid are underway, but not yet completed.^5,6

Alendronate reduces vertebral fracture risk across the board

Wells et al identified 11 RCTs for the alendronate review (3 primary and 8 secondary prevention trials), representing a total of 12,068 women.³ (For definitions of what constituted a primary vs a secondary prevention trial, see the box.)

Doses of alendronate ranged from 1 to 20 mg daily, with most studies using doses of 5 or 10 mg. Treatment duration ranged from 1 to 4 years.

A look at the relative risk (RR) for primary and secondary prevention at different fracture sites (TABLE 1) highlights similarities and differences. The risk reduction for vertebral fractures was statistically significant—and about the same—for women being treated with alendronate for primary and secondary prevention (RR=0.55; 95% confidence interval [CI], 0.38-0.80; RR=0.55; 95% CI, 0.43-0.69, respectively). For all other (nonvertebral) fractures in patients being treated with alendronate, only the outcomes for secondary prevention were statistically significant.

Risedronate is effective only for secondary prevention

Seven RCTs, including 2 primary and 5 secondary prevention trials, were included in the Cochrane review of risedronate, representing a total of 14,049 women.⁴ Doses ranged from 2.5 to 5 mg daily, but also included cyclical dosing—for example, taking 5 mg/d for the first 2 weeks of every month. Treatment duration ranged from 2 to 3 years.

At doses of 5 mg/d, there were no statistically significant decreases in fracture risk at any site in the primary prevention trials (TABLE 1), although the quality of evidence assessed was low. For secondary prevention, however, the risk reduction for vertebral fracture was significant (RR=0.61; 95% CI, 0.50-0.76), as were the reductions in risk for nonvertebral and hip fractures.

 

TABLE 1
Fracture risk reduction: How the bisphosphonates compare*

Study	Vertebral fracture RR (95% CI)	Nonvertebral fracture (hip, wrist, others) RR (95% CI)	Hip fracture RR (95% CI)	Wrist fracture RR (95% CI)
Primary prevention
Alendronate3	0.55 (0.38-0.80)	0.89 (0.76-1.04)	0.79 (0.44-1.44)	1.19 (0.87-1.62)
Risedronate4	0.97 (0.42-2.25)	0.81 (0.25-2.58)	N/A	N/A
Secondary prevention
Alendronate3	0.55 (0.43-0.69)	0.77 (0.64-0.92)	0.47 (0.26-0.85)	0.50 (0.34-0.73)
Risedronate4	0.61 (0.50-0.76)	0.80 (0.72-0.90)	0.74 (0.59-0.94)	0.67 (0.42-1.07)†
Ibandronate15,16   Oral daily   Oral intermittent	0.62 (0.42-0.75) 0.50 (0.26-0.66)	No effect)‡ No effect	N/A N/A	N/A N/A
Zoledronic acid22	0.30 (0.2-0.38)	0.75)§ (N/A)	0.59¶ (0.42-0.83)	N/A
CI, confidence interval; N/A, not available; RR, relative risk. *Bold type indicates statistical significance (P<.05). †P=.10. ‡RR of nonvertebral fracture was 0.69 (P=.013) for daily oral ibandronate in the subgroup with femoral neck BMD T-score <–3.0. §P<.001. ¶Hazard ratio.

What are the absolute benefits? A look at number needed to treat
In addition to looking at the RR, the authors of both the alendronate and risedronate reviews calculated the number needed to treat (NNT) to prevent one fracture (TABLE 2) in the trial participants;^3,4 they focused on the secondary prevention outcomes, as these were statistically significant. The reviewers also estimated what the NNT would be if the risk reductions achieved with alendronate and risedronate in the reviews occurred when treating community-based samples of women at moderate compared with high fracture risk.

The biggest differences involved hip fracture: For alendronate, if a community-based sample of women at moderate risk of fracture were treated with the drug and the reduction in RR seen in the secondary prevention trials applied, the NNT would be 100. Thus, for every 100 women treated for 5 years with alendronate, 1 hip fracture would be prevented. However, if this same RR reduction were applied to women at high risk of fracture, the NNT would be only 22.³ For risedronate, the estimated NNT to prevent one hip fracture in women at moderate risk was 203, compared with only 45 for women at high risk.⁴ These estimates indicate that the benefits of bisphosphonate therapy in preventing fractures are greatest in women with a high underlying fracture risk.

TABLE 2
NNT analysis: Women at higher risk are most likely to benefit^3,4

	NNT
	Observed in secondary prevention trials in reviews	Estimated for community-based sample of women with
		High fracture risk*	Moderate fracture risk*
Alendronate (10 mg/d)
Vertebral fracture	19	20	42
Nonvertebral fracture	47	16	27
Hip fracture	146	22	100
Wrist fracture	69	N/A	N/A
Risedronate (5 mg/d)
Vertebral fracture	19	23	49
Nonvertebral fracture	49	19	31
Hip fracture	138	45	203
Wrist fracture	N/A	N/A	N/A
N/A, not available; NNT, number needed to treat. *NNT calculated by applying the relative risk reduction observed in the reviews to published estimates of 5-year fracture risk in a community-based sample of women >50 years of age at moderate and high risk.

Adverse effects do not increase with longer-term treatment

In both the alendronate and risedronate reviews, adverse effects and the risk of discontinuing treatment due to adverse events were similar in the intervention and control groups.^3,4 Postmarketing data suggest that there is potential for upper gastrointestinal (GI) problems, however;⁷ osteonecrosis of the jaw has also been reported infrequently.^8,9 More recently, there have been reports of a possible link between bisphosphonates and atypical femoral fractures, which we’ll say more about in a bit.

Some potential adverse events—eg, osteonecrosis of the jaw and atypical femoral fractures—may be related to treatment duration. The maximum duration of the trials included in these meta-analyses was 4 years for alendronate and 3 years for risedronate. However, additional published data do not appear to support a relation between adverse events and treatment duration.

For alendronate, researchers extended the Fracture Incidence Trial (FIT) for a 10-year follow-up,^10,11 comparing women who took the drug for the first 5 years with women who took it for 10 years. Adverse effects were similar in both groups.

For risedronate, researchers followed a small subsample (n=164) of the participants in the Vertical Efficacy with Risedronate Therapy (VERT) Study Group for up to 7 years.^12,13 For the first 5 years, half of the participants took 5 mg/d risedronate, while the other half took a placebo. During the final 2 years, all participants received 5 mg/d risedronate. The incidence of adverse events among those who took the drug for 7 years was similar to that reported in the first 3 years of the original trial.¹³

Ibandronate studies focus on dose

Nonvertebral fracture. The Cochrane systematic review examining ibandronate for postmenopausal osteoporosis is not yet completed.⁵ However, Cranney et al performed a pooled analysis of individual patient data from 8 RCTs to examine the efficacy of different doses of the drug for the secondary prevention of nonvertebral fracture.¹⁴ (No studies of the drug for primary prevention have been done.) After 2 years of treatment at higher doses of ibandronate (annual cumulative exposure ≥10.8 mg, equivalent to 150 mg orally/month, 3 mg IV quarterly, or 2 mg IV every 2 months), the hazard ratio was 0.62 (95% CI, 0.396-0.974), compared with those taking lower doses (annual cumulative exposure of 5.5 mg). The individual results of the 2 largest trials did not demonstrate an effect on nonvertebral fracture, except in the subgroup of women with very low femoral neck bone mineral density (BMD) (T-scores <–3.0). ^15-17

 

Vertebral fracture. There is no meta-analysis available with vertebral fracture outcomes for ibandronate, so we present the results of individual secondary prevention trials.

One was a double-blind RCT with 2496 participants, comparing women taking either 2.5 mg/d of ibandronate or 20 mg on alternate days with a group on placebo.^15,16 The results? Those in both the daily and the intermittent treatment arms had significant risk reductions (RR=0.62; 95% CI, 0.42-0.75; RR=0.50; 95% CI, 0.26-0.66, respectively), after taking the drug for 3 years (TABLE 1), compared with those on placebo.^15,16 The other RCT—a trial in which 2862 women received either quarterly intravenous (IV) injections of 1 or 0.5 mg ibandronate or placebo—did not demonstrate a significant reduction in vertebral fracture.¹⁷ This was attributed to an insufficient dose of the drug, a supposition supported by improvements in BMD in patients receiving higher doses of ibandronate.^18,19

Oral ibandronate has been well tolerated in clinical trials in terms of GI side effects.^20,21 Injection site reactions have been reported in those receiving IV infusions,¹⁷ and both IV and monthly oral ibandronate may be associated with mild, self-limiting flu-like symptoms.

Zoledronic acid RCTs show reduced fracture, mortality risk
Black et al studied the efficacy of zoledronic acid in a randomized, double-blind, placebo-controlled trial of 7736 postmenopausal women between the ages of 65 and 89 years.²² The women, all of whom had osteoporosis, received an IV infusion of either zoledronic acid (5 mg) or placebo at baseline, and again at 12 and 24 months. Vertebral and nonvertebral fractures, as well as hip fracture, were significantly reduced in the treatment group compared with placebo (TABLE 1).

In another RCT with 2127 participants, Lyles et al examined the effectiveness of 5 mg zoledronic acid IV given within 90 days of surgical repair of a hip fracture. In the intervention group, there was a 35% risk reduction in new clinical fractures (8.6% vs 13.9% for those on placebo; P=.001); mortality was also lower in the zoledronic acid group (9.6% vs 13.3%; P=.01).²³

In both trials, the number of patients who had serious adverse events or dropped out because of an adverse event was similar in the treatment and placebo groups. In both studies, too, a sizeable number of patients treated with zoledronic acid reported flu-like symptoms up to 3 days after receiving an infusion, particularly after the first one. Cardiovascular events were similar across intervention groups in both studies, with one exception: In Black’s study,²² there was an increased incidence of serious atrial fibrillation in the zoledronic acid group (1.3% vs 0.5% for the placebo group).

Other issues to keep in mind

Atypical femoral fractures. Published data suggest an association between bisphosphonate use and atypical femoral fractures, particularly with longer-term use,²⁴ although whether there is a causal link is unclear. Atypical femoral fractures occur with little or no trauma along the femur from just distal to the lesser trochanter to just proximal to the supracondylar flare.

In 2010, the FDA announced requirements for a black box warning about a possible link,²⁵ highlighting the uncertainty about both the optimal duration of bisphosphonate therapy and the cause of these fractures.

While concerns about such a link remain, it is important to note that atypical femoral fractures are very uncommon: Current estimates are that they account for less than 1% of hip/femoral fractures. What’s more, far more fractures are prevented by the use of bisphosphonates than are associated with their use, with an estimated ratio of up to 29:1.²⁴

Dosing schedules. Adherence to treatment is of key importance in maximizing outcomes from osteoporosis treatments, and is frequently low.^26,27 One way of improving adherence is to reduce the frequency of dosing required.²⁷ With that in mind, researchers have tested intermittent dosing regimens, using noninferiority or bridging trials.

Such studies have led to a number of approved dosing regimens—70 mg weekly for alendronate; 150 mg monthly and 35 mg weekly for risedronate; and 150 mg PO monthly and 3 mg IV quarterly for ibandronate among them. In making decisions about dosing, family physicians should consider patient preferences, but be aware that there are no direct efficacy data from RCTs to support these dosing regimens.

Calcium and vitamin D. The major fracture prevention trials of bisphosphonates have featured women who are calcium- and vitamin D-replete. In a recent study of 1515 women undergoing treatment with alendronate, risedronate, or raloxifene, however, that wasn’t always the case. ²⁸ After 13 months, 115 participants suffered from a new clinical fracture. The adjusted odds ratio for fractures in women with vitamin D deficiency compared with those with normal levels of vitamin D was 1.77 (95% CI, 1.20-2.59; P=.004), an indication of the importance of maintaining adequate vitamin D levels in patients taking bisphosphonates.

 

In clinical practice, it is important to ensure that patients being treated with bisphosphonates are not deficient in vitamin D. While direct evidence of poorer outcomes associated with low calcium levels is lacking, it is reasonable to also assess calcium intake and to ensure that patients have adequate intake of both. (For more on calcium and vitamin D requirements, see the Institute of Medicine’s recent report at http://www.iom.edu/Reports/2010/Dietary-Reference-Intakes-for-Calcium-and-Vitamin-D/Report-Brief.aspx) and “The IOM’s report on calcium and vitamin D: Should it change the way you practice?”.

 

What’s best for your patients?

All these bisphosphonates have demonstrated efficacy for the secondary prevention of vertebral fracture. All except ibandronate have demonstrated efficacy for nonvertebral fracture, as well, and the evidence suggests that ibandronate will also be effective if adequate doses are given. Thus, for women at significant risk for fracture, it seems clear that the benefits of treatment outweigh the risks. The case is not so clearcut for women at lower risk. Evidence to support the use of bisphosphonates for primary prevention is limited, other than for alendronate—which has been shown to provide primary prevention of vertebral fracture.

Which bisphosphonate is best depends on patient preferences and individual profiles. (See “How would you treat these patients?”.) In the absence of head-to-head RCTs, it isn’t possible to comment on the relative efficacy of the various bisphosphonates or their adverse event profiles. Indeed, the authors of the 2 Cochrane reviews completed to date note that trial participants have been healthier, with fewer comorbidities, than many of the postmenopausal women seen by primary care physicians. Head-to-head studies conducted in family practice settings would be an important addition to the body of evidence for the prevention of osteoporotic fracture.

How would you treat these patients?

CASE 1 Mrs. A is an active 67-year-old in good health. On a recent hike, she lost her footing and sustained a Colles’ fracture when she fell, although her fall was only from standing height. Now, you are concerned that she might have osteoporosis.

A dual-energy x-ray absorptiometry (DXA) scan confirms this suspicion: Mrs. A’s lumbar spine T-score is –2.6. A dietary review reveals that she has a satisfactory calcium intake, and lab work shows that her serum vitamin D levels are normal. Mrs. A wants to discuss treatment options with you.

What immediate treatment do you consider?

Mrs. A has no contraindications to any FDA-approved treatment for osteoporosis; you suggest she begin taking bisphosphonates, explaining that they are first-line treatment to prevent subsequent osteoporotic fractures. You briefly discuss other options, but note that raloxifene only reduces the risk of vertebral fractures and parathyroid hormone is effective (but very expensive) and requires daily injections, and is therefore generally used for severe osteoporosis. Your patient asks about bisphosphonates’ side effects, particularly the serious jaw problems she’s heard about.

You explain that for the most part, oral bisphosphonates are well tolerated, but that there is a potential for upper gastrointestinal (GI) problems—which is why it’s important to remain upright for at least 30 minutes after taking the medication. You tell her that the risk of developing osteonecrosis of the jaw is very low when the medication is taken at the doses needed for osteoporosis treatment, but that the risk may increase after tooth extraction or dental surgery. Mrs. A has no current dental symptoms and at her usual yearly dental check-up 9 months ago, there were no problems noted, so dental review before starting treatment is not needed. Should she develop any jaw pain, however, she should see you or her dentist immediately.

You also advise her of the possible link between bisphosphonates and atypical femoral fracture, but point out that such fractures are extremely rare—and that the medication prevents far more fractures than it has the potential to cause. You tell her to contact you immediately if she develops pain in the groin or thigh or experiences GI distress.

Which bisphosphonate do you prescribe?

You inform Mrs. A that alendronate has the longest follow-up data of the oral bisphosphonates and has demonstrated efficacy for the secondary prevention of wrist fractures, that risedronate and ibandronate have the advantage of being able to be taken monthly rather than weekly, and that zoledronic acid can be administered in a yearly infusion. She opts for alendronate. You prescribe a weekly dose of 70 mg and ask her to return in 3 months, and to call before then if any problems arise.

CASE 2 Mrs. Y, age 82, recently sustained a fractured femoral neck, which was treated surgically at the local hospital. She was discharged with a prescription for alendronate to treat her osteoporosis and prevent further fractures; her husband has brought her in today to get a new prescription.

During the visit, he reminds you that Mrs. Y has problems with memory. He also says he’s finding it increasingly difficult to ensure that his wife remains upright for 30 minutes after taking alendronate, and that she has begun complaining of indigestion.

 

What do you decide to do?

An inability to stay upright for 30 minutes after drug administration is a contraindication to the use of oral bisphosphonates. The presence of upper GI symptoms is also a concern. You offer Mrs. Y the option of a once-yearly IV infusion of zoledronic acid instead, and she and her husband agree to this. Before scheduling a follow-up visit, you discuss the patient’s nutritional intake, and discover that she consumes only a moderate amount of calcium—at most 2 servings of dairy products per day. You also note that her serum vitamin D level was not checked in the hospital. You order lab work, with a view to correcting any deficiency before proceeding with a zoledronic infusion (due to the risk of tetany) and to maintaining her on an appropriate level of calcium and vitamin D intake, using supplements only if necessary.

CORRESPONDENCE Tania Winzenberg, MBBS, Menzies Research Institute, Private Bag 23, Hobart, Tasmania, Australia 7001; [email protected]

An estimated 10 million US residents, most of them women over the age of 50, suffer from osteoporosis, and another 33 million have low bone mass.¹ Together, they incur more than 2 million osteoporotic fractures annually.^1,2 In addition to the high cost of a single osteoporotic fracture in terms of morbidity, mortality, and health care spending, individuals who sustain one such fracture are at high risk for another. That risk can be greatly reduced with appropriate treatment.

Bisphosphonates, which act on osteoclasts to inhibit bone resorption, are first-line therapy for prevention of osteoporotic fractures. Four bisphosphonates—alendronate, ibandronate, risedronate, and zoledronic acid—are approved by the US Food and Drug Administration (FDA) for the treatment of postmenopausal osteoporosis.

While menopause itself increases a woman’s risk for osteoporotic fracture, questions remain about when to initiate preventive therapy, which patients are candidates for bisphosphonates, and whether bisphosphonates are effective for primary as well as secondary prevention. This overview from the Cochrane Musculoskeletal Group (CMSG) addresses those questions.

To help you provide optimal treatment for postmenopausal patients, we present the findings of recently conducted systematic reviews of 2 bisphosphonates—alendronate and risedronate—from the Cochrane Database of Systematic Reviews,^3,4 in context with the available evidence on the efficacy of ibandronate and zoledronic acid. Cochrane reviews of ibandronate and zoledronic acid are underway, but not yet completed.^5,6

Alendronate reduces vertebral fracture risk across the board

Wells et al identified 11 RCTs for the alendronate review (3 primary and 8 secondary prevention trials), representing a total of 12,068 women.³ (For definitions of what constituted a primary vs a secondary prevention trial, see the box.)

Doses of alendronate ranged from 1 to 20 mg daily, with most studies using doses of 5 or 10 mg. Treatment duration ranged from 1 to 4 years.

A look at the relative risk (RR) for primary and secondary prevention at different fracture sites (TABLE 1) highlights similarities and differences. The risk reduction for vertebral fractures was statistically significant—and about the same—for women being treated with alendronate for primary and secondary prevention (RR=0.55; 95% confidence interval [CI], 0.38-0.80; RR=0.55; 95% CI, 0.43-0.69, respectively). For all other (nonvertebral) fractures in patients being treated with alendronate, only the outcomes for secondary prevention were statistically significant.

Risedronate is effective only for secondary prevention

Seven RCTs, including 2 primary and 5 secondary prevention trials, were included in the Cochrane review of risedronate, representing a total of 14,049 women.⁴ Doses ranged from 2.5 to 5 mg daily, but also included cyclical dosing—for example, taking 5 mg/d for the first 2 weeks of every month. Treatment duration ranged from 2 to 3 years.

At doses of 5 mg/d, there were no statistically significant decreases in fracture risk at any site in the primary prevention trials (TABLE 1), although the quality of evidence assessed was low. For secondary prevention, however, the risk reduction for vertebral fracture was significant (RR=0.61; 95% CI, 0.50-0.76), as were the reductions in risk for nonvertebral and hip fractures.

 

TABLE 1
Fracture risk reduction: How the bisphosphonates compare*

Study	Vertebral fracture RR (95% CI)	Nonvertebral fracture (hip, wrist, others) RR (95% CI)	Hip fracture RR (95% CI)	Wrist fracture RR (95% CI)
Primary prevention
Alendronate3	0.55 (0.38-0.80)	0.89 (0.76-1.04)	0.79 (0.44-1.44)	1.19 (0.87-1.62)
Risedronate4	0.97 (0.42-2.25)	0.81 (0.25-2.58)	N/A	N/A
Secondary prevention
Alendronate3	0.55 (0.43-0.69)	0.77 (0.64-0.92)	0.47 (0.26-0.85)	0.50 (0.34-0.73)
Risedronate4	0.61 (0.50-0.76)	0.80 (0.72-0.90)	0.74 (0.59-0.94)	0.67 (0.42-1.07)†
Ibandronate15,16   Oral daily   Oral intermittent	0.62 (0.42-0.75) 0.50 (0.26-0.66)	No effect)‡ No effect	N/A N/A	N/A N/A
Zoledronic acid22	0.30 (0.2-0.38)	0.75)§ (N/A)	0.59¶ (0.42-0.83)	N/A
CI, confidence interval; N/A, not available; RR, relative risk. *Bold type indicates statistical significance (P<.05). †P=.10. ‡RR of nonvertebral fracture was 0.69 (P=.013) for daily oral ibandronate in the subgroup with femoral neck BMD T-score <–3.0. §P<.001. ¶Hazard ratio.

What are the absolute benefits? A look at number needed to treat
In addition to looking at the RR, the authors of both the alendronate and risedronate reviews calculated the number needed to treat (NNT) to prevent one fracture (TABLE 2) in the trial participants;^3,4 they focused on the secondary prevention outcomes, as these were statistically significant. The reviewers also estimated what the NNT would be if the risk reductions achieved with alendronate and risedronate in the reviews occurred when treating community-based samples of women at moderate compared with high fracture risk.

The biggest differences involved hip fracture: For alendronate, if a community-based sample of women at moderate risk of fracture were treated with the drug and the reduction in RR seen in the secondary prevention trials applied, the NNT would be 100. Thus, for every 100 women treated for 5 years with alendronate, 1 hip fracture would be prevented. However, if this same RR reduction were applied to women at high risk of fracture, the NNT would be only 22.³ For risedronate, the estimated NNT to prevent one hip fracture in women at moderate risk was 203, compared with only 45 for women at high risk.⁴ These estimates indicate that the benefits of bisphosphonate therapy in preventing fractures are greatest in women with a high underlying fracture risk.

TABLE 2
NNT analysis: Women at higher risk are most likely to benefit^3,4

	NNT
	Observed in secondary prevention trials in reviews	Estimated for community-based sample of women with
		High fracture risk*	Moderate fracture risk*
Alendronate (10 mg/d)
Vertebral fracture	19	20	42
Nonvertebral fracture	47	16	27
Hip fracture	146	22	100
Wrist fracture	69	N/A	N/A
Risedronate (5 mg/d)
Vertebral fracture	19	23	49
Nonvertebral fracture	49	19	31
Hip fracture	138	45	203
Wrist fracture	N/A	N/A	N/A
N/A, not available; NNT, number needed to treat. *NNT calculated by applying the relative risk reduction observed in the reviews to published estimates of 5-year fracture risk in a community-based sample of women >50 years of age at moderate and high risk.

Adverse effects do not increase with longer-term treatment

In both the alendronate and risedronate reviews, adverse effects and the risk of discontinuing treatment due to adverse events were similar in the intervention and control groups.^3,4 Postmarketing data suggest that there is potential for upper gastrointestinal (GI) problems, however;⁷ osteonecrosis of the jaw has also been reported infrequently.^8,9 More recently, there have been reports of a possible link between bisphosphonates and atypical femoral fractures, which we’ll say more about in a bit.

Some potential adverse events—eg, osteonecrosis of the jaw and atypical femoral fractures—may be related to treatment duration. The maximum duration of the trials included in these meta-analyses was 4 years for alendronate and 3 years for risedronate. However, additional published data do not appear to support a relation between adverse events and treatment duration.

For alendronate, researchers extended the Fracture Incidence Trial (FIT) for a 10-year follow-up,^10,11 comparing women who took the drug for the first 5 years with women who took it for 10 years. Adverse effects were similar in both groups.

For risedronate, researchers followed a small subsample (n=164) of the participants in the Vertical Efficacy with Risedronate Therapy (VERT) Study Group for up to 7 years.^12,13 For the first 5 years, half of the participants took 5 mg/d risedronate, while the other half took a placebo. During the final 2 years, all participants received 5 mg/d risedronate. The incidence of adverse events among those who took the drug for 7 years was similar to that reported in the first 3 years of the original trial.¹³

Ibandronate studies focus on dose

Nonvertebral fracture. The Cochrane systematic review examining ibandronate for postmenopausal osteoporosis is not yet completed.⁵ However, Cranney et al performed a pooled analysis of individual patient data from 8 RCTs to examine the efficacy of different doses of the drug for the secondary prevention of nonvertebral fracture.¹⁴ (No studies of the drug for primary prevention have been done.) After 2 years of treatment at higher doses of ibandronate (annual cumulative exposure ≥10.8 mg, equivalent to 150 mg orally/month, 3 mg IV quarterly, or 2 mg IV every 2 months), the hazard ratio was 0.62 (95% CI, 0.396-0.974), compared with those taking lower doses (annual cumulative exposure of 5.5 mg). The individual results of the 2 largest trials did not demonstrate an effect on nonvertebral fracture, except in the subgroup of women with very low femoral neck bone mineral density (BMD) (T-scores <–3.0). ^15-17

 

Vertebral fracture. There is no meta-analysis available with vertebral fracture outcomes for ibandronate, so we present the results of individual secondary prevention trials.

One was a double-blind RCT with 2496 participants, comparing women taking either 2.5 mg/d of ibandronate or 20 mg on alternate days with a group on placebo.^15,16 The results? Those in both the daily and the intermittent treatment arms had significant risk reductions (RR=0.62; 95% CI, 0.42-0.75; RR=0.50; 95% CI, 0.26-0.66, respectively), after taking the drug for 3 years (TABLE 1), compared with those on placebo.^15,16 The other RCT—a trial in which 2862 women received either quarterly intravenous (IV) injections of 1 or 0.5 mg ibandronate or placebo—did not demonstrate a significant reduction in vertebral fracture.¹⁷ This was attributed to an insufficient dose of the drug, a supposition supported by improvements in BMD in patients receiving higher doses of ibandronate.^18,19

Oral ibandronate has been well tolerated in clinical trials in terms of GI side effects.^20,21 Injection site reactions have been reported in those receiving IV infusions,¹⁷ and both IV and monthly oral ibandronate may be associated with mild, self-limiting flu-like symptoms.

Zoledronic acid RCTs show reduced fracture, mortality risk
Black et al studied the efficacy of zoledronic acid in a randomized, double-blind, placebo-controlled trial of 7736 postmenopausal women between the ages of 65 and 89 years.²² The women, all of whom had osteoporosis, received an IV infusion of either zoledronic acid (5 mg) or placebo at baseline, and again at 12 and 24 months. Vertebral and nonvertebral fractures, as well as hip fracture, were significantly reduced in the treatment group compared with placebo (TABLE 1).

In another RCT with 2127 participants, Lyles et al examined the effectiveness of 5 mg zoledronic acid IV given within 90 days of surgical repair of a hip fracture. In the intervention group, there was a 35% risk reduction in new clinical fractures (8.6% vs 13.9% for those on placebo; P=.001); mortality was also lower in the zoledronic acid group (9.6% vs 13.3%; P=.01).²³

In both trials, the number of patients who had serious adverse events or dropped out because of an adverse event was similar in the treatment and placebo groups. In both studies, too, a sizeable number of patients treated with zoledronic acid reported flu-like symptoms up to 3 days after receiving an infusion, particularly after the first one. Cardiovascular events were similar across intervention groups in both studies, with one exception: In Black’s study,²² there was an increased incidence of serious atrial fibrillation in the zoledronic acid group (1.3% vs 0.5% for the placebo group).

Other issues to keep in mind

Atypical femoral fractures. Published data suggest an association between bisphosphonate use and atypical femoral fractures, particularly with longer-term use,²⁴ although whether there is a causal link is unclear. Atypical femoral fractures occur with little or no trauma along the femur from just distal to the lesser trochanter to just proximal to the supracondylar flare.

In 2010, the FDA announced requirements for a black box warning about a possible link,²⁵ highlighting the uncertainty about both the optimal duration of bisphosphonate therapy and the cause of these fractures.

While concerns about such a link remain, it is important to note that atypical femoral fractures are very uncommon: Current estimates are that they account for less than 1% of hip/femoral fractures. What’s more, far more fractures are prevented by the use of bisphosphonates than are associated with their use, with an estimated ratio of up to 29:1.²⁴

Dosing schedules. Adherence to treatment is of key importance in maximizing outcomes from osteoporosis treatments, and is frequently low.^26,27 One way of improving adherence is to reduce the frequency of dosing required.²⁷ With that in mind, researchers have tested intermittent dosing regimens, using noninferiority or bridging trials.

Such studies have led to a number of approved dosing regimens—70 mg weekly for alendronate; 150 mg monthly and 35 mg weekly for risedronate; and 150 mg PO monthly and 3 mg IV quarterly for ibandronate among them. In making decisions about dosing, family physicians should consider patient preferences, but be aware that there are no direct efficacy data from RCTs to support these dosing regimens.

Calcium and vitamin D. The major fracture prevention trials of bisphosphonates have featured women who are calcium- and vitamin D-replete. In a recent study of 1515 women undergoing treatment with alendronate, risedronate, or raloxifene, however, that wasn’t always the case. ²⁸ After 13 months, 115 participants suffered from a new clinical fracture. The adjusted odds ratio for fractures in women with vitamin D deficiency compared with those with normal levels of vitamin D was 1.77 (95% CI, 1.20-2.59; P=.004), an indication of the importance of maintaining adequate vitamin D levels in patients taking bisphosphonates.

 

In clinical practice, it is important to ensure that patients being treated with bisphosphonates are not deficient in vitamin D. While direct evidence of poorer outcomes associated with low calcium levels is lacking, it is reasonable to also assess calcium intake and to ensure that patients have adequate intake of both. (For more on calcium and vitamin D requirements, see the Institute of Medicine’s recent report at http://www.iom.edu/Reports/2010/Dietary-Reference-Intakes-for-Calcium-and-Vitamin-D/Report-Brief.aspx) and “The IOM’s report on calcium and vitamin D: Should it change the way you practice?”.

 

What’s best for your patients?

All these bisphosphonates have demonstrated efficacy for the secondary prevention of vertebral fracture. All except ibandronate have demonstrated efficacy for nonvertebral fracture, as well, and the evidence suggests that ibandronate will also be effective if adequate doses are given. Thus, for women at significant risk for fracture, it seems clear that the benefits of treatment outweigh the risks. The case is not so clearcut for women at lower risk. Evidence to support the use of bisphosphonates for primary prevention is limited, other than for alendronate—which has been shown to provide primary prevention of vertebral fracture.

Which bisphosphonate is best depends on patient preferences and individual profiles. (See “How would you treat these patients?”.) In the absence of head-to-head RCTs, it isn’t possible to comment on the relative efficacy of the various bisphosphonates or their adverse event profiles. Indeed, the authors of the 2 Cochrane reviews completed to date note that trial participants have been healthier, with fewer comorbidities, than many of the postmenopausal women seen by primary care physicians. Head-to-head studies conducted in family practice settings would be an important addition to the body of evidence for the prevention of osteoporotic fracture.

How would you treat these patients?

CASE 1 Mrs. A is an active 67-year-old in good health. On a recent hike, she lost her footing and sustained a Colles’ fracture when she fell, although her fall was only from standing height. Now, you are concerned that she might have osteoporosis.

A dual-energy x-ray absorptiometry (DXA) scan confirms this suspicion: Mrs. A’s lumbar spine T-score is –2.6. A dietary review reveals that she has a satisfactory calcium intake, and lab work shows that her serum vitamin D levels are normal. Mrs. A wants to discuss treatment options with you.

What immediate treatment do you consider?

Mrs. A has no contraindications to any FDA-approved treatment for osteoporosis; you suggest she begin taking bisphosphonates, explaining that they are first-line treatment to prevent subsequent osteoporotic fractures. You briefly discuss other options, but note that raloxifene only reduces the risk of vertebral fractures and parathyroid hormone is effective (but very expensive) and requires daily injections, and is therefore generally used for severe osteoporosis. Your patient asks about bisphosphonates’ side effects, particularly the serious jaw problems she’s heard about.

You explain that for the most part, oral bisphosphonates are well tolerated, but that there is a potential for upper gastrointestinal (GI) problems—which is why it’s important to remain upright for at least 30 minutes after taking the medication. You tell her that the risk of developing osteonecrosis of the jaw is very low when the medication is taken at the doses needed for osteoporosis treatment, but that the risk may increase after tooth extraction or dental surgery. Mrs. A has no current dental symptoms and at her usual yearly dental check-up 9 months ago, there were no problems noted, so dental review before starting treatment is not needed. Should she develop any jaw pain, however, she should see you or her dentist immediately.

You also advise her of the possible link between bisphosphonates and atypical femoral fracture, but point out that such fractures are extremely rare—and that the medication prevents far more fractures than it has the potential to cause. You tell her to contact you immediately if she develops pain in the groin or thigh or experiences GI distress.

Which bisphosphonate do you prescribe?

You inform Mrs. A that alendronate has the longest follow-up data of the oral bisphosphonates and has demonstrated efficacy for the secondary prevention of wrist fractures, that risedronate and ibandronate have the advantage of being able to be taken monthly rather than weekly, and that zoledronic acid can be administered in a yearly infusion. She opts for alendronate. You prescribe a weekly dose of 70 mg and ask her to return in 3 months, and to call before then if any problems arise.

CASE 2 Mrs. Y, age 82, recently sustained a fractured femoral neck, which was treated surgically at the local hospital. She was discharged with a prescription for alendronate to treat her osteoporosis and prevent further fractures; her husband has brought her in today to get a new prescription.

During the visit, he reminds you that Mrs. Y has problems with memory. He also says he’s finding it increasingly difficult to ensure that his wife remains upright for 30 minutes after taking alendronate, and that she has begun complaining of indigestion.

 

What do you decide to do?

An inability to stay upright for 30 minutes after drug administration is a contraindication to the use of oral bisphosphonates. The presence of upper GI symptoms is also a concern. You offer Mrs. Y the option of a once-yearly IV infusion of zoledronic acid instead, and she and her husband agree to this. Before scheduling a follow-up visit, you discuss the patient’s nutritional intake, and discover that she consumes only a moderate amount of calcium—at most 2 servings of dairy products per day. You also note that her serum vitamin D level was not checked in the hospital. You order lab work, with a view to correcting any deficiency before proceeding with a zoledronic infusion (due to the risk of tetany) and to maintaining her on an appropriate level of calcium and vitamin D intake, using supplements only if necessary.

CORRESPONDENCE Tania Winzenberg, MBBS, Menzies Research Institute, Private Bag 23, Hobart, Tasmania, Australia 7001; [email protected]

An estimated 10 million US residents, most of them women over the age of 50, suffer from osteoporosis, and another 33 million have low bone mass.¹ Together, they incur more than 2 million osteoporotic fractures annually.^1,2 In addition to the high cost of a single osteoporotic fracture in terms of morbidity, mortality, and health care spending, individuals who sustain one such fracture are at high risk for another. That risk can be greatly reduced with appropriate treatment.

Bisphosphonates, which act on osteoclasts to inhibit bone resorption, are first-line therapy for prevention of osteoporotic fractures. Four bisphosphonates—alendronate, ibandronate, risedronate, and zoledronic acid—are approved by the US Food and Drug Administration (FDA) for the treatment of postmenopausal osteoporosis.

While menopause itself increases a woman’s risk for osteoporotic fracture, questions remain about when to initiate preventive therapy, which patients are candidates for bisphosphonates, and whether bisphosphonates are effective for primary as well as secondary prevention. This overview from the Cochrane Musculoskeletal Group (CMSG) addresses those questions.

To help you provide optimal treatment for postmenopausal patients, we present the findings of recently conducted systematic reviews of 2 bisphosphonates—alendronate and risedronate—from the Cochrane Database of Systematic Reviews,^3,4 in context with the available evidence on the efficacy of ibandronate and zoledronic acid. Cochrane reviews of ibandronate and zoledronic acid are underway, but not yet completed.^5,6

Alendronate reduces vertebral fracture risk across the board

Wells et al identified 11 RCTs for the alendronate review (3 primary and 8 secondary prevention trials), representing a total of 12,068 women.³ (For definitions of what constituted a primary vs a secondary prevention trial, see the box.)

Doses of alendronate ranged from 1 to 20 mg daily, with most studies using doses of 5 or 10 mg. Treatment duration ranged from 1 to 4 years.

A look at the relative risk (RR) for primary and secondary prevention at different fracture sites (TABLE 1) highlights similarities and differences. The risk reduction for vertebral fractures was statistically significant—and about the same—for women being treated with alendronate for primary and secondary prevention (RR=0.55; 95% confidence interval [CI], 0.38-0.80; RR=0.55; 95% CI, 0.43-0.69, respectively). For all other (nonvertebral) fractures in patients being treated with alendronate, only the outcomes for secondary prevention were statistically significant.

Risedronate is effective only for secondary prevention

Seven RCTs, including 2 primary and 5 secondary prevention trials, were included in the Cochrane review of risedronate, representing a total of 14,049 women.⁴ Doses ranged from 2.5 to 5 mg daily, but also included cyclical dosing—for example, taking 5 mg/d for the first 2 weeks of every month. Treatment duration ranged from 2 to 3 years.

At doses of 5 mg/d, there were no statistically significant decreases in fracture risk at any site in the primary prevention trials (TABLE 1), although the quality of evidence assessed was low. For secondary prevention, however, the risk reduction for vertebral fracture was significant (RR=0.61; 95% CI, 0.50-0.76), as were the reductions in risk for nonvertebral and hip fractures.

 

TABLE 1
Fracture risk reduction: How the bisphosphonates compare*

Study	Vertebral fracture RR (95% CI)	Nonvertebral fracture (hip, wrist, others) RR (95% CI)	Hip fracture RR (95% CI)	Wrist fracture RR (95% CI)
Primary prevention
Alendronate3	0.55 (0.38-0.80)	0.89 (0.76-1.04)	0.79 (0.44-1.44)	1.19 (0.87-1.62)
Risedronate4	0.97 (0.42-2.25)	0.81 (0.25-2.58)	N/A	N/A
Secondary prevention
Alendronate3	0.55 (0.43-0.69)	0.77 (0.64-0.92)	0.47 (0.26-0.85)	0.50 (0.34-0.73)
Risedronate4	0.61 (0.50-0.76)	0.80 (0.72-0.90)	0.74 (0.59-0.94)	0.67 (0.42-1.07)†
Ibandronate15,16   Oral daily   Oral intermittent	0.62 (0.42-0.75) 0.50 (0.26-0.66)	No effect)‡ No effect	N/A N/A	N/A N/A
Zoledronic acid22	0.30 (0.2-0.38)	0.75)§ (N/A)	0.59¶ (0.42-0.83)	N/A
CI, confidence interval; N/A, not available; RR, relative risk. *Bold type indicates statistical significance (P<.05). †P=.10. ‡RR of nonvertebral fracture was 0.69 (P=.013) for daily oral ibandronate in the subgroup with femoral neck BMD T-score <–3.0. §P<.001. ¶Hazard ratio.

What are the absolute benefits? A look at number needed to treat
In addition to looking at the RR, the authors of both the alendronate and risedronate reviews calculated the number needed to treat (NNT) to prevent one fracture (TABLE 2) in the trial participants;^3,4 they focused on the secondary prevention outcomes, as these were statistically significant. The reviewers also estimated what the NNT would be if the risk reductions achieved with alendronate and risedronate in the reviews occurred when treating community-based samples of women at moderate compared with high fracture risk.

The biggest differences involved hip fracture: For alendronate, if a community-based sample of women at moderate risk of fracture were treated with the drug and the reduction in RR seen in the secondary prevention trials applied, the NNT would be 100. Thus, for every 100 women treated for 5 years with alendronate, 1 hip fracture would be prevented. However, if this same RR reduction were applied to women at high risk of fracture, the NNT would be only 22.³ For risedronate, the estimated NNT to prevent one hip fracture in women at moderate risk was 203, compared with only 45 for women at high risk.⁴ These estimates indicate that the benefits of bisphosphonate therapy in preventing fractures are greatest in women with a high underlying fracture risk.

TABLE 2
NNT analysis: Women at higher risk are most likely to benefit^3,4

	NNT
	Observed in secondary prevention trials in reviews	Estimated for community-based sample of women with
		High fracture risk*	Moderate fracture risk*
Alendronate (10 mg/d)
Vertebral fracture	19	20	42
Nonvertebral fracture	47	16	27
Hip fracture	146	22	100
Wrist fracture	69	N/A	N/A
Risedronate (5 mg/d)
Vertebral fracture	19	23	49
Nonvertebral fracture	49	19	31
Hip fracture	138	45	203
Wrist fracture	N/A	N/A	N/A
N/A, not available; NNT, number needed to treat. *NNT calculated by applying the relative risk reduction observed in the reviews to published estimates of 5-year fracture risk in a community-based sample of women >50 years of age at moderate and high risk.

Adverse effects do not increase with longer-term treatment

In both the alendronate and risedronate reviews, adverse effects and the risk of discontinuing treatment due to adverse events were similar in the intervention and control groups.^3,4 Postmarketing data suggest that there is potential for upper gastrointestinal (GI) problems, however;⁷ osteonecrosis of the jaw has also been reported infrequently.^8,9 More recently, there have been reports of a possible link between bisphosphonates and atypical femoral fractures, which we’ll say more about in a bit.

Some potential adverse events—eg, osteonecrosis of the jaw and atypical femoral fractures—may be related to treatment duration. The maximum duration of the trials included in these meta-analyses was 4 years for alendronate and 3 years for risedronate. However, additional published data do not appear to support a relation between adverse events and treatment duration.

For alendronate, researchers extended the Fracture Incidence Trial (FIT) for a 10-year follow-up,^10,11 comparing women who took the drug for the first 5 years with women who took it for 10 years. Adverse effects were similar in both groups.

For risedronate, researchers followed a small subsample (n=164) of the participants in the Vertical Efficacy with Risedronate Therapy (VERT) Study Group for up to 7 years.^12,13 For the first 5 years, half of the participants took 5 mg/d risedronate, while the other half took a placebo. During the final 2 years, all participants received 5 mg/d risedronate. The incidence of adverse events among those who took the drug for 7 years was similar to that reported in the first 3 years of the original trial.¹³

Ibandronate studies focus on dose

Nonvertebral fracture. The Cochrane systematic review examining ibandronate for postmenopausal osteoporosis is not yet completed.⁵ However, Cranney et al performed a pooled analysis of individual patient data from 8 RCTs to examine the efficacy of different doses of the drug for the secondary prevention of nonvertebral fracture.¹⁴ (No studies of the drug for primary prevention have been done.) After 2 years of treatment at higher doses of ibandronate (annual cumulative exposure ≥10.8 mg, equivalent to 150 mg orally/month, 3 mg IV quarterly, or 2 mg IV every 2 months), the hazard ratio was 0.62 (95% CI, 0.396-0.974), compared with those taking lower doses (annual cumulative exposure of 5.5 mg). The individual results of the 2 largest trials did not demonstrate an effect on nonvertebral fracture, except in the subgroup of women with very low femoral neck bone mineral density (BMD) (T-scores <–3.0). ^15-17

 

Vertebral fracture. There is no meta-analysis available with vertebral fracture outcomes for ibandronate, so we present the results of individual secondary prevention trials.

One was a double-blind RCT with 2496 participants, comparing women taking either 2.5 mg/d of ibandronate or 20 mg on alternate days with a group on placebo.^15,16 The results? Those in both the daily and the intermittent treatment arms had significant risk reductions (RR=0.62; 95% CI, 0.42-0.75; RR=0.50; 95% CI, 0.26-0.66, respectively), after taking the drug for 3 years (TABLE 1), compared with those on placebo.^15,16 The other RCT—a trial in which 2862 women received either quarterly intravenous (IV) injections of 1 or 0.5 mg ibandronate or placebo—did not demonstrate a significant reduction in vertebral fracture.¹⁷ This was attributed to an insufficient dose of the drug, a supposition supported by improvements in BMD in patients receiving higher doses of ibandronate.^18,19

Oral ibandronate has been well tolerated in clinical trials in terms of GI side effects.^20,21 Injection site reactions have been reported in those receiving IV infusions,¹⁷ and both IV and monthly oral ibandronate may be associated with mild, self-limiting flu-like symptoms.

Zoledronic acid RCTs show reduced fracture, mortality risk
Black et al studied the efficacy of zoledronic acid in a randomized, double-blind, placebo-controlled trial of 7736 postmenopausal women between the ages of 65 and 89 years.²² The women, all of whom had osteoporosis, received an IV infusion of either zoledronic acid (5 mg) or placebo at baseline, and again at 12 and 24 months. Vertebral and nonvertebral fractures, as well as hip fracture, were significantly reduced in the treatment group compared with placebo (TABLE 1).

In another RCT with 2127 participants, Lyles et al examined the effectiveness of 5 mg zoledronic acid IV given within 90 days of surgical repair of a hip fracture. In the intervention group, there was a 35% risk reduction in new clinical fractures (8.6% vs 13.9% for those on placebo; P=.001); mortality was also lower in the zoledronic acid group (9.6% vs 13.3%; P=.01).²³

In both trials, the number of patients who had serious adverse events or dropped out because of an adverse event was similar in the treatment and placebo groups. In both studies, too, a sizeable number of patients treated with zoledronic acid reported flu-like symptoms up to 3 days after receiving an infusion, particularly after the first one. Cardiovascular events were similar across intervention groups in both studies, with one exception: In Black’s study,²² there was an increased incidence of serious atrial fibrillation in the zoledronic acid group (1.3% vs 0.5% for the placebo group).

Other issues to keep in mind

Atypical femoral fractures. Published data suggest an association between bisphosphonate use and atypical femoral fractures, particularly with longer-term use,²⁴ although whether there is a causal link is unclear. Atypical femoral fractures occur with little or no trauma along the femur from just distal to the lesser trochanter to just proximal to the supracondylar flare.

In 2010, the FDA announced requirements for a black box warning about a possible link,²⁵ highlighting the uncertainty about both the optimal duration of bisphosphonate therapy and the cause of these fractures.

While concerns about such a link remain, it is important to note that atypical femoral fractures are very uncommon: Current estimates are that they account for less than 1% of hip/femoral fractures. What’s more, far more fractures are prevented by the use of bisphosphonates than are associated with their use, with an estimated ratio of up to 29:1.²⁴

Dosing schedules. Adherence to treatment is of key importance in maximizing outcomes from osteoporosis treatments, and is frequently low.^26,27 One way of improving adherence is to reduce the frequency of dosing required.²⁷ With that in mind, researchers have tested intermittent dosing regimens, using noninferiority or bridging trials.

Such studies have led to a number of approved dosing regimens—70 mg weekly for alendronate; 150 mg monthly and 35 mg weekly for risedronate; and 150 mg PO monthly and 3 mg IV quarterly for ibandronate among them. In making decisions about dosing, family physicians should consider patient preferences, but be aware that there are no direct efficacy data from RCTs to support these dosing regimens.

Calcium and vitamin D. The major fracture prevention trials of bisphosphonates have featured women who are calcium- and vitamin D-replete. In a recent study of 1515 women undergoing treatment with alendronate, risedronate, or raloxifene, however, that wasn’t always the case. ²⁸ After 13 months, 115 participants suffered from a new clinical fracture. The adjusted odds ratio for fractures in women with vitamin D deficiency compared with those with normal levels of vitamin D was 1.77 (95% CI, 1.20-2.59; P=.004), an indication of the importance of maintaining adequate vitamin D levels in patients taking bisphosphonates.

 

In clinical practice, it is important to ensure that patients being treated with bisphosphonates are not deficient in vitamin D. While direct evidence of poorer outcomes associated with low calcium levels is lacking, it is reasonable to also assess calcium intake and to ensure that patients have adequate intake of both. (For more on calcium and vitamin D requirements, see the Institute of Medicine’s recent report at http://www.iom.edu/Reports/2010/Dietary-Reference-Intakes-for-Calcium-and-Vitamin-D/Report-Brief.aspx) and “The IOM’s report on calcium and vitamin D: Should it change the way you practice?”.

 

What’s best for your patients?

All these bisphosphonates have demonstrated efficacy for the secondary prevention of vertebral fracture. All except ibandronate have demonstrated efficacy for nonvertebral fracture, as well, and the evidence suggests that ibandronate will also be effective if adequate doses are given. Thus, for women at significant risk for fracture, it seems clear that the benefits of treatment outweigh the risks. The case is not so clearcut for women at lower risk. Evidence to support the use of bisphosphonates for primary prevention is limited, other than for alendronate—which has been shown to provide primary prevention of vertebral fracture.

Which bisphosphonate is best depends on patient preferences and individual profiles. (See “How would you treat these patients?”.) In the absence of head-to-head RCTs, it isn’t possible to comment on the relative efficacy of the various bisphosphonates or their adverse event profiles. Indeed, the authors of the 2 Cochrane reviews completed to date note that trial participants have been healthier, with fewer comorbidities, than many of the postmenopausal women seen by primary care physicians. Head-to-head studies conducted in family practice settings would be an important addition to the body of evidence for the prevention of osteoporotic fracture.

How would you treat these patients?

CASE 1 Mrs. A is an active 67-year-old in good health. On a recent hike, she lost her footing and sustained a Colles’ fracture when she fell, although her fall was only from standing height. Now, you are concerned that she might have osteoporosis.

A dual-energy x-ray absorptiometry (DXA) scan confirms this suspicion: Mrs. A’s lumbar spine T-score is –2.6. A dietary review reveals that she has a satisfactory calcium intake, and lab work shows that her serum vitamin D levels are normal. Mrs. A wants to discuss treatment options with you.

What immediate treatment do you consider?

Mrs. A has no contraindications to any FDA-approved treatment for osteoporosis; you suggest she begin taking bisphosphonates, explaining that they are first-line treatment to prevent subsequent osteoporotic fractures. You briefly discuss other options, but note that raloxifene only reduces the risk of vertebral fractures and parathyroid hormone is effective (but very expensive) and requires daily injections, and is therefore generally used for severe osteoporosis. Your patient asks about bisphosphonates’ side effects, particularly the serious jaw problems she’s heard about.

You explain that for the most part, oral bisphosphonates are well tolerated, but that there is a potential for upper gastrointestinal (GI) problems—which is why it’s important to remain upright for at least 30 minutes after taking the medication. You tell her that the risk of developing osteonecrosis of the jaw is very low when the medication is taken at the doses needed for osteoporosis treatment, but that the risk may increase after tooth extraction or dental surgery. Mrs. A has no current dental symptoms and at her usual yearly dental check-up 9 months ago, there were no problems noted, so dental review before starting treatment is not needed. Should she develop any jaw pain, however, she should see you or her dentist immediately.

You also advise her of the possible link between bisphosphonates and atypical femoral fracture, but point out that such fractures are extremely rare—and that the medication prevents far more fractures than it has the potential to cause. You tell her to contact you immediately if she develops pain in the groin or thigh or experiences GI distress.

Which bisphosphonate do you prescribe?

You inform Mrs. A that alendronate has the longest follow-up data of the oral bisphosphonates and has demonstrated efficacy for the secondary prevention of wrist fractures, that risedronate and ibandronate have the advantage of being able to be taken monthly rather than weekly, and that zoledronic acid can be administered in a yearly infusion. She opts for alendronate. You prescribe a weekly dose of 70 mg and ask her to return in 3 months, and to call before then if any problems arise.

CASE 2 Mrs. Y, age 82, recently sustained a fractured femoral neck, which was treated surgically at the local hospital. She was discharged with a prescription for alendronate to treat her osteoporosis and prevent further fractures; her husband has brought her in today to get a new prescription.

During the visit, he reminds you that Mrs. Y has problems with memory. He also says he’s finding it increasingly difficult to ensure that his wife remains upright for 30 minutes after taking alendronate, and that she has begun complaining of indigestion.

 

What do you decide to do?

An inability to stay upright for 30 minutes after drug administration is a contraindication to the use of oral bisphosphonates. The presence of upper GI symptoms is also a concern. You offer Mrs. Y the option of a once-yearly IV infusion of zoledronic acid instead, and she and her husband agree to this. Before scheduling a follow-up visit, you discuss the patient’s nutritional intake, and discover that she consumes only a moderate amount of calcium—at most 2 servings of dairy products per day. You also note that her serum vitamin D level was not checked in the hospital. You order lab work, with a view to correcting any deficiency before proceeding with a zoledronic infusion (due to the risk of tetany) and to maintaining her on an appropriate level of calcium and vitamin D intake, using supplements only if necessary.

CORRESPONDENCE Tania Winzenberg, MBBS, Menzies Research Institute, Private Bag 23, Hobart, Tasmania, Australia 7001; [email protected]

CASE Jane T, a 53-year-old patient, calls her family physician’s office for a same-day appointment; she has severe right upper quadrant pain that developed a few hours ago. When Jane comes in, she tells her physician that the pain feels like the gallbladder attacks she used to have—before her gallbladder was removed 2 years ago. She has nausea but no vomiting, is afebrile, and has no urinary symptoms.

A series of in-office tests—urinalysis, complete blood count, comprehensive metabolic profile, amylase, and lipase— are all normal. The physician gives Jane an intramuscular injection of ketorolac and a prescription for oral tramadol, and sends her for a right upper quadrant ultrasound, which is also normal. The next morning, the pain intensifies, and Jane goes to the emergency department, where she undergoes computed tomography of the abdomen and pelvis—also normal. After a night in the hospital for observation, she is released. She returns to the family physician 3 days later, this time with an erythematous papular rash in a dermatomal distribution over her back and right upper quadrant that her doctor immediately recognizes as shingles.

Jane is not alone. Each year, about 1 million US residents develop herpes zoster (HZ),¹ and 70% to 80% of them experience prodromal pain in the affected dermatome.² For some, the pain is significant enough to prompt a medical work-up to rule out other potential causes, such as myocardial infarction, nephrolithiasis, pancreatitis, cholecystitis, and appendicitis.

The time and resources spent on such a work-up may be unavoidable when a patient presents with severe pain. But alert primary care physicians can avoid unnecessary diagnostic tests by being aware of the prodromal symptoms of HZ and being on the lookout for the rash that follows.

Age alone is a key factor in the detection of HZ, of course. One in 3 people will develop shingles during their lifetime,¹ with half of all cases occurring in people ages 60 and older.³ In addition to early detection and treatment, physicians can do their part to battle HZ by routinely recommending the shingles vaccine (Zostavax) to patients in this age group.

Diagnosing HZ: From prodrome to rash

For many patients, an abnormal skin sensation on one side of the body, such as itching, burning, or altered sensitivity to touch, is the first symptom of HZ. These sensations, including pain that can range from mild to severe, may precede the rash by days or even weeks.⁴ Systemic symptoms are far less common; less than 20% of patients develop fever, headache, malaise, or fatigue as part of the HZ prodrome.²

The shingles rash is usually unilateral and does not cross the midline. However, it may occur in up to 3 adjacent dermatomes. The trunk is the most common site for the rash, but it may also develop on the face, buttocks, or other parts of the body. The lesions start as erythematous papules and evolve into vesicles within 12 to 24 hours.⁵

Once the rash emerges, HZ can usually be diagnosed clinically in a primary care setting, and laboratory testing should be considered only when diagnosis is uncertain. In a cohort study of 260 patients older than 50 years with clinically diagnosed HZ, 236 (91%) cases were confirmed on serologic testing.⁶ In an Icelandic study, 93% of 505 cases were diagnosed correctly by general practitioners, using expert opinion and clinical course as the gold standard.⁷

If diagnostic testing is necessary, physicians have a number of choices:

Varicella zoster polymerase chain reaction (PCR) test. PCR testing for HZ can provide rapid and reliable diagnosis and is becoming more widely available, but its use should be limited because of the cost (approximately $300).

Tzanck smear. This test is quick and inexpensive, and can reliably diagnose a herpetic lesion based on the presence of acantholytic and multinucleated giant cells in a sample collected from the base of a vesicle.⁸ However, this technique cannot differentiate HZ from herpes simplex infection, and lack of experience with collection or interpretation of the Tzanck smear limits its usefulness.

 

Serologic testing. Serology has limited utility in the diagnosis of acute HZ, but may provide a retrospective diagnosis, if needed. In a study of 260 patients older than 50 years with clinically diagnosed acute HZ, varicella zoster IgA or IgM was positive in 61% of patients at the time of presentation, and in 91% of patients 5 to 10 days later.⁶

Viral culture. Obtaining a viral culture of varicella zoster is another option, but it is not recommended, as sensitivity is poor and incubation requires several days.

The course of illness, and risk of complications

For some patients, the acute pain and hypersensitivity at the site of the rash resolve in several days; for others, this may take several weeks or more. One recent study found a median of 32.5 days for pain duration in patients ages 50 and older.⁹ The suffering can last far longer, however, if complications arise.

Postherpetic neuralgia (PHN), a chronic and often debilitating condition with pain that can last months, or even indefinitely, affects about 10% to 15% of patients with HZ.¹⁰ Risk factors for the development of PHN include advanced age, female sex, presence of a prodrome, severe acute HZ pain, and a severe rash.¹¹

Trigeminal nerve involvement. HZ affects the first branch of the trigeminal nerve in about 10% to 15% of patients.⁵ In such cases, the rash may erupt on the forehead, periocular area, and nose. Patients with trigeminal nerve involvement are at significant risk for ocular complications (HZ ophthalmicus), including keratitis, iritis, and possible vision loss, and should be treated and referred to an ophthalmologist without delay.

In addition to these complications, others reported in a review of 859 patients include bacterial skin infection, motor neuropathy, and, rarely, meningitis and HZ oticus.¹² Advanced age markedly increased the likelihood of complications.

Initiate treatment without delay

Multiple randomized controlled clinical trials have demonstrated the efficacy of oral antiviral treatment in reducing the duration of viral shedding, accelerating rash healing, and reducing the severity and duration of acute HZ pain.² In all the studies, however, antiviral therapy was started within 72 hours of the onset of the rash; the efficacy of initiating antiviral treatment after >72 hours has not been systematically studied.² When it’s not possible to begin therapy within this time frame, however, many experts recommend initiating therapy as soon as possible thereafter.¹

Three antiviral agents—acyclovir, famciclovir, and valacyclovir—have been approved by the US Food and Drug Administration to treat HZ. Evidence suggests that famciclovir and valacyclovir have comparable efficacy with regard to resolution of both the rash and the acute pain,¹³ and result in more rapid pain resolution compared with acyclovir.^14,15 Famciclovir and valacyclovir also offer simpler dosing schedules—both are taken 3 times a day, while acyclovir requires 5 daily doses— but they are significantly more expensive (TABLE).

Oral antiviral therapy is strongly recommended for patients who are older than 50 and those who have moderate-to-severe pain or rash—or whose rash appears somewhere other than the trunk.² But given the safety of oral antiviral agents, treatment can be considered for younger patients and those with milder cases of HZ, as well. (Routine use of antiviral agents is not indicated for unexplained unilateral pain, as varicella zoster infection without the classic rash [zoster sine herpete] is a rare cause.¹⁶)

Results regarding the efficacy of oral antiviral agents for reducing the duration of chronic pain and preventing PHN are mixed.² A recent Cochrane review concluded that oral acyclovir does not significantly reduce the incidence of PHN and that there is insufficient evidence to determine if other antivirals do.¹⁷

TABLE
FDA-approved oral antiviral regimens

Drug	Dosing regimen	Cost of regimen*
Acyclovir	800 mg 5 times/d for 7-10 days	$55.97
Famciclovir	500 mg tid for 7 days	$319.99
Valacyclovir	1000 mg tid for 7 days	$315.99
*Source: http://www.drugstore.com. Accessed December 6, 2010.

Add a corticosteroid? The evidence is mixed
Oral corticosteroids have been studied as an adjunct to antiviral therapy for the treatment of HZ. One clinical trial of 208 immunocompetent adults older than 50 found that the addition of a 21-day prednisone taper to acyclovir led to accelerated healing of cutaneous lesions, cessation of analgesic use, and return to normal activities and uninterrupted sleep.¹⁸ However, this study and another randomized trial of oral corticosteroids did not show that steroids had any effect on longer-term pain relief or the development of PHN.^18,19 A recent Cochrane review concluded that there is insufficient evidence that corticosteroids are safe or effective in the prevention of PHN.²⁰ Given the potential adverse effects of oral corticosteroids, their use should be weighed carefully.

 

Give analgesics for shingles pain
Many clinical trials have looked at the efficacy of different analgesics in the treatment of PHN, but data regarding analgesics for the treatment of acute HZ pain are limited. One RCT of 87 patients older than 50 divided participants into 3 groups: One group took controlled-release oxycodone, another received a placebo, and the third group took gabapentin.²¹ (The study did not include patients with mild pain, for whom nonnarcotic analgesics would likely be more appropriate.)

The researchers found that the oxycodone significantly reduced acute HZ pain during the first 2 weeks of treatment as compared with placebo or gabapentin. There was no statistically significant reduction in pain for the gabapentin group, compared with those on placebo. The oxycodone group did have the highest dropout rate (27.6% vs 6.9% for the placebo group), however, primarily because of constipation. This study showed that narcotic analgesics are effective and relatively well tolerated for the treatment of acute HZ pain.²¹

Because severe pain with acute HZ is a well-established risk factor for the development of PHN, there is interest in determining whether effective pain control in the acute setting decreases the risk of chronic pain. One placebo-controlled trial of 72 patients older than 60 years found that 25 mg amitriptyline daily, started within 48 hours of rash onset and continued for 90 days, reduced pain prevalence by more than half at 6 months from diagnosis.²² This study did not control for the use of antiviral agents, however, so further investigation is needed.

CASE Jane T began a course of antiviral therapy with valacyclovir shortly after her rash appeared, and continued to take oral tramadol for the pain. Her rash and pain level improved over the next several days, and within 2 weeks she was fully recovered.

Prevention: Vaccination holds the key

HZ is contagious and can cause primary varicella in people who are susceptible. Indeed, one study found that 15.5% of susceptible household contacts developed varicella after exposure to HZ.¹ Advise patients with HZ to avoid contact with those at high risk for severe varicella—including pregnant women, premature infants, and immunocompromised individuals of all ages—until their lesions are crusted. They can further avoid transmission by keeping the lesions covered.²³

Increased use of the HZ vaccine, however, is the key to prevention of shingles. The Centers for Disease Control and Prevention (CDC) recommends Zostavax, a live attenuated varicella zoster vaccine given as a single subcutaneous injection, for people ages 60 and older. Compared with the varicella vaccines designed for children, Zostavax has a significantly higher potency in order to elicit a significant and durable response in older adults.²⁴

The vaccine is generally safe, with a mild injection site reaction being the most common adverse event. No evidence exists of transmission of virus from vaccine recipients to contacts.¹ Like other live virus vaccines, Zostavax is contraindicated in pregnant women and immunocompromised patients. It can be given to patients regardless of their history of chicken pox or previous episodes of HZ, as studies have shown that the recurrence rate for HZ is similar to the rate for initial episodes.

How well does it work? In a Shingles Prevention Study Group trial of 38,546 people 60 years of age or older, the vaccine reduced the incidence of HZ by 51% and the incidence of PHN by 67% over a 3-year follow-up period.²⁵ The vaccine was most effective for the prevention of HZ in the 60- to 69-year age group, but there was no significant difference in its efficacy in preventing PHN or reducing the burden of illness (a measure based on the incidence, severity, and duration of pain and discomfort) in 60- to 69-year-olds vs those ages 70 and older.²⁵ An analysis by the CDC suggests that approximately 17 people would need to be vaccinated with Zostavax to prevent one case of HZ, and approximately 31 people would need to be vaccinated to prevent one case of PHN.²⁴

Ongoing studies are examining the safety and efficacy of Zostavax for patients ages 50 to 59.²⁶ Although results thus far look promising, there is no recommendation for routine vaccination for this age group, and insurance companies do not routinely cover the cost of vaccinating them.

While primary care physicians generally favor the concept of HZ vaccination,²⁷ a CDC survey conducted in 2007—a year after the vaccine received FDA approval—found that only 1.9% of eligible patients received the vaccine.²⁸ Physicians cite concerns about reimbursement as a barrier to its use.²⁸

 

Zostavax is not covered by Medicare Part B, in contrast to other adult vaccines, such as influenza and pneumococcal.²⁹ However, the HZ vaccine is covered by many private insurers, as well as by Medicare Part D. Advise patients to check with their insurance carrier for specific details regarding their coverage, as some plans require the patient to purchase the vaccine from a pharmacy prior to administration in a physician’s office.

CORRESPONDENCE Sarah L. Cartwright, MD, Wake Forest University School of Medicine, Department of Family and Community Medicine, Medical Center Boulevard, Winston-Salem, NC 27157; [email protected]

CASE Jane T, a 53-year-old patient, calls her family physician’s office for a same-day appointment; she has severe right upper quadrant pain that developed a few hours ago. When Jane comes in, she tells her physician that the pain feels like the gallbladder attacks she used to have—before her gallbladder was removed 2 years ago. She has nausea but no vomiting, is afebrile, and has no urinary symptoms.

A series of in-office tests—urinalysis, complete blood count, comprehensive metabolic profile, amylase, and lipase— are all normal. The physician gives Jane an intramuscular injection of ketorolac and a prescription for oral tramadol, and sends her for a right upper quadrant ultrasound, which is also normal. The next morning, the pain intensifies, and Jane goes to the emergency department, where she undergoes computed tomography of the abdomen and pelvis—also normal. After a night in the hospital for observation, she is released. She returns to the family physician 3 days later, this time with an erythematous papular rash in a dermatomal distribution over her back and right upper quadrant that her doctor immediately recognizes as shingles.

Jane is not alone. Each year, about 1 million US residents develop herpes zoster (HZ),¹ and 70% to 80% of them experience prodromal pain in the affected dermatome.² For some, the pain is significant enough to prompt a medical work-up to rule out other potential causes, such as myocardial infarction, nephrolithiasis, pancreatitis, cholecystitis, and appendicitis.

The time and resources spent on such a work-up may be unavoidable when a patient presents with severe pain. But alert primary care physicians can avoid unnecessary diagnostic tests by being aware of the prodromal symptoms of HZ and being on the lookout for the rash that follows.

Age alone is a key factor in the detection of HZ, of course. One in 3 people will develop shingles during their lifetime,¹ with half of all cases occurring in people ages 60 and older.³ In addition to early detection and treatment, physicians can do their part to battle HZ by routinely recommending the shingles vaccine (Zostavax) to patients in this age group.

Diagnosing HZ: From prodrome to rash

For many patients, an abnormal skin sensation on one side of the body, such as itching, burning, or altered sensitivity to touch, is the first symptom of HZ. These sensations, including pain that can range from mild to severe, may precede the rash by days or even weeks.⁴ Systemic symptoms are far less common; less than 20% of patients develop fever, headache, malaise, or fatigue as part of the HZ prodrome.²

The shingles rash is usually unilateral and does not cross the midline. However, it may occur in up to 3 adjacent dermatomes. The trunk is the most common site for the rash, but it may also develop on the face, buttocks, or other parts of the body. The lesions start as erythematous papules and evolve into vesicles within 12 to 24 hours.⁵

Once the rash emerges, HZ can usually be diagnosed clinically in a primary care setting, and laboratory testing should be considered only when diagnosis is uncertain. In a cohort study of 260 patients older than 50 years with clinically diagnosed HZ, 236 (91%) cases were confirmed on serologic testing.⁶ In an Icelandic study, 93% of 505 cases were diagnosed correctly by general practitioners, using expert opinion and clinical course as the gold standard.⁷

If diagnostic testing is necessary, physicians have a number of choices:

Varicella zoster polymerase chain reaction (PCR) test. PCR testing for HZ can provide rapid and reliable diagnosis and is becoming more widely available, but its use should be limited because of the cost (approximately $300).

Tzanck smear. This test is quick and inexpensive, and can reliably diagnose a herpetic lesion based on the presence of acantholytic and multinucleated giant cells in a sample collected from the base of a vesicle.⁸ However, this technique cannot differentiate HZ from herpes simplex infection, and lack of experience with collection or interpretation of the Tzanck smear limits its usefulness.

 

Serologic testing. Serology has limited utility in the diagnosis of acute HZ, but may provide a retrospective diagnosis, if needed. In a study of 260 patients older than 50 years with clinically diagnosed acute HZ, varicella zoster IgA or IgM was positive in 61% of patients at the time of presentation, and in 91% of patients 5 to 10 days later.⁶

Viral culture. Obtaining a viral culture of varicella zoster is another option, but it is not recommended, as sensitivity is poor and incubation requires several days.

The course of illness, and risk of complications

For some patients, the acute pain and hypersensitivity at the site of the rash resolve in several days; for others, this may take several weeks or more. One recent study found a median of 32.5 days for pain duration in patients ages 50 and older.⁹ The suffering can last far longer, however, if complications arise.

Postherpetic neuralgia (PHN), a chronic and often debilitating condition with pain that can last months, or even indefinitely, affects about 10% to 15% of patients with HZ.¹⁰ Risk factors for the development of PHN include advanced age, female sex, presence of a prodrome, severe acute HZ pain, and a severe rash.¹¹

Trigeminal nerve involvement. HZ affects the first branch of the trigeminal nerve in about 10% to 15% of patients.⁵ In such cases, the rash may erupt on the forehead, periocular area, and nose. Patients with trigeminal nerve involvement are at significant risk for ocular complications (HZ ophthalmicus), including keratitis, iritis, and possible vision loss, and should be treated and referred to an ophthalmologist without delay.

In addition to these complications, others reported in a review of 859 patients include bacterial skin infection, motor neuropathy, and, rarely, meningitis and HZ oticus.¹² Advanced age markedly increased the likelihood of complications.

Initiate treatment without delay

Multiple randomized controlled clinical trials have demonstrated the efficacy of oral antiviral treatment in reducing the duration of viral shedding, accelerating rash healing, and reducing the severity and duration of acute HZ pain.² In all the studies, however, antiviral therapy was started within 72 hours of the onset of the rash; the efficacy of initiating antiviral treatment after >72 hours has not been systematically studied.² When it’s not possible to begin therapy within this time frame, however, many experts recommend initiating therapy as soon as possible thereafter.¹

Three antiviral agents—acyclovir, famciclovir, and valacyclovir—have been approved by the US Food and Drug Administration to treat HZ. Evidence suggests that famciclovir and valacyclovir have comparable efficacy with regard to resolution of both the rash and the acute pain,¹³ and result in more rapid pain resolution compared with acyclovir.^14,15 Famciclovir and valacyclovir also offer simpler dosing schedules—both are taken 3 times a day, while acyclovir requires 5 daily doses— but they are significantly more expensive (TABLE).

Oral antiviral therapy is strongly recommended for patients who are older than 50 and those who have moderate-to-severe pain or rash—or whose rash appears somewhere other than the trunk.² But given the safety of oral antiviral agents, treatment can be considered for younger patients and those with milder cases of HZ, as well. (Routine use of antiviral agents is not indicated for unexplained unilateral pain, as varicella zoster infection without the classic rash [zoster sine herpete] is a rare cause.¹⁶)

Results regarding the efficacy of oral antiviral agents for reducing the duration of chronic pain and preventing PHN are mixed.² A recent Cochrane review concluded that oral acyclovir does not significantly reduce the incidence of PHN and that there is insufficient evidence to determine if other antivirals do.¹⁷

TABLE
FDA-approved oral antiviral regimens

Drug	Dosing regimen	Cost of regimen*
Acyclovir	800 mg 5 times/d for 7-10 days	$55.97
Famciclovir	500 mg tid for 7 days	$319.99
Valacyclovir	1000 mg tid for 7 days	$315.99
*Source: http://www.drugstore.com. Accessed December 6, 2010.

Add a corticosteroid? The evidence is mixed
Oral corticosteroids have been studied as an adjunct to antiviral therapy for the treatment of HZ. One clinical trial of 208 immunocompetent adults older than 50 found that the addition of a 21-day prednisone taper to acyclovir led to accelerated healing of cutaneous lesions, cessation of analgesic use, and return to normal activities and uninterrupted sleep.¹⁸ However, this study and another randomized trial of oral corticosteroids did not show that steroids had any effect on longer-term pain relief or the development of PHN.^18,19 A recent Cochrane review concluded that there is insufficient evidence that corticosteroids are safe or effective in the prevention of PHN.²⁰ Given the potential adverse effects of oral corticosteroids, their use should be weighed carefully.

 

Give analgesics for shingles pain
Many clinical trials have looked at the efficacy of different analgesics in the treatment of PHN, but data regarding analgesics for the treatment of acute HZ pain are limited. One RCT of 87 patients older than 50 divided participants into 3 groups: One group took controlled-release oxycodone, another received a placebo, and the third group took gabapentin.²¹ (The study did not include patients with mild pain, for whom nonnarcotic analgesics would likely be more appropriate.)

The researchers found that the oxycodone significantly reduced acute HZ pain during the first 2 weeks of treatment as compared with placebo or gabapentin. There was no statistically significant reduction in pain for the gabapentin group, compared with those on placebo. The oxycodone group did have the highest dropout rate (27.6% vs 6.9% for the placebo group), however, primarily because of constipation. This study showed that narcotic analgesics are effective and relatively well tolerated for the treatment of acute HZ pain.²¹

Because severe pain with acute HZ is a well-established risk factor for the development of PHN, there is interest in determining whether effective pain control in the acute setting decreases the risk of chronic pain. One placebo-controlled trial of 72 patients older than 60 years found that 25 mg amitriptyline daily, started within 48 hours of rash onset and continued for 90 days, reduced pain prevalence by more than half at 6 months from diagnosis.²² This study did not control for the use of antiviral agents, however, so further investigation is needed.

CASE Jane T began a course of antiviral therapy with valacyclovir shortly after her rash appeared, and continued to take oral tramadol for the pain. Her rash and pain level improved over the next several days, and within 2 weeks she was fully recovered.

Prevention: Vaccination holds the key

HZ is contagious and can cause primary varicella in people who are susceptible. Indeed, one study found that 15.5% of susceptible household contacts developed varicella after exposure to HZ.¹ Advise patients with HZ to avoid contact with those at high risk for severe varicella—including pregnant women, premature infants, and immunocompromised individuals of all ages—until their lesions are crusted. They can further avoid transmission by keeping the lesions covered.²³

Increased use of the HZ vaccine, however, is the key to prevention of shingles. The Centers for Disease Control and Prevention (CDC) recommends Zostavax, a live attenuated varicella zoster vaccine given as a single subcutaneous injection, for people ages 60 and older. Compared with the varicella vaccines designed for children, Zostavax has a significantly higher potency in order to elicit a significant and durable response in older adults.²⁴

The vaccine is generally safe, with a mild injection site reaction being the most common adverse event. No evidence exists of transmission of virus from vaccine recipients to contacts.¹ Like other live virus vaccines, Zostavax is contraindicated in pregnant women and immunocompromised patients. It can be given to patients regardless of their history of chicken pox or previous episodes of HZ, as studies have shown that the recurrence rate for HZ is similar to the rate for initial episodes.

How well does it work? In a Shingles Prevention Study Group trial of 38,546 people 60 years of age or older, the vaccine reduced the incidence of HZ by 51% and the incidence of PHN by 67% over a 3-year follow-up period.²⁵ The vaccine was most effective for the prevention of HZ in the 60- to 69-year age group, but there was no significant difference in its efficacy in preventing PHN or reducing the burden of illness (a measure based on the incidence, severity, and duration of pain and discomfort) in 60- to 69-year-olds vs those ages 70 and older.²⁵ An analysis by the CDC suggests that approximately 17 people would need to be vaccinated with Zostavax to prevent one case of HZ, and approximately 31 people would need to be vaccinated to prevent one case of PHN.²⁴

Ongoing studies are examining the safety and efficacy of Zostavax for patients ages 50 to 59.²⁶ Although results thus far look promising, there is no recommendation for routine vaccination for this age group, and insurance companies do not routinely cover the cost of vaccinating them.

While primary care physicians generally favor the concept of HZ vaccination,²⁷ a CDC survey conducted in 2007—a year after the vaccine received FDA approval—found that only 1.9% of eligible patients received the vaccine.²⁸ Physicians cite concerns about reimbursement as a barrier to its use.²⁸

 

Zostavax is not covered by Medicare Part B, in contrast to other adult vaccines, such as influenza and pneumococcal.²⁹ However, the HZ vaccine is covered by many private insurers, as well as by Medicare Part D. Advise patients to check with their insurance carrier for specific details regarding their coverage, as some plans require the patient to purchase the vaccine from a pharmacy prior to administration in a physician’s office.

CORRESPONDENCE Sarah L. Cartwright, MD, Wake Forest University School of Medicine, Department of Family and Community Medicine, Medical Center Boulevard, Winston-Salem, NC 27157; [email protected]

CASE Jane T, a 53-year-old patient, calls her family physician’s office for a same-day appointment; she has severe right upper quadrant pain that developed a few hours ago. When Jane comes in, she tells her physician that the pain feels like the gallbladder attacks she used to have—before her gallbladder was removed 2 years ago. She has nausea but no vomiting, is afebrile, and has no urinary symptoms.

A series of in-office tests—urinalysis, complete blood count, comprehensive metabolic profile, amylase, and lipase— are all normal. The physician gives Jane an intramuscular injection of ketorolac and a prescription for oral tramadol, and sends her for a right upper quadrant ultrasound, which is also normal. The next morning, the pain intensifies, and Jane goes to the emergency department, where she undergoes computed tomography of the abdomen and pelvis—also normal. After a night in the hospital for observation, she is released. She returns to the family physician 3 days later, this time with an erythematous papular rash in a dermatomal distribution over her back and right upper quadrant that her doctor immediately recognizes as shingles.

Jane is not alone. Each year, about 1 million US residents develop herpes zoster (HZ),¹ and 70% to 80% of them experience prodromal pain in the affected dermatome.² For some, the pain is significant enough to prompt a medical work-up to rule out other potential causes, such as myocardial infarction, nephrolithiasis, pancreatitis, cholecystitis, and appendicitis.

The time and resources spent on such a work-up may be unavoidable when a patient presents with severe pain. But alert primary care physicians can avoid unnecessary diagnostic tests by being aware of the prodromal symptoms of HZ and being on the lookout for the rash that follows.

Age alone is a key factor in the detection of HZ, of course. One in 3 people will develop shingles during their lifetime,¹ with half of all cases occurring in people ages 60 and older.³ In addition to early detection and treatment, physicians can do their part to battle HZ by routinely recommending the shingles vaccine (Zostavax) to patients in this age group.

Diagnosing HZ: From prodrome to rash

For many patients, an abnormal skin sensation on one side of the body, such as itching, burning, or altered sensitivity to touch, is the first symptom of HZ. These sensations, including pain that can range from mild to severe, may precede the rash by days or even weeks.⁴ Systemic symptoms are far less common; less than 20% of patients develop fever, headache, malaise, or fatigue as part of the HZ prodrome.²

The shingles rash is usually unilateral and does not cross the midline. However, it may occur in up to 3 adjacent dermatomes. The trunk is the most common site for the rash, but it may also develop on the face, buttocks, or other parts of the body. The lesions start as erythematous papules and evolve into vesicles within 12 to 24 hours.⁵

Once the rash emerges, HZ can usually be diagnosed clinically in a primary care setting, and laboratory testing should be considered only when diagnosis is uncertain. In a cohort study of 260 patients older than 50 years with clinically diagnosed HZ, 236 (91%) cases were confirmed on serologic testing.⁶ In an Icelandic study, 93% of 505 cases were diagnosed correctly by general practitioners, using expert opinion and clinical course as the gold standard.⁷

If diagnostic testing is necessary, physicians have a number of choices:

Varicella zoster polymerase chain reaction (PCR) test. PCR testing for HZ can provide rapid and reliable diagnosis and is becoming more widely available, but its use should be limited because of the cost (approximately $300).

Tzanck smear. This test is quick and inexpensive, and can reliably diagnose a herpetic lesion based on the presence of acantholytic and multinucleated giant cells in a sample collected from the base of a vesicle.⁸ However, this technique cannot differentiate HZ from herpes simplex infection, and lack of experience with collection or interpretation of the Tzanck smear limits its usefulness.

 

Serologic testing. Serology has limited utility in the diagnosis of acute HZ, but may provide a retrospective diagnosis, if needed. In a study of 260 patients older than 50 years with clinically diagnosed acute HZ, varicella zoster IgA or IgM was positive in 61% of patients at the time of presentation, and in 91% of patients 5 to 10 days later.⁶

Viral culture. Obtaining a viral culture of varicella zoster is another option, but it is not recommended, as sensitivity is poor and incubation requires several days.

The course of illness, and risk of complications

For some patients, the acute pain and hypersensitivity at the site of the rash resolve in several days; for others, this may take several weeks or more. One recent study found a median of 32.5 days for pain duration in patients ages 50 and older.⁹ The suffering can last far longer, however, if complications arise.

Postherpetic neuralgia (PHN), a chronic and often debilitating condition with pain that can last months, or even indefinitely, affects about 10% to 15% of patients with HZ.¹⁰ Risk factors for the development of PHN include advanced age, female sex, presence of a prodrome, severe acute HZ pain, and a severe rash.¹¹

Trigeminal nerve involvement. HZ affects the first branch of the trigeminal nerve in about 10% to 15% of patients.⁵ In such cases, the rash may erupt on the forehead, periocular area, and nose. Patients with trigeminal nerve involvement are at significant risk for ocular complications (HZ ophthalmicus), including keratitis, iritis, and possible vision loss, and should be treated and referred to an ophthalmologist without delay.

In addition to these complications, others reported in a review of 859 patients include bacterial skin infection, motor neuropathy, and, rarely, meningitis and HZ oticus.¹² Advanced age markedly increased the likelihood of complications.

Initiate treatment without delay

Multiple randomized controlled clinical trials have demonstrated the efficacy of oral antiviral treatment in reducing the duration of viral shedding, accelerating rash healing, and reducing the severity and duration of acute HZ pain.² In all the studies, however, antiviral therapy was started within 72 hours of the onset of the rash; the efficacy of initiating antiviral treatment after >72 hours has not been systematically studied.² When it’s not possible to begin therapy within this time frame, however, many experts recommend initiating therapy as soon as possible thereafter.¹

Three antiviral agents—acyclovir, famciclovir, and valacyclovir—have been approved by the US Food and Drug Administration to treat HZ. Evidence suggests that famciclovir and valacyclovir have comparable efficacy with regard to resolution of both the rash and the acute pain,¹³ and result in more rapid pain resolution compared with acyclovir.^14,15 Famciclovir and valacyclovir also offer simpler dosing schedules—both are taken 3 times a day, while acyclovir requires 5 daily doses— but they are significantly more expensive (TABLE).

Oral antiviral therapy is strongly recommended for patients who are older than 50 and those who have moderate-to-severe pain or rash—or whose rash appears somewhere other than the trunk.² But given the safety of oral antiviral agents, treatment can be considered for younger patients and those with milder cases of HZ, as well. (Routine use of antiviral agents is not indicated for unexplained unilateral pain, as varicella zoster infection without the classic rash [zoster sine herpete] is a rare cause.¹⁶)

Results regarding the efficacy of oral antiviral agents for reducing the duration of chronic pain and preventing PHN are mixed.² A recent Cochrane review concluded that oral acyclovir does not significantly reduce the incidence of PHN and that there is insufficient evidence to determine if other antivirals do.¹⁷

TABLE
FDA-approved oral antiviral regimens

Drug	Dosing regimen	Cost of regimen*
Acyclovir	800 mg 5 times/d for 7-10 days	$55.97
Famciclovir	500 mg tid for 7 days	$319.99
Valacyclovir	1000 mg tid for 7 days	$315.99
*Source: http://www.drugstore.com. Accessed December 6, 2010.

Add a corticosteroid? The evidence is mixed
Oral corticosteroids have been studied as an adjunct to antiviral therapy for the treatment of HZ. One clinical trial of 208 immunocompetent adults older than 50 found that the addition of a 21-day prednisone taper to acyclovir led to accelerated healing of cutaneous lesions, cessation of analgesic use, and return to normal activities and uninterrupted sleep.¹⁸ However, this study and another randomized trial of oral corticosteroids did not show that steroids had any effect on longer-term pain relief or the development of PHN.^18,19 A recent Cochrane review concluded that there is insufficient evidence that corticosteroids are safe or effective in the prevention of PHN.²⁰ Given the potential adverse effects of oral corticosteroids, their use should be weighed carefully.

 

Give analgesics for shingles pain
Many clinical trials have looked at the efficacy of different analgesics in the treatment of PHN, but data regarding analgesics for the treatment of acute HZ pain are limited. One RCT of 87 patients older than 50 divided participants into 3 groups: One group took controlled-release oxycodone, another received a placebo, and the third group took gabapentin.²¹ (The study did not include patients with mild pain, for whom nonnarcotic analgesics would likely be more appropriate.)

The researchers found that the oxycodone significantly reduced acute HZ pain during the first 2 weeks of treatment as compared with placebo or gabapentin. There was no statistically significant reduction in pain for the gabapentin group, compared with those on placebo. The oxycodone group did have the highest dropout rate (27.6% vs 6.9% for the placebo group), however, primarily because of constipation. This study showed that narcotic analgesics are effective and relatively well tolerated for the treatment of acute HZ pain.²¹

Because severe pain with acute HZ is a well-established risk factor for the development of PHN, there is interest in determining whether effective pain control in the acute setting decreases the risk of chronic pain. One placebo-controlled trial of 72 patients older than 60 years found that 25 mg amitriptyline daily, started within 48 hours of rash onset and continued for 90 days, reduced pain prevalence by more than half at 6 months from diagnosis.²² This study did not control for the use of antiviral agents, however, so further investigation is needed.

CASE Jane T began a course of antiviral therapy with valacyclovir shortly after her rash appeared, and continued to take oral tramadol for the pain. Her rash and pain level improved over the next several days, and within 2 weeks she was fully recovered.

Prevention: Vaccination holds the key

HZ is contagious and can cause primary varicella in people who are susceptible. Indeed, one study found that 15.5% of susceptible household contacts developed varicella after exposure to HZ.¹ Advise patients with HZ to avoid contact with those at high risk for severe varicella—including pregnant women, premature infants, and immunocompromised individuals of all ages—until their lesions are crusted. They can further avoid transmission by keeping the lesions covered.²³

Increased use of the HZ vaccine, however, is the key to prevention of shingles. The Centers for Disease Control and Prevention (CDC) recommends Zostavax, a live attenuated varicella zoster vaccine given as a single subcutaneous injection, for people ages 60 and older. Compared with the varicella vaccines designed for children, Zostavax has a significantly higher potency in order to elicit a significant and durable response in older adults.²⁴

The vaccine is generally safe, with a mild injection site reaction being the most common adverse event. No evidence exists of transmission of virus from vaccine recipients to contacts.¹ Like other live virus vaccines, Zostavax is contraindicated in pregnant women and immunocompromised patients. It can be given to patients regardless of their history of chicken pox or previous episodes of HZ, as studies have shown that the recurrence rate for HZ is similar to the rate for initial episodes.

How well does it work? In a Shingles Prevention Study Group trial of 38,546 people 60 years of age or older, the vaccine reduced the incidence of HZ by 51% and the incidence of PHN by 67% over a 3-year follow-up period.²⁵ The vaccine was most effective for the prevention of HZ in the 60- to 69-year age group, but there was no significant difference in its efficacy in preventing PHN or reducing the burden of illness (a measure based on the incidence, severity, and duration of pain and discomfort) in 60- to 69-year-olds vs those ages 70 and older.²⁵ An analysis by the CDC suggests that approximately 17 people would need to be vaccinated with Zostavax to prevent one case of HZ, and approximately 31 people would need to be vaccinated to prevent one case of PHN.²⁴

Ongoing studies are examining the safety and efficacy of Zostavax for patients ages 50 to 59.²⁶ Although results thus far look promising, there is no recommendation for routine vaccination for this age group, and insurance companies do not routinely cover the cost of vaccinating them.

While primary care physicians generally favor the concept of HZ vaccination,²⁷ a CDC survey conducted in 2007—a year after the vaccine received FDA approval—found that only 1.9% of eligible patients received the vaccine.²⁸ Physicians cite concerns about reimbursement as a barrier to its use.²⁸

 

Zostavax is not covered by Medicare Part B, in contrast to other adult vaccines, such as influenza and pneumococcal.²⁹ However, the HZ vaccine is covered by many private insurers, as well as by Medicare Part D. Advise patients to check with their insurance carrier for specific details regarding their coverage, as some plans require the patient to purchase the vaccine from a pharmacy prior to administration in a physician’s office.

CORRESPONDENCE Sarah L. Cartwright, MD, Wake Forest University School of Medicine, Department of Family and Community Medicine, Medical Center Boulevard, Winston-Salem, NC 27157; [email protected]

Findings from the Women’s Health Initiative (WHI) and the Heart and Estrogen/progestin Replacement Study^1,2 have left physicians and patients confused about the risks and benefits of hormone therapy (HT) and have dramatically affected prescription patterns.³ After the WHI trial findings were published in 2002,¹ use of HT declined dramatically; many women discontinued therapy or switched to lower doses, while others turned to alternate therapies.⁴ This, despite long-standing evidence that HT administered as estrogen alone (ET; for hysterectomized women) or in combination with progestin (EPT; for nonhysterectomized women) effectively controls menopausal symptoms—hot flashes, vaginal atrophy, insomnia, and sexual problems.⁵

When interpreting results of recent clinical trials, it is important to consider how closely the trial subjects resemble patients in your practice. Patients in HT clinical studies may range from younger women who are newly menopausal to older women who experienced menopause decades ago. Women also have differing risk factors that determine whether HT is appropriate treatment.

Recent reanalyses of WHI data and other studies, as well as new guidelines from the North American Menopause Society (NAMS), have helped to clarify the benefit–risk profile of HT according to patient characteristics. This article places clinical trial evidence in perspective and explains how you can evaluate the benefit–risk profile of HT for individuals.

What are the benefits of HT?

The primary indication for HT is treatment of vasomotor symptoms, which are common at the time of menopause and can diminish quality of life.⁵ The efficacy of HT in alleviating these symptoms is well established.⁶ Hot flash rates are highest in women during the first 2 years postmenopause,⁷ and most women use HT for up to 2 years.⁸ A study of women who had recently become postmenopausal (45-58 years of age) showed a significant reduction in vasomotor symptoms over 5 years with ET/EPT.⁹

Both oral and vaginal ET effectively relieve vaginal dryness.^5,10 A meta-analysis of 10 clinical trials showed that low-dose vaginal ET was as effective as systemic ET in providing relief of the signs and symptoms of urogenital atrophy.¹¹

Nonhormonal treatments are also sometimes prescribed off label to treat vasomotor symptoms for women who cannot or choose not to use estrogens. Such agents include selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors, clonidine, and gabapentin.

A meta-analysis found that these treatments were more effective than placebo in reducing hot flashes in postmenopausal women, but the magnitude of symptom relief with these drugs has been less than that observed with estrogens.¹² In another study, off-label use of antidepressants greatly attenuated hot flashes for some patients.¹³

NAMS recommends that women with moderate-to-severe menopause-related hot flashes who have concerns with, or contraindications to, estrogen-containing treatments, consider other treatments, such as SSRIs or gabapentin;⁷ however, high-quality studies evaluating these therapies in women with moderate-to-severe hot flashes are lacking.¹²

Phytoestrogens such as soy compounds and black cohosh may be helpful, although results have been variable in clinical trials.¹⁴ Common adverse events associated with black cohosh treatment include gastrointestinal complaints and rashes. There have been rare reports of liver toxicity, suggesting the need for further investigation.¹⁵

Protecting bone mass density and reducing risk of fractures
Estrogen therapy. In the WHI study, ET reduced the rates of hip fractures (P=.01), clinical vertebral fractures (P=.02), and total osteoporotic fractures (P<.001).¹⁶ The reduced risk was not affected by patient age.¹⁷ The randomized Women’s Health, Osteoporosis, Progestin, Estrogen (HOPE) study showed protection against early bone loss with ET vs placebo. After 2 years of follow-up, 55% of placebo-treated patients exhibited >2% loss of spine bone-mass density, compared with just 7% of women using ET (0.625 mg/d).¹⁸

Estrogen-progestin therapy. The WHI study^1,19 confirmed the reduced risk of osteoporotic fractures with EPT seen in previous clinical studies, and the Women’s HOPE study¹⁸ confirmed EPT’s protective effect against bone loss. In a meta-analysis of HT studies (most of which used EPT), the benefits associated with HT in fracture prevention were particularly marked in women younger than 60 years,²⁰ although no effect of age or time since menopause was observed in the WHI study.¹⁹ Initiation of EPT soon after menopause has been shown to improve postural balance to levels seen in premenopausal women, which may contribute to protection against fracture.²¹

 

Nonhormonal therapy for bone health. For women who are not candidates for HT, therapeutic options for maintaining bone health include bisphosphonates, raloxifene, teriparatide, and calcitonin.²² In addition to calcium and vitamin D supplementation, the NAMS guidelines recommend bisphosphonates as first-line treatment, followed by raloxifene, for postmenopausal women with low bone mass or younger postmenopausal women with osteoporosis who are at greater risk of spine fracture than hip fracture.²³ Teriparatide is generally reserved for women at high risk of fracture.²³ Calcitonin, typically administered as a nasal spray, is approved for osteoporosis treatment, but not prevention. It is generally considered an alternative for patients who cannot tolerate other therapies.²³ Denosumab, a monoclonal antibody, is a new drug indicated in women at high risk for fracture or who cannot tolerate other therapies.

What are the potential risks of HT?

Risk factors associated with HT relate to a woman’s baseline disease risks: age; age at menopause; cause of menopause; time elapsed since menopause; prior use of any hormone; types, routes of administration, and doses of HT used; and medical conditions emerging during treatment.⁵ When assessing the benefit–risk profile of HT for any patient, take into account the woman’s health profile as well as the chance of harm associated with any particular therapy.

Cardiovascular disease: Timing of HT matters
Estrogen therapy. Although observational studies,^24,25 such as the Nurses’ Health Study, suggest a reduced risk of cardiovascular events with ET, randomized clinical trials^16,26 have shown either no effect or increased risk of cardiovascular disease among women using ET. In the ET arm of the WHI study,^16,26,27 there was an increased risk of stroke and a trend toward increased risk of peripheral arterial disease, but no effect on the incidence of coronary heart disease (including myocardial infarction and coronary death).

The disparity between observational and randomized clinical trial results is now believed to be a result of differences in patient characteristics (particularly age) and timing of initiation of HT in both types of studies.⁵ Demographic or biologic differences influence the effects of HT on cardiovascular risk. This timing hypothesis is supported by data from an observational study,²⁸ meta-analysis of clinical trials,²⁹ secondary analyses from the WHI,³⁰ and a substudy of the WHI (WHI-Coronary Artery Calcium Study).³¹

Estrogen-progestin therapy. As with ET, observational studies^24,25 have indicated a reduced risk of cardiovascular events with EPT, whereas randomized clinical trials^1,26,32 have shown either no effect or increased risk of cardiovascular disease in women using EPT. A recent observational study of women taking primarily EPT (87%; 13% on ET) for a mean duration of 8.3 years found no significant difference in the risk of cardiovascular disease between groups exposed to HT and those unexposed (relative risk, 0.84; 95% confidence interval [CI], 0.16-4.13).³³

The WHI study demonstrated an increase in cardiovascular event risk with EPT, particularly during the first year of treatment.¹ However, when results were adjusted for age and time since menopause, this risk was isolated to women ≥20 years past menopause, contrasting with a trend toward reduced risk of coronary heart disease in women who initiated HT within 10 years of menopause.³⁰

In the Women’s International Study of Long Duration Oestrogen After Menopause (WISDOM), there was a significant increase in the number of major cardiovascular events with EPT vs placebo.³² However, as in the original WHI study, most women in the WISDOM study were age 65 or older and thus did not fall into the younger age category that experiences cardiovascular benefit from HT.

Influence of age on cardiovascular risk. In the WHI and WISDOM studies,^1,16,32 women tended to be at least 10 years postmenopause, whereas the observational studies included younger women who started HT sooner after menopause. The WHI data have shown no increased risk of cardiovascular disease with ET overall and have shown lower coronary artery disease risk in women ages 50 to 59 years.²⁶ There was also a trend for reduced cardiovascular risk with EPT among women who were up to 10 years postmenopause.³⁰

In a meta-analysis³⁴ of randomized studies, there was a reduction in the risk of cardiovascular events with HT in women younger than 60 years, but an increased risk of events during the first year of treatment in older women. HT has been associated with reduced blood pressure in women who are <5 years postmenopause but not in women ≥5 years postmenopause.³⁵ Thus, the data appear to support the hypothesis of a “therapeutic window” during which ET or EPT may be cardioprotective in younger, newly menopausal women, and an increased risk for cardiovascular disease with EPT, principally confined to older women at an increased distance from menopause.

 

Thromboembolism: Patient age makes a difference
Estrogen therapy. Observational data from the UK General Practice Research Database, which included women ages 55 to 79 years, demonstrated a reduced risk of deep vein thrombosis (P=.008) and a trend toward reduced risk of venous thromboembolism (VTE; P=.057) among users of ET.³⁶ However, the ET arm of the WHI showed an early increased risk of venous thrombosis, particularly within the first 2 years of use.³⁷ The absolute incidence of VTE (including deep vein thrombosis and pulmonary embolism) was relatively low in the study, and risk of pulmonary embolism alone was not significantly different from that seen with placebo; however, the use of conjugated estrogens did increase the relative risk of VTE in postmenopausal women without a uterus. Risk also increased with obesity.³⁷

Estrogen-progestin therapy. The WHI study demonstrated an increased risk of VTE with EPT compared with placebo, the risk increasing with advancing age and obesity.³⁸ In addition, the risk of VTE was significantly greater with EPT than with ET in the same study.³⁷ In women younger than 60 years, the projected 5-year risk associated with EPT was 1.4% in obese women, compared with less than 0.5% in women of normal weight. In the WISDOM study, which involved women older than 65 years, there was a significant increase in VTE incidence with EPT vs placebo (hazard ratio [HR], 7.36; 95% CI, 2.20-24.60).³²

Thrombotic risk in perspective. The risk of VTE is an important determinant of the benefit–risk profile when prescribing HT. Data from observational and randomized trials have shown an increased risk of VTE with oral HT.^5,39 In women with preexisting cardiovascular disease, the use of statins appeared to negate the increased risk of thromboembolism with EPT.⁴⁰ In the WHI trials, the absolute VTE risk associated with either EPT (7 per 10,000 women per year of use) or ET (4 per 10,000 women per year of use) in women younger than 60 years was lower than in older women³⁷—and considered rare by NAMS consensus. Thus, for otherwise healthy newly menopausal women younger than 60 years, carefully consider the benefits of ET or EPT against the negligible risk of thromboembolism.

Limited observational data suggest lower risks of VTE with transdermal ET compared with oral ET,⁴¹ but there is no conclusive evidence from randomized controlled trials on this subject.⁵ Low-dose oral and transdermal formulations may provide promising routes of administration, pending further studies. Evidence suggests that women with a history of VTE or women who have factor V Leiden are at increased risk for VTE with HT use.³⁹ Use caution, therefore, when considering HT in women at higher risk of VTE, such as those with prior VTE or thrombogenic mutations, those undergoing surgery, or those who are immobilized.³⁹

Estrogen therapy. Observational studies have suggested an increased incidence of breast cancer among women using ET for more than 1 year, with the risk increasing as use continues.36,42 In contrast, results of the WHI study showed that invasive breast cancer was diagnosed at a 23% lower rate in the ET group than in the placebo group, although this difference did not reach statistical significance (P=.06).16 The Women’s Health Study showed no association between current use of ET and the risk of total breast cancer or invasive breast cancer.43 The degree of breast cancer risk may depend on dose, as a meta-analysis of studies showed no increase in breast cancer risk with use of ET at ≤0.625 mg/d.44 In addition, the incidence of breast cancer has been shown to be lower in women who do not have benign breast disease or first-degree relatives with breast cancer.45

Estrogen-progestin therapy. Observational studies have shown an increased risk of breast cancer with EPT.^42,46 In the WHI study, there was a significantly increased relative risk of invasive breast cancer in women receiving EPT over a follow-up of 5.6 years (HR, 1.24; 95% CI, 1.02-1.50).⁴⁷ However, some have noted that the observed increase in the incidence of invasive breast cancer in the EPT arm vs placebo was not statistically significant and could have resulted from chance alone.⁴⁸ A recent analysis of breast cancer incidence in the United States found a sharp decrease from 2002 to 2003,⁴⁹ suggesting that breast cancer risk diminished soon after discontinuation of EPT for many women following the publication of the WHI results.

 

A newly published WHI follow-up study has yielded similar findings regarding the incidence of invasive breast cancer with EPT. The small increase in cancer incidence compared with placebo was associated with positive nodes and the death rate in this group was also higher (2.6 deaths vs 1.3 per 10,000 women). These findings do not apply to ET alone.⁵⁰

Breast cancer risk in perspective. When interpreting increased risk, consider the absolute risk. In the WHI study, the absolute risk of invasive breast cancer increased by 4 to 6 cases per 10,000 women per year in the EPT group vs placebo.⁴⁷ Similarly, a systematic review of clinical studies showed that EPT was associated with an increase of 4 breast cancer cases per 10,000 women per year.⁵¹ The increased risk of breast cancer with combined EPT is similar to that associated with early menarche or late menopause and is smaller than that associated with nulliparity or having children after 30 years of age.⁵²

Assessing risks and benefits for the potential HT patient

The first step in treating patients who have hot flashes is to determine the extent of their symptoms and the effect on their quality of life (TABLE).^5,10,23 Two hot flashes a day is considered mild and will usually respond to lifestyle measures such as exercising, avoiding alcohol and spicy foods, and staying in a cool environment. If the patient wakes in the night with hot flashes and night sweats that lead to insomnia, this may be more serious and require treatment. Consider HT for moderate-to-severe hot flashes—ie, 5 to 7 a day. HT is the only pharmacologic therapy indicated for the treatment of hot flashes.

Although professional guidelines recommend appropriate use of HT, publication of the WHI study caused many patients to mistrust and fear hormonal approaches to managing menopausal symptoms.^3,4,53 Among those who discontinued HT, many have had vasomotor symptoms recur, and some patients remain untreated.⁵³ A thorough discussion of individual needs and risk factors can help assess whether a patient is a suitable candidate for HT, and patient education and counseling may help alleviate concerns.⁵⁴

When considering HT for a patient, take into account risk factors, such as baseline disease, age at menopause, cause of menopause, prior hormone use, variations in HT used, and age and time elapsed since menopause.⁵ An individual’s risks for cardiovascular disease, breast cancer, and osteoporotic fractures will help determine the most appropriate treatment.⁵⁵ In the WHI, symptomatic women who were younger and closer to the menopausal transition experienced the greatest relief of vasomotor symptoms with EPT and were less likely to experience adverse effects compared with older women.⁵⁶ The WHI data also showed that the prevalence of menopausal symptoms decreased with increasing age, occurring most commonly in women ages 50 to 54 years.⁵⁶ The WHI findings have been shown to apply to HT regimens in general.⁵⁷

Specific recommendations. Current prescribing guidelines⁵ recommend using ET/EPT to treat moderate-to-severe vasomotor symptoms associated with menopause when the benefits of short-term therapy outweigh the risks. For women who experience mainly vaginal symptoms rather than vasomotor symptoms, vaginal ET is recommended.

HT is not recommended for coronary protection in women of any age, as there is evidence that use in older women increases the risk of cardiovascular events.⁵ However, HT does not appear to increase the risk of CV events if initiated by women ages 50 to 59 years or by those within 10 years of menopause. There is evidence of an increased risk of VTE with oral HT, although absolute risk is low in women ages 50 to 59 years.⁵

To prevent further bone loss and reduce the risk of osteoporotic fracture in women with established reduction in bone mass, the guidelines recommend extended use of HT, regardless of menopausal symptoms, when alternate therapies are not appropriate or cause side effects or when the safety and hazards of extended use of alternate therapies are not well established.⁵

Breast cancer risk increases with EPT use beyond 3 to 5 years, although the absolute risk is still considered rare.⁵ Clinical evidence, including findings from the WHI study¹⁶ and the Women’s Health Study,⁴³ shows no increase in the risk of breast cancer in women receiving ET. Further, the risk of breast cancer with ET may be lower in certain subgroups of women, such as those with lower Gail risk estimates based on age, history of benign breast disease, age of menarche, age of first birth, race/ ethnicity, and mothers and sisters with breast cancer;⁵⁸ women with no first-degree relatives with breast cancer; women without benign breast disease; and women with no prior hormone use.⁴⁵

 

Initiating HT for symptom control in newly menopausal women may provide additional benefits, such as reduced osteoporosis and cardiovascular risk, that outweigh the small risks associated with HT in this younger age group.

Evaluate the relative risks vs benefits, and use the lowest effective dose. Evaluate older women in a similar fashion. Those who continue to experience symptoms after discontinuing HT can be restarted on low-dose HT if symptoms do not abate.

TABLE
Select hormone therapy according to nature and severity of symptoms^5,10,23

Symptoms	Severity	Treatment
2 hot flashes per day	Mild	Exercise Diet Environmental temperature regulation
5-7 hot flashes per day Nighttime awakenings Night sweats/insomnia	Moderate-to-severe	HT for appropriate patients
Vaginal symptoms only (atrophic vaginitis)	Moderate-to-severe	Vaginal estrogen therapy
Osteoporosis	Established reduction in bone mass	Calcium + vitamin D plus bisphosphonate or raloxifene or extended HT for appropriate patients when preceding therapies are not tolerated or not appropriate
Optimal candidates for HT: recently menopausal (<10 years) <60 years of age no risk factors for cardiovascular disease or breast cancer.
HT, hormone therapy.

CORRESPONDENCE Michelle P. Warren, MD, Presbyterian Hospital, 622 West 168th Street, New York, NY 10032; [email protected]

Findings from the Women’s Health Initiative (WHI) and the Heart and Estrogen/progestin Replacement Study^1,2 have left physicians and patients confused about the risks and benefits of hormone therapy (HT) and have dramatically affected prescription patterns.³ After the WHI trial findings were published in 2002,¹ use of HT declined dramatically; many women discontinued therapy or switched to lower doses, while others turned to alternate therapies.⁴ This, despite long-standing evidence that HT administered as estrogen alone (ET; for hysterectomized women) or in combination with progestin (EPT; for nonhysterectomized women) effectively controls menopausal symptoms—hot flashes, vaginal atrophy, insomnia, and sexual problems.⁵

When interpreting results of recent clinical trials, it is important to consider how closely the trial subjects resemble patients in your practice. Patients in HT clinical studies may range from younger women who are newly menopausal to older women who experienced menopause decades ago. Women also have differing risk factors that determine whether HT is appropriate treatment.

Recent reanalyses of WHI data and other studies, as well as new guidelines from the North American Menopause Society (NAMS), have helped to clarify the benefit–risk profile of HT according to patient characteristics. This article places clinical trial evidence in perspective and explains how you can evaluate the benefit–risk profile of HT for individuals.

What are the benefits of HT?

The primary indication for HT is treatment of vasomotor symptoms, which are common at the time of menopause and can diminish quality of life.⁵ The efficacy of HT in alleviating these symptoms is well established.⁶ Hot flash rates are highest in women during the first 2 years postmenopause,⁷ and most women use HT for up to 2 years.⁸ A study of women who had recently become postmenopausal (45-58 years of age) showed a significant reduction in vasomotor symptoms over 5 years with ET/EPT.⁹

Both oral and vaginal ET effectively relieve vaginal dryness.^5,10 A meta-analysis of 10 clinical trials showed that low-dose vaginal ET was as effective as systemic ET in providing relief of the signs and symptoms of urogenital atrophy.¹¹

Nonhormonal treatments are also sometimes prescribed off label to treat vasomotor symptoms for women who cannot or choose not to use estrogens. Such agents include selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors, clonidine, and gabapentin.

A meta-analysis found that these treatments were more effective than placebo in reducing hot flashes in postmenopausal women, but the magnitude of symptom relief with these drugs has been less than that observed with estrogens.¹² In another study, off-label use of antidepressants greatly attenuated hot flashes for some patients.¹³

NAMS recommends that women with moderate-to-severe menopause-related hot flashes who have concerns with, or contraindications to, estrogen-containing treatments, consider other treatments, such as SSRIs or gabapentin;⁷ however, high-quality studies evaluating these therapies in women with moderate-to-severe hot flashes are lacking.¹²

Phytoestrogens such as soy compounds and black cohosh may be helpful, although results have been variable in clinical trials.¹⁴ Common adverse events associated with black cohosh treatment include gastrointestinal complaints and rashes. There have been rare reports of liver toxicity, suggesting the need for further investigation.¹⁵

Protecting bone mass density and reducing risk of fractures
Estrogen therapy. In the WHI study, ET reduced the rates of hip fractures (P=.01), clinical vertebral fractures (P=.02), and total osteoporotic fractures (P<.001).¹⁶ The reduced risk was not affected by patient age.¹⁷ The randomized Women’s Health, Osteoporosis, Progestin, Estrogen (HOPE) study showed protection against early bone loss with ET vs placebo. After 2 years of follow-up, 55% of placebo-treated patients exhibited >2% loss of spine bone-mass density, compared with just 7% of women using ET (0.625 mg/d).¹⁸

Estrogen-progestin therapy. The WHI study^1,19 confirmed the reduced risk of osteoporotic fractures with EPT seen in previous clinical studies, and the Women’s HOPE study¹⁸ confirmed EPT’s protective effect against bone loss. In a meta-analysis of HT studies (most of which used EPT), the benefits associated with HT in fracture prevention were particularly marked in women younger than 60 years,²⁰ although no effect of age or time since menopause was observed in the WHI study.¹⁹ Initiation of EPT soon after menopause has been shown to improve postural balance to levels seen in premenopausal women, which may contribute to protection against fracture.²¹

 

Nonhormonal therapy for bone health. For women who are not candidates for HT, therapeutic options for maintaining bone health include bisphosphonates, raloxifene, teriparatide, and calcitonin.²² In addition to calcium and vitamin D supplementation, the NAMS guidelines recommend bisphosphonates as first-line treatment, followed by raloxifene, for postmenopausal women with low bone mass or younger postmenopausal women with osteoporosis who are at greater risk of spine fracture than hip fracture.²³ Teriparatide is generally reserved for women at high risk of fracture.²³ Calcitonin, typically administered as a nasal spray, is approved for osteoporosis treatment, but not prevention. It is generally considered an alternative for patients who cannot tolerate other therapies.²³ Denosumab, a monoclonal antibody, is a new drug indicated in women at high risk for fracture or who cannot tolerate other therapies.

What are the potential risks of HT?

Risk factors associated with HT relate to a woman’s baseline disease risks: age; age at menopause; cause of menopause; time elapsed since menopause; prior use of any hormone; types, routes of administration, and doses of HT used; and medical conditions emerging during treatment.⁵ When assessing the benefit–risk profile of HT for any patient, take into account the woman’s health profile as well as the chance of harm associated with any particular therapy.

Cardiovascular disease: Timing of HT matters
Estrogen therapy. Although observational studies,^24,25 such as the Nurses’ Health Study, suggest a reduced risk of cardiovascular events with ET, randomized clinical trials^16,26 have shown either no effect or increased risk of cardiovascular disease among women using ET. In the ET arm of the WHI study,^16,26,27 there was an increased risk of stroke and a trend toward increased risk of peripheral arterial disease, but no effect on the incidence of coronary heart disease (including myocardial infarction and coronary death).

The disparity between observational and randomized clinical trial results is now believed to be a result of differences in patient characteristics (particularly age) and timing of initiation of HT in both types of studies.⁵ Demographic or biologic differences influence the effects of HT on cardiovascular risk. This timing hypothesis is supported by data from an observational study,²⁸ meta-analysis of clinical trials,²⁹ secondary analyses from the WHI,³⁰ and a substudy of the WHI (WHI-Coronary Artery Calcium Study).³¹

Estrogen-progestin therapy. As with ET, observational studies^24,25 have indicated a reduced risk of cardiovascular events with EPT, whereas randomized clinical trials^1,26,32 have shown either no effect or increased risk of cardiovascular disease in women using EPT. A recent observational study of women taking primarily EPT (87%; 13% on ET) for a mean duration of 8.3 years found no significant difference in the risk of cardiovascular disease between groups exposed to HT and those unexposed (relative risk, 0.84; 95% confidence interval [CI], 0.16-4.13).³³

The WHI study demonstrated an increase in cardiovascular event risk with EPT, particularly during the first year of treatment.¹ However, when results were adjusted for age and time since menopause, this risk was isolated to women ≥20 years past menopause, contrasting with a trend toward reduced risk of coronary heart disease in women who initiated HT within 10 years of menopause.³⁰

In the Women’s International Study of Long Duration Oestrogen After Menopause (WISDOM), there was a significant increase in the number of major cardiovascular events with EPT vs placebo.³² However, as in the original WHI study, most women in the WISDOM study were age 65 or older and thus did not fall into the younger age category that experiences cardiovascular benefit from HT.

Influence of age on cardiovascular risk. In the WHI and WISDOM studies,^1,16,32 women tended to be at least 10 years postmenopause, whereas the observational studies included younger women who started HT sooner after menopause. The WHI data have shown no increased risk of cardiovascular disease with ET overall and have shown lower coronary artery disease risk in women ages 50 to 59 years.²⁶ There was also a trend for reduced cardiovascular risk with EPT among women who were up to 10 years postmenopause.³⁰

In a meta-analysis³⁴ of randomized studies, there was a reduction in the risk of cardiovascular events with HT in women younger than 60 years, but an increased risk of events during the first year of treatment in older women. HT has been associated with reduced blood pressure in women who are <5 years postmenopause but not in women ≥5 years postmenopause.³⁵ Thus, the data appear to support the hypothesis of a “therapeutic window” during which ET or EPT may be cardioprotective in younger, newly menopausal women, and an increased risk for cardiovascular disease with EPT, principally confined to older women at an increased distance from menopause.

 

Thromboembolism: Patient age makes a difference
Estrogen therapy. Observational data from the UK General Practice Research Database, which included women ages 55 to 79 years, demonstrated a reduced risk of deep vein thrombosis (P=.008) and a trend toward reduced risk of venous thromboembolism (VTE; P=.057) among users of ET.³⁶ However, the ET arm of the WHI showed an early increased risk of venous thrombosis, particularly within the first 2 years of use.³⁷ The absolute incidence of VTE (including deep vein thrombosis and pulmonary embolism) was relatively low in the study, and risk of pulmonary embolism alone was not significantly different from that seen with placebo; however, the use of conjugated estrogens did increase the relative risk of VTE in postmenopausal women without a uterus. Risk also increased with obesity.³⁷

Estrogen-progestin therapy. The WHI study demonstrated an increased risk of VTE with EPT compared with placebo, the risk increasing with advancing age and obesity.³⁸ In addition, the risk of VTE was significantly greater with EPT than with ET in the same study.³⁷ In women younger than 60 years, the projected 5-year risk associated with EPT was 1.4% in obese women, compared with less than 0.5% in women of normal weight. In the WISDOM study, which involved women older than 65 years, there was a significant increase in VTE incidence with EPT vs placebo (hazard ratio [HR], 7.36; 95% CI, 2.20-24.60).³²

Thrombotic risk in perspective. The risk of VTE is an important determinant of the benefit–risk profile when prescribing HT. Data from observational and randomized trials have shown an increased risk of VTE with oral HT.^5,39 In women with preexisting cardiovascular disease, the use of statins appeared to negate the increased risk of thromboembolism with EPT.⁴⁰ In the WHI trials, the absolute VTE risk associated with either EPT (7 per 10,000 women per year of use) or ET (4 per 10,000 women per year of use) in women younger than 60 years was lower than in older women³⁷—and considered rare by NAMS consensus. Thus, for otherwise healthy newly menopausal women younger than 60 years, carefully consider the benefits of ET or EPT against the negligible risk of thromboembolism.

Limited observational data suggest lower risks of VTE with transdermal ET compared with oral ET,⁴¹ but there is no conclusive evidence from randomized controlled trials on this subject.⁵ Low-dose oral and transdermal formulations may provide promising routes of administration, pending further studies. Evidence suggests that women with a history of VTE or women who have factor V Leiden are at increased risk for VTE with HT use.³⁹ Use caution, therefore, when considering HT in women at higher risk of VTE, such as those with prior VTE or thrombogenic mutations, those undergoing surgery, or those who are immobilized.³⁹

Estrogen therapy. Observational studies have suggested an increased incidence of breast cancer among women using ET for more than 1 year, with the risk increasing as use continues.36,42 In contrast, results of the WHI study showed that invasive breast cancer was diagnosed at a 23% lower rate in the ET group than in the placebo group, although this difference did not reach statistical significance (P=.06).16 The Women’s Health Study showed no association between current use of ET and the risk of total breast cancer or invasive breast cancer.43 The degree of breast cancer risk may depend on dose, as a meta-analysis of studies showed no increase in breast cancer risk with use of ET at ≤0.625 mg/d.44 In addition, the incidence of breast cancer has been shown to be lower in women who do not have benign breast disease or first-degree relatives with breast cancer.45

Estrogen-progestin therapy. Observational studies have shown an increased risk of breast cancer with EPT.^42,46 In the WHI study, there was a significantly increased relative risk of invasive breast cancer in women receiving EPT over a follow-up of 5.6 years (HR, 1.24; 95% CI, 1.02-1.50).⁴⁷ However, some have noted that the observed increase in the incidence of invasive breast cancer in the EPT arm vs placebo was not statistically significant and could have resulted from chance alone.⁴⁸ A recent analysis of breast cancer incidence in the United States found a sharp decrease from 2002 to 2003,⁴⁹ suggesting that breast cancer risk diminished soon after discontinuation of EPT for many women following the publication of the WHI results.

 

A newly published WHI follow-up study has yielded similar findings regarding the incidence of invasive breast cancer with EPT. The small increase in cancer incidence compared with placebo was associated with positive nodes and the death rate in this group was also higher (2.6 deaths vs 1.3 per 10,000 women). These findings do not apply to ET alone.⁵⁰

Breast cancer risk in perspective. When interpreting increased risk, consider the absolute risk. In the WHI study, the absolute risk of invasive breast cancer increased by 4 to 6 cases per 10,000 women per year in the EPT group vs placebo.⁴⁷ Similarly, a systematic review of clinical studies showed that EPT was associated with an increase of 4 breast cancer cases per 10,000 women per year.⁵¹ The increased risk of breast cancer with combined EPT is similar to that associated with early menarche or late menopause and is smaller than that associated with nulliparity or having children after 30 years of age.⁵²

Assessing risks and benefits for the potential HT patient

The first step in treating patients who have hot flashes is to determine the extent of their symptoms and the effect on their quality of life (TABLE).^5,10,23 Two hot flashes a day is considered mild and will usually respond to lifestyle measures such as exercising, avoiding alcohol and spicy foods, and staying in a cool environment. If the patient wakes in the night with hot flashes and night sweats that lead to insomnia, this may be more serious and require treatment. Consider HT for moderate-to-severe hot flashes—ie, 5 to 7 a day. HT is the only pharmacologic therapy indicated for the treatment of hot flashes.

Although professional guidelines recommend appropriate use of HT, publication of the WHI study caused many patients to mistrust and fear hormonal approaches to managing menopausal symptoms.^3,4,53 Among those who discontinued HT, many have had vasomotor symptoms recur, and some patients remain untreated.⁵³ A thorough discussion of individual needs and risk factors can help assess whether a patient is a suitable candidate for HT, and patient education and counseling may help alleviate concerns.⁵⁴

When considering HT for a patient, take into account risk factors, such as baseline disease, age at menopause, cause of menopause, prior hormone use, variations in HT used, and age and time elapsed since menopause.⁵ An individual’s risks for cardiovascular disease, breast cancer, and osteoporotic fractures will help determine the most appropriate treatment.⁵⁵ In the WHI, symptomatic women who were younger and closer to the menopausal transition experienced the greatest relief of vasomotor symptoms with EPT and were less likely to experience adverse effects compared with older women.⁵⁶ The WHI data also showed that the prevalence of menopausal symptoms decreased with increasing age, occurring most commonly in women ages 50 to 54 years.⁵⁶ The WHI findings have been shown to apply to HT regimens in general.⁵⁷

Specific recommendations. Current prescribing guidelines⁵ recommend using ET/EPT to treat moderate-to-severe vasomotor symptoms associated with menopause when the benefits of short-term therapy outweigh the risks. For women who experience mainly vaginal symptoms rather than vasomotor symptoms, vaginal ET is recommended.

HT is not recommended for coronary protection in women of any age, as there is evidence that use in older women increases the risk of cardiovascular events.⁵ However, HT does not appear to increase the risk of CV events if initiated by women ages 50 to 59 years or by those within 10 years of menopause. There is evidence of an increased risk of VTE with oral HT, although absolute risk is low in women ages 50 to 59 years.⁵

To prevent further bone loss and reduce the risk of osteoporotic fracture in women with established reduction in bone mass, the guidelines recommend extended use of HT, regardless of menopausal symptoms, when alternate therapies are not appropriate or cause side effects or when the safety and hazards of extended use of alternate therapies are not well established.⁵

Breast cancer risk increases with EPT use beyond 3 to 5 years, although the absolute risk is still considered rare.⁵ Clinical evidence, including findings from the WHI study¹⁶ and the Women’s Health Study,⁴³ shows no increase in the risk of breast cancer in women receiving ET. Further, the risk of breast cancer with ET may be lower in certain subgroups of women, such as those with lower Gail risk estimates based on age, history of benign breast disease, age of menarche, age of first birth, race/ ethnicity, and mothers and sisters with breast cancer;⁵⁸ women with no first-degree relatives with breast cancer; women without benign breast disease; and women with no prior hormone use.⁴⁵

 

Initiating HT for symptom control in newly menopausal women may provide additional benefits, such as reduced osteoporosis and cardiovascular risk, that outweigh the small risks associated with HT in this younger age group.

Evaluate the relative risks vs benefits, and use the lowest effective dose. Evaluate older women in a similar fashion. Those who continue to experience symptoms after discontinuing HT can be restarted on low-dose HT if symptoms do not abate.

TABLE
Select hormone therapy according to nature and severity of symptoms^5,10,23

Symptoms	Severity	Treatment
2 hot flashes per day	Mild	Exercise Diet Environmental temperature regulation
5-7 hot flashes per day Nighttime awakenings Night sweats/insomnia	Moderate-to-severe	HT for appropriate patients
Vaginal symptoms only (atrophic vaginitis)	Moderate-to-severe	Vaginal estrogen therapy
Osteoporosis	Established reduction in bone mass	Calcium + vitamin D plus bisphosphonate or raloxifene or extended HT for appropriate patients when preceding therapies are not tolerated or not appropriate
Optimal candidates for HT: recently menopausal (<10 years) <60 years of age no risk factors for cardiovascular disease or breast cancer.
HT, hormone therapy.

CORRESPONDENCE Michelle P. Warren, MD, Presbyterian Hospital, 622 West 168th Street, New York, NY 10032; [email protected]

Findings from the Women’s Health Initiative (WHI) and the Heart and Estrogen/progestin Replacement Study^1,2 have left physicians and patients confused about the risks and benefits of hormone therapy (HT) and have dramatically affected prescription patterns.³ After the WHI trial findings were published in 2002,¹ use of HT declined dramatically; many women discontinued therapy or switched to lower doses, while others turned to alternate therapies.⁴ This, despite long-standing evidence that HT administered as estrogen alone (ET; for hysterectomized women) or in combination with progestin (EPT; for nonhysterectomized women) effectively controls menopausal symptoms—hot flashes, vaginal atrophy, insomnia, and sexual problems.⁵

When interpreting results of recent clinical trials, it is important to consider how closely the trial subjects resemble patients in your practice. Patients in HT clinical studies may range from younger women who are newly menopausal to older women who experienced menopause decades ago. Women also have differing risk factors that determine whether HT is appropriate treatment.

Recent reanalyses of WHI data and other studies, as well as new guidelines from the North American Menopause Society (NAMS), have helped to clarify the benefit–risk profile of HT according to patient characteristics. This article places clinical trial evidence in perspective and explains how you can evaluate the benefit–risk profile of HT for individuals.

What are the benefits of HT?

The primary indication for HT is treatment of vasomotor symptoms, which are common at the time of menopause and can diminish quality of life.⁵ The efficacy of HT in alleviating these symptoms is well established.⁶ Hot flash rates are highest in women during the first 2 years postmenopause,⁷ and most women use HT for up to 2 years.⁸ A study of women who had recently become postmenopausal (45-58 years of age) showed a significant reduction in vasomotor symptoms over 5 years with ET/EPT.⁹

Both oral and vaginal ET effectively relieve vaginal dryness.^5,10 A meta-analysis of 10 clinical trials showed that low-dose vaginal ET was as effective as systemic ET in providing relief of the signs and symptoms of urogenital atrophy.¹¹

Nonhormonal treatments are also sometimes prescribed off label to treat vasomotor symptoms for women who cannot or choose not to use estrogens. Such agents include selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors, clonidine, and gabapentin.

A meta-analysis found that these treatments were more effective than placebo in reducing hot flashes in postmenopausal women, but the magnitude of symptom relief with these drugs has been less than that observed with estrogens.¹² In another study, off-label use of antidepressants greatly attenuated hot flashes for some patients.¹³

NAMS recommends that women with moderate-to-severe menopause-related hot flashes who have concerns with, or contraindications to, estrogen-containing treatments, consider other treatments, such as SSRIs or gabapentin;⁷ however, high-quality studies evaluating these therapies in women with moderate-to-severe hot flashes are lacking.¹²

Phytoestrogens such as soy compounds and black cohosh may be helpful, although results have been variable in clinical trials.¹⁴ Common adverse events associated with black cohosh treatment include gastrointestinal complaints and rashes. There have been rare reports of liver toxicity, suggesting the need for further investigation.¹⁵

Protecting bone mass density and reducing risk of fractures
Estrogen therapy. In the WHI study, ET reduced the rates of hip fractures (P=.01), clinical vertebral fractures (P=.02), and total osteoporotic fractures (P<.001).¹⁶ The reduced risk was not affected by patient age.¹⁷ The randomized Women’s Health, Osteoporosis, Progestin, Estrogen (HOPE) study showed protection against early bone loss with ET vs placebo. After 2 years of follow-up, 55% of placebo-treated patients exhibited >2% loss of spine bone-mass density, compared with just 7% of women using ET (0.625 mg/d).¹⁸

Estrogen-progestin therapy. The WHI study^1,19 confirmed the reduced risk of osteoporotic fractures with EPT seen in previous clinical studies, and the Women’s HOPE study¹⁸ confirmed EPT’s protective effect against bone loss. In a meta-analysis of HT studies (most of which used EPT), the benefits associated with HT in fracture prevention were particularly marked in women younger than 60 years,²⁰ although no effect of age or time since menopause was observed in the WHI study.¹⁹ Initiation of EPT soon after menopause has been shown to improve postural balance to levels seen in premenopausal women, which may contribute to protection against fracture.²¹

 

Nonhormonal therapy for bone health. For women who are not candidates for HT, therapeutic options for maintaining bone health include bisphosphonates, raloxifene, teriparatide, and calcitonin.²² In addition to calcium and vitamin D supplementation, the NAMS guidelines recommend bisphosphonates as first-line treatment, followed by raloxifene, for postmenopausal women with low bone mass or younger postmenopausal women with osteoporosis who are at greater risk of spine fracture than hip fracture.²³ Teriparatide is generally reserved for women at high risk of fracture.²³ Calcitonin, typically administered as a nasal spray, is approved for osteoporosis treatment, but not prevention. It is generally considered an alternative for patients who cannot tolerate other therapies.²³ Denosumab, a monoclonal antibody, is a new drug indicated in women at high risk for fracture or who cannot tolerate other therapies.

What are the potential risks of HT?

Risk factors associated with HT relate to a woman’s baseline disease risks: age; age at menopause; cause of menopause; time elapsed since menopause; prior use of any hormone; types, routes of administration, and doses of HT used; and medical conditions emerging during treatment.⁵ When assessing the benefit–risk profile of HT for any patient, take into account the woman’s health profile as well as the chance of harm associated with any particular therapy.

Cardiovascular disease: Timing of HT matters
Estrogen therapy. Although observational studies,^24,25 such as the Nurses’ Health Study, suggest a reduced risk of cardiovascular events with ET, randomized clinical trials^16,26 have shown either no effect or increased risk of cardiovascular disease among women using ET. In the ET arm of the WHI study,^16,26,27 there was an increased risk of stroke and a trend toward increased risk of peripheral arterial disease, but no effect on the incidence of coronary heart disease (including myocardial infarction and coronary death).

The disparity between observational and randomized clinical trial results is now believed to be a result of differences in patient characteristics (particularly age) and timing of initiation of HT in both types of studies.⁵ Demographic or biologic differences influence the effects of HT on cardiovascular risk. This timing hypothesis is supported by data from an observational study,²⁸ meta-analysis of clinical trials,²⁹ secondary analyses from the WHI,³⁰ and a substudy of the WHI (WHI-Coronary Artery Calcium Study).³¹

Estrogen-progestin therapy. As with ET, observational studies^24,25 have indicated a reduced risk of cardiovascular events with EPT, whereas randomized clinical trials^1,26,32 have shown either no effect or increased risk of cardiovascular disease in women using EPT. A recent observational study of women taking primarily EPT (87%; 13% on ET) for a mean duration of 8.3 years found no significant difference in the risk of cardiovascular disease between groups exposed to HT and those unexposed (relative risk, 0.84; 95% confidence interval [CI], 0.16-4.13).³³

The WHI study demonstrated an increase in cardiovascular event risk with EPT, particularly during the first year of treatment.¹ However, when results were adjusted for age and time since menopause, this risk was isolated to women ≥20 years past menopause, contrasting with a trend toward reduced risk of coronary heart disease in women who initiated HT within 10 years of menopause.³⁰

In the Women’s International Study of Long Duration Oestrogen After Menopause (WISDOM), there was a significant increase in the number of major cardiovascular events with EPT vs placebo.³² However, as in the original WHI study, most women in the WISDOM study were age 65 or older and thus did not fall into the younger age category that experiences cardiovascular benefit from HT.

Influence of age on cardiovascular risk. In the WHI and WISDOM studies,^1,16,32 women tended to be at least 10 years postmenopause, whereas the observational studies included younger women who started HT sooner after menopause. The WHI data have shown no increased risk of cardiovascular disease with ET overall and have shown lower coronary artery disease risk in women ages 50 to 59 years.²⁶ There was also a trend for reduced cardiovascular risk with EPT among women who were up to 10 years postmenopause.³⁰

In a meta-analysis³⁴ of randomized studies, there was a reduction in the risk of cardiovascular events with HT in women younger than 60 years, but an increased risk of events during the first year of treatment in older women. HT has been associated with reduced blood pressure in women who are <5 years postmenopause but not in women ≥5 years postmenopause.³⁵ Thus, the data appear to support the hypothesis of a “therapeutic window” during which ET or EPT may be cardioprotective in younger, newly menopausal women, and an increased risk for cardiovascular disease with EPT, principally confined to older women at an increased distance from menopause.

 

Thromboembolism: Patient age makes a difference
Estrogen therapy. Observational data from the UK General Practice Research Database, which included women ages 55 to 79 years, demonstrated a reduced risk of deep vein thrombosis (P=.008) and a trend toward reduced risk of venous thromboembolism (VTE; P=.057) among users of ET.³⁶ However, the ET arm of the WHI showed an early increased risk of venous thrombosis, particularly within the first 2 years of use.³⁷ The absolute incidence of VTE (including deep vein thrombosis and pulmonary embolism) was relatively low in the study, and risk of pulmonary embolism alone was not significantly different from that seen with placebo; however, the use of conjugated estrogens did increase the relative risk of VTE in postmenopausal women without a uterus. Risk also increased with obesity.³⁷

Estrogen-progestin therapy. The WHI study demonstrated an increased risk of VTE with EPT compared with placebo, the risk increasing with advancing age and obesity.³⁸ In addition, the risk of VTE was significantly greater with EPT than with ET in the same study.³⁷ In women younger than 60 years, the projected 5-year risk associated with EPT was 1.4% in obese women, compared with less than 0.5% in women of normal weight. In the WISDOM study, which involved women older than 65 years, there was a significant increase in VTE incidence with EPT vs placebo (hazard ratio [HR], 7.36; 95% CI, 2.20-24.60).³²

Thrombotic risk in perspective. The risk of VTE is an important determinant of the benefit–risk profile when prescribing HT. Data from observational and randomized trials have shown an increased risk of VTE with oral HT.^5,39 In women with preexisting cardiovascular disease, the use of statins appeared to negate the increased risk of thromboembolism with EPT.⁴⁰ In the WHI trials, the absolute VTE risk associated with either EPT (7 per 10,000 women per year of use) or ET (4 per 10,000 women per year of use) in women younger than 60 years was lower than in older women³⁷—and considered rare by NAMS consensus. Thus, for otherwise healthy newly menopausal women younger than 60 years, carefully consider the benefits of ET or EPT against the negligible risk of thromboembolism.

Limited observational data suggest lower risks of VTE with transdermal ET compared with oral ET,⁴¹ but there is no conclusive evidence from randomized controlled trials on this subject.⁵ Low-dose oral and transdermal formulations may provide promising routes of administration, pending further studies. Evidence suggests that women with a history of VTE or women who have factor V Leiden are at increased risk for VTE with HT use.³⁹ Use caution, therefore, when considering HT in women at higher risk of VTE, such as those with prior VTE or thrombogenic mutations, those undergoing surgery, or those who are immobilized.³⁹

Estrogen therapy. Observational studies have suggested an increased incidence of breast cancer among women using ET for more than 1 year, with the risk increasing as use continues.36,42 In contrast, results of the WHI study showed that invasive breast cancer was diagnosed at a 23% lower rate in the ET group than in the placebo group, although this difference did not reach statistical significance (P=.06).16 The Women’s Health Study showed no association between current use of ET and the risk of total breast cancer or invasive breast cancer.43 The degree of breast cancer risk may depend on dose, as a meta-analysis of studies showed no increase in breast cancer risk with use of ET at ≤0.625 mg/d.44 In addition, the incidence of breast cancer has been shown to be lower in women who do not have benign breast disease or first-degree relatives with breast cancer.45

Estrogen-progestin therapy. Observational studies have shown an increased risk of breast cancer with EPT.^42,46 In the WHI study, there was a significantly increased relative risk of invasive breast cancer in women receiving EPT over a follow-up of 5.6 years (HR, 1.24; 95% CI, 1.02-1.50).⁴⁷ However, some have noted that the observed increase in the incidence of invasive breast cancer in the EPT arm vs placebo was not statistically significant and could have resulted from chance alone.⁴⁸ A recent analysis of breast cancer incidence in the United States found a sharp decrease from 2002 to 2003,⁴⁹ suggesting that breast cancer risk diminished soon after discontinuation of EPT for many women following the publication of the WHI results.

 

A newly published WHI follow-up study has yielded similar findings regarding the incidence of invasive breast cancer with EPT. The small increase in cancer incidence compared with placebo was associated with positive nodes and the death rate in this group was also higher (2.6 deaths vs 1.3 per 10,000 women). These findings do not apply to ET alone.⁵⁰

Breast cancer risk in perspective. When interpreting increased risk, consider the absolute risk. In the WHI study, the absolute risk of invasive breast cancer increased by 4 to 6 cases per 10,000 women per year in the EPT group vs placebo.⁴⁷ Similarly, a systematic review of clinical studies showed that EPT was associated with an increase of 4 breast cancer cases per 10,000 women per year.⁵¹ The increased risk of breast cancer with combined EPT is similar to that associated with early menarche or late menopause and is smaller than that associated with nulliparity or having children after 30 years of age.⁵²

Assessing risks and benefits for the potential HT patient

The first step in treating patients who have hot flashes is to determine the extent of their symptoms and the effect on their quality of life (TABLE).^5,10,23 Two hot flashes a day is considered mild and will usually respond to lifestyle measures such as exercising, avoiding alcohol and spicy foods, and staying in a cool environment. If the patient wakes in the night with hot flashes and night sweats that lead to insomnia, this may be more serious and require treatment. Consider HT for moderate-to-severe hot flashes—ie, 5 to 7 a day. HT is the only pharmacologic therapy indicated for the treatment of hot flashes.

Although professional guidelines recommend appropriate use of HT, publication of the WHI study caused many patients to mistrust and fear hormonal approaches to managing menopausal symptoms.^3,4,53 Among those who discontinued HT, many have had vasomotor symptoms recur, and some patients remain untreated.⁵³ A thorough discussion of individual needs and risk factors can help assess whether a patient is a suitable candidate for HT, and patient education and counseling may help alleviate concerns.⁵⁴

When considering HT for a patient, take into account risk factors, such as baseline disease, age at menopause, cause of menopause, prior hormone use, variations in HT used, and age and time elapsed since menopause.⁵ An individual’s risks for cardiovascular disease, breast cancer, and osteoporotic fractures will help determine the most appropriate treatment.⁵⁵ In the WHI, symptomatic women who were younger and closer to the menopausal transition experienced the greatest relief of vasomotor symptoms with EPT and were less likely to experience adverse effects compared with older women.⁵⁶ The WHI data also showed that the prevalence of menopausal symptoms decreased with increasing age, occurring most commonly in women ages 50 to 54 years.⁵⁶ The WHI findings have been shown to apply to HT regimens in general.⁵⁷

Specific recommendations. Current prescribing guidelines⁵ recommend using ET/EPT to treat moderate-to-severe vasomotor symptoms associated with menopause when the benefits of short-term therapy outweigh the risks. For women who experience mainly vaginal symptoms rather than vasomotor symptoms, vaginal ET is recommended.

HT is not recommended for coronary protection in women of any age, as there is evidence that use in older women increases the risk of cardiovascular events.⁵ However, HT does not appear to increase the risk of CV events if initiated by women ages 50 to 59 years or by those within 10 years of menopause. There is evidence of an increased risk of VTE with oral HT, although absolute risk is low in women ages 50 to 59 years.⁵

To prevent further bone loss and reduce the risk of osteoporotic fracture in women with established reduction in bone mass, the guidelines recommend extended use of HT, regardless of menopausal symptoms, when alternate therapies are not appropriate or cause side effects or when the safety and hazards of extended use of alternate therapies are not well established.⁵

Breast cancer risk increases with EPT use beyond 3 to 5 years, although the absolute risk is still considered rare.⁵ Clinical evidence, including findings from the WHI study¹⁶ and the Women’s Health Study,⁴³ shows no increase in the risk of breast cancer in women receiving ET. Further, the risk of breast cancer with ET may be lower in certain subgroups of women, such as those with lower Gail risk estimates based on age, history of benign breast disease, age of menarche, age of first birth, race/ ethnicity, and mothers and sisters with breast cancer;⁵⁸ women with no first-degree relatives with breast cancer; women without benign breast disease; and women with no prior hormone use.⁴⁵

 

Initiating HT for symptom control in newly menopausal women may provide additional benefits, such as reduced osteoporosis and cardiovascular risk, that outweigh the small risks associated with HT in this younger age group.

Evaluate the relative risks vs benefits, and use the lowest effective dose. Evaluate older women in a similar fashion. Those who continue to experience symptoms after discontinuing HT can be restarted on low-dose HT if symptoms do not abate.

TABLE
Select hormone therapy according to nature and severity of symptoms^5,10,23

Symptoms	Severity	Treatment
2 hot flashes per day	Mild	Exercise Diet Environmental temperature regulation
5-7 hot flashes per day Nighttime awakenings Night sweats/insomnia	Moderate-to-severe	HT for appropriate patients
Vaginal symptoms only (atrophic vaginitis)	Moderate-to-severe	Vaginal estrogen therapy
Osteoporosis	Established reduction in bone mass	Calcium + vitamin D plus bisphosphonate or raloxifene or extended HT for appropriate patients when preceding therapies are not tolerated or not appropriate
Optimal candidates for HT: recently menopausal (<10 years) <60 years of age no risk factors for cardiovascular disease or breast cancer.
HT, hormone therapy.

CORRESPONDENCE Michelle P. Warren, MD, Presbyterian Hospital, 622 West 168th Street, New York, NY 10032; [email protected]

Being in practice for 42 years was like running a marathon. Things seem easy and pleasant at first, but then as time goes by, you hit the “wall” and you feel like you can’t go on. “It’s just too hard,” you think. And you wonder: “What am I doing here?”

In an actual marathon, you hit that wall somewhere around the 20-mile mark. (At least that’s what my son tells me.) But in my family medicine practice, I hit the wall at the 10-year mark.

If, like me, you decide not to quit, the endorphins kick in. You feel a high and know you could go on like this forever. You wonder to yourself: “Can life really be this good?”

And then, as the years pass by, you and your patients change and you know the race is coming to an end. It’s time to stop running. Yet, there are many losses in giving up practice. After spending nearly a lifetime as a doctor, it’s hard to give up that identity. That’s who you are, and who you have been.

In my case, I saw the doctor-patient relationship as a “covenant, not a contract,” as Gayle Stephens, MD, described it, and my role as a physician was to prescribe myself as my most potent therapy, as taught by Michael Balint.¹

David Loxterkamp has written about “being there” as the prime service of the family doctor.² But in retiring you are not there—at least not the way you once were.

How about lunch, doc?

When I retired 5 years ago, many patients wanted to “go out to lunch” or in some way maintain our relationship. I avoided this, saying that I thought it was important for them to develop a relationship with their new doctor. This was (and is) true, but I’ve come to realize that it is not the most important reason to pass on such invitations.

Lovers breaking up say they can “still be friends,” even though they know that is impossible. They can neither give up the special feelings they have had, nor the memories of those feelings that will always be a relevant part of their lives. Similarly, I have too much invested in these relationships to “just be friends.”

Moving on
I have moved on. My wife of 52 years and I travel and visit our children and grandchildren. I take and teach classes at a program for retired people. I have more free time than I have ever had, and I don’t miss the constant sense of responsibility for others, or the time spent agonizing over mistakes. But it was the right time to leave practice when technological advancements were accelerating at lightning speed, and my energy level was no longer keeping pace.

Mixed emotions when I talk to patients

Despite not wanting to have lunch with my former patients, I must confess that I periodically call some of them to see how they are doing. I realize that it is really more for me than for them—but I try not to make that obvious. Our conversations leave me with such mixed emotions.

Feeling guilty
Bob and his family were patients of mine almost from the day I started. I attended their daughters’ weddings, shared in their tragedies, cared for multiple illnesses, and counseled the children. When Bob was diagnosed with Alzheimer’s disease, I told him it was very early and we would go through it together and learn from each other. Then I retired.

I know through my conversations with him and his family that he has gone on with good care. But he has gone on without me.

I feel guilty.

I realize that some of this is ego—a loss of importance. But mainly I feel badly that I am not fulfilling that promise I made to him. And I have “cheated” myself out of the pleasure of learning and giving.

Feeling incomplete
I was particularly close with Marylou and her family. I attended birthday parties, cared for her and her husband’s chronic illnesses, supported them through the illness and death of their daughter, and listened when that’s all I could do. Last year, Marylou called me when she was diagnosed with breast cancer. I stayed in touch and expressed my pleasure when she did well. But, I wasn’t involved in the therapy decisions and I wasn’t there when it was time to cry or talk to the family.

 

It made me feel incomplete.

Feeling humbled
Recently I got a letter from a urologist regarding a former patient of mine, Robin.

Robin was diagnosed with prostate cancer about 10 years ago, when I was still his physician. Obviously, the new urologist didn’t know that I had retired. So I forwarded the note to Robin’s new family physician and called Robin to see how he was.

I still felt a tremendous sense of responsibility for Robin’s diagnosis. I had never screened him for prostate cancer. But as he reminded me at the time of his diagnosis, he and I had discussed screening. It’s just that Robin, who knows much about medicine and was always involved in his own decisions, had chosen not to pursue it.

Now 10 years later, Robin and I were catching up. As we talked, Robin revealed that he had multiple complications requiring permanent catheters and that he’d had to give up work.

“I wish you were still in practice,” he said to me. “I miss our talks.”

With that, I felt humbled.

Talking to Robin got me thinking. As doctors, we spend so much time worrying about doing the right thing and giving the right advice that we sometimes forget that we need to have confidence in our patients and their ability to make their own decisions. We need to know when to let go.

“Being there”
Jane was another person who emerged from my professional past. I had known her for years. Not only was she my patient, but I saw her when she came in with her father, sister, and mother for their appointments. Together, we had cared for her family members through their illnesses and deaths.

One day after my retirement, she called to get some advice for a problem she was having with her stepson. I listened, gave some suggestions about whom to see, and offered to stay in touch. She thanked me, saying she didn’t know who else to call.

I hung up thinking how hard it is to “be there” when you are not there.

Jane’s call reminded me of a lesson I’d given years ago to a class of first-year medical students. I had brought in a patient of mine and together, in front of the class, we discussed the doctor-patient relationship.

I asked my patient what was most important about our relationship. She said that when she was diagnosed with diabetes, I gave her my private home phone number.

I responded, “Mrs. E, in our 15 years together, how many times have you used that number?”

“None,” was her reply.

Med students, take note

I really don’t know if my retirement has been easier for my patients than for me. I certainly hope so. Part of my job was to encourage their independence and self-sufficiency. My emotional dependence on them is my problem and I suspect one that is not that uncommon among doctors. I am still teaching and doing some research. Some of my retired friends still go to grand rounds and travel to medical meetings, even though they don’t see any patients.

I have few regrets in retiring from my practice. It was the right thing to do at the right time. Do I miss it every day? Yes, but I also feel so lucky to have worked as a family physician for 42 years.

I once heard a British family physician define the family doctor as someone you can go to and talk to about anything you want. To me, the family doctor is someone who knows you—really knows you—in a way that no one else does. A family doctor is someone who can cry with a patient about a loss, not because the physician can appreciate the loss, but because the patient’s loss is the physician’s loss, too.

I wish more young medical students understood the depth of the connections we make as family physicians, and just how rewarding the work can be. If they did, there would certainly be more students choosing a career in family medicine.

Acknowledgement
I thank Nancy W. Merenstein, the first reader of everything I write and my constant supporter; Paula Preisach, manager and organizer of my academic career; and Jonathan Han, MD, David Loxterkamp, MD, Jennifer Middleton, MD, MPH, and Allen Shaughnessy, PharmD, for helpful comments and suggestions on earlier drafts of this paper.

 

CORRESPONDENCE
Joel H. Merenstein, MD, UPMC St. Margaret, 3937 Butler Street, Pittsburgh, PA 15201; [email protected]

Being in practice for 42 years was like running a marathon. Things seem easy and pleasant at first, but then as time goes by, you hit the “wall” and you feel like you can’t go on. “It’s just too hard,” you think. And you wonder: “What am I doing here?”

In an actual marathon, you hit that wall somewhere around the 20-mile mark. (At least that’s what my son tells me.) But in my family medicine practice, I hit the wall at the 10-year mark.

If, like me, you decide not to quit, the endorphins kick in. You feel a high and know you could go on like this forever. You wonder to yourself: “Can life really be this good?”

And then, as the years pass by, you and your patients change and you know the race is coming to an end. It’s time to stop running. Yet, there are many losses in giving up practice. After spending nearly a lifetime as a doctor, it’s hard to give up that identity. That’s who you are, and who you have been.

In my case, I saw the doctor-patient relationship as a “covenant, not a contract,” as Gayle Stephens, MD, described it, and my role as a physician was to prescribe myself as my most potent therapy, as taught by Michael Balint.¹

David Loxterkamp has written about “being there” as the prime service of the family doctor.² But in retiring you are not there—at least not the way you once were.

How about lunch, doc?

When I retired 5 years ago, many patients wanted to “go out to lunch” or in some way maintain our relationship. I avoided this, saying that I thought it was important for them to develop a relationship with their new doctor. This was (and is) true, but I’ve come to realize that it is not the most important reason to pass on such invitations.

Lovers breaking up say they can “still be friends,” even though they know that is impossible. They can neither give up the special feelings they have had, nor the memories of those feelings that will always be a relevant part of their lives. Similarly, I have too much invested in these relationships to “just be friends.”

Moving on
I have moved on. My wife of 52 years and I travel and visit our children and grandchildren. I take and teach classes at a program for retired people. I have more free time than I have ever had, and I don’t miss the constant sense of responsibility for others, or the time spent agonizing over mistakes. But it was the right time to leave practice when technological advancements were accelerating at lightning speed, and my energy level was no longer keeping pace.

Mixed emotions when I talk to patients

Despite not wanting to have lunch with my former patients, I must confess that I periodically call some of them to see how they are doing. I realize that it is really more for me than for them—but I try not to make that obvious. Our conversations leave me with such mixed emotions.

Feeling guilty
Bob and his family were patients of mine almost from the day I started. I attended their daughters’ weddings, shared in their tragedies, cared for multiple illnesses, and counseled the children. When Bob was diagnosed with Alzheimer’s disease, I told him it was very early and we would go through it together and learn from each other. Then I retired.

I know through my conversations with him and his family that he has gone on with good care. But he has gone on without me.

I feel guilty.

I realize that some of this is ego—a loss of importance. But mainly I feel badly that I am not fulfilling that promise I made to him. And I have “cheated” myself out of the pleasure of learning and giving.

Feeling incomplete
I was particularly close with Marylou and her family. I attended birthday parties, cared for her and her husband’s chronic illnesses, supported them through the illness and death of their daughter, and listened when that’s all I could do. Last year, Marylou called me when she was diagnosed with breast cancer. I stayed in touch and expressed my pleasure when she did well. But, I wasn’t involved in the therapy decisions and I wasn’t there when it was time to cry or talk to the family.

 

It made me feel incomplete.

Feeling humbled
Recently I got a letter from a urologist regarding a former patient of mine, Robin.

Robin was diagnosed with prostate cancer about 10 years ago, when I was still his physician. Obviously, the new urologist didn’t know that I had retired. So I forwarded the note to Robin’s new family physician and called Robin to see how he was.

I still felt a tremendous sense of responsibility for Robin’s diagnosis. I had never screened him for prostate cancer. But as he reminded me at the time of his diagnosis, he and I had discussed screening. It’s just that Robin, who knows much about medicine and was always involved in his own decisions, had chosen not to pursue it.

Now 10 years later, Robin and I were catching up. As we talked, Robin revealed that he had multiple complications requiring permanent catheters and that he’d had to give up work.

“I wish you were still in practice,” he said to me. “I miss our talks.”

With that, I felt humbled.

Talking to Robin got me thinking. As doctors, we spend so much time worrying about doing the right thing and giving the right advice that we sometimes forget that we need to have confidence in our patients and their ability to make their own decisions. We need to know when to let go.

“Being there”
Jane was another person who emerged from my professional past. I had known her for years. Not only was she my patient, but I saw her when she came in with her father, sister, and mother for their appointments. Together, we had cared for her family members through their illnesses and deaths.

One day after my retirement, she called to get some advice for a problem she was having with her stepson. I listened, gave some suggestions about whom to see, and offered to stay in touch. She thanked me, saying she didn’t know who else to call.

I hung up thinking how hard it is to “be there” when you are not there.

Jane’s call reminded me of a lesson I’d given years ago to a class of first-year medical students. I had brought in a patient of mine and together, in front of the class, we discussed the doctor-patient relationship.

I asked my patient what was most important about our relationship. She said that when she was diagnosed with diabetes, I gave her my private home phone number.

I responded, “Mrs. E, in our 15 years together, how many times have you used that number?”

“None,” was her reply.

Med students, take note

I really don’t know if my retirement has been easier for my patients than for me. I certainly hope so. Part of my job was to encourage their independence and self-sufficiency. My emotional dependence on them is my problem and I suspect one that is not that uncommon among doctors. I am still teaching and doing some research. Some of my retired friends still go to grand rounds and travel to medical meetings, even though they don’t see any patients.

I have few regrets in retiring from my practice. It was the right thing to do at the right time. Do I miss it every day? Yes, but I also feel so lucky to have worked as a family physician for 42 years.

I once heard a British family physician define the family doctor as someone you can go to and talk to about anything you want. To me, the family doctor is someone who knows you—really knows you—in a way that no one else does. A family doctor is someone who can cry with a patient about a loss, not because the physician can appreciate the loss, but because the patient’s loss is the physician’s loss, too.

I wish more young medical students understood the depth of the connections we make as family physicians, and just how rewarding the work can be. If they did, there would certainly be more students choosing a career in family medicine.

Acknowledgement
I thank Nancy W. Merenstein, the first reader of everything I write and my constant supporter; Paula Preisach, manager and organizer of my academic career; and Jonathan Han, MD, David Loxterkamp, MD, Jennifer Middleton, MD, MPH, and Allen Shaughnessy, PharmD, for helpful comments and suggestions on earlier drafts of this paper.

 

CORRESPONDENCE
Joel H. Merenstein, MD, UPMC St. Margaret, 3937 Butler Street, Pittsburgh, PA 15201; [email protected]

Being in practice for 42 years was like running a marathon. Things seem easy and pleasant at first, but then as time goes by, you hit the “wall” and you feel like you can’t go on. “It’s just too hard,” you think. And you wonder: “What am I doing here?”

In an actual marathon, you hit that wall somewhere around the 20-mile mark. (At least that’s what my son tells me.) But in my family medicine practice, I hit the wall at the 10-year mark.

If, like me, you decide not to quit, the endorphins kick in. You feel a high and know you could go on like this forever. You wonder to yourself: “Can life really be this good?”

And then, as the years pass by, you and your patients change and you know the race is coming to an end. It’s time to stop running. Yet, there are many losses in giving up practice. After spending nearly a lifetime as a doctor, it’s hard to give up that identity. That’s who you are, and who you have been.

In my case, I saw the doctor-patient relationship as a “covenant, not a contract,” as Gayle Stephens, MD, described it, and my role as a physician was to prescribe myself as my most potent therapy, as taught by Michael Balint.¹

David Loxterkamp has written about “being there” as the prime service of the family doctor.² But in retiring you are not there—at least not the way you once were.

How about lunch, doc?

When I retired 5 years ago, many patients wanted to “go out to lunch” or in some way maintain our relationship. I avoided this, saying that I thought it was important for them to develop a relationship with their new doctor. This was (and is) true, but I’ve come to realize that it is not the most important reason to pass on such invitations.

Lovers breaking up say they can “still be friends,” even though they know that is impossible. They can neither give up the special feelings they have had, nor the memories of those feelings that will always be a relevant part of their lives. Similarly, I have too much invested in these relationships to “just be friends.”

Moving on
I have moved on. My wife of 52 years and I travel and visit our children and grandchildren. I take and teach classes at a program for retired people. I have more free time than I have ever had, and I don’t miss the constant sense of responsibility for others, or the time spent agonizing over mistakes. But it was the right time to leave practice when technological advancements were accelerating at lightning speed, and my energy level was no longer keeping pace.

Mixed emotions when I talk to patients

Despite not wanting to have lunch with my former patients, I must confess that I periodically call some of them to see how they are doing. I realize that it is really more for me than for them—but I try not to make that obvious. Our conversations leave me with such mixed emotions.

Feeling guilty
Bob and his family were patients of mine almost from the day I started. I attended their daughters’ weddings, shared in their tragedies, cared for multiple illnesses, and counseled the children. When Bob was diagnosed with Alzheimer’s disease, I told him it was very early and we would go through it together and learn from each other. Then I retired.

I know through my conversations with him and his family that he has gone on with good care. But he has gone on without me.

I feel guilty.

I realize that some of this is ego—a loss of importance. But mainly I feel badly that I am not fulfilling that promise I made to him. And I have “cheated” myself out of the pleasure of learning and giving.

Feeling incomplete
I was particularly close with Marylou and her family. I attended birthday parties, cared for her and her husband’s chronic illnesses, supported them through the illness and death of their daughter, and listened when that’s all I could do. Last year, Marylou called me when she was diagnosed with breast cancer. I stayed in touch and expressed my pleasure when she did well. But, I wasn’t involved in the therapy decisions and I wasn’t there when it was time to cry or talk to the family.

 

It made me feel incomplete.

Feeling humbled
Recently I got a letter from a urologist regarding a former patient of mine, Robin.

Robin was diagnosed with prostate cancer about 10 years ago, when I was still his physician. Obviously, the new urologist didn’t know that I had retired. So I forwarded the note to Robin’s new family physician and called Robin to see how he was.

I still felt a tremendous sense of responsibility for Robin’s diagnosis. I had never screened him for prostate cancer. But as he reminded me at the time of his diagnosis, he and I had discussed screening. It’s just that Robin, who knows much about medicine and was always involved in his own decisions, had chosen not to pursue it.

Now 10 years later, Robin and I were catching up. As we talked, Robin revealed that he had multiple complications requiring permanent catheters and that he’d had to give up work.

“I wish you were still in practice,” he said to me. “I miss our talks.”

With that, I felt humbled.

Talking to Robin got me thinking. As doctors, we spend so much time worrying about doing the right thing and giving the right advice that we sometimes forget that we need to have confidence in our patients and their ability to make their own decisions. We need to know when to let go.

“Being there”
Jane was another person who emerged from my professional past. I had known her for years. Not only was she my patient, but I saw her when she came in with her father, sister, and mother for their appointments. Together, we had cared for her family members through their illnesses and deaths.

One day after my retirement, she called to get some advice for a problem she was having with her stepson. I listened, gave some suggestions about whom to see, and offered to stay in touch. She thanked me, saying she didn’t know who else to call.

I hung up thinking how hard it is to “be there” when you are not there.

Jane’s call reminded me of a lesson I’d given years ago to a class of first-year medical students. I had brought in a patient of mine and together, in front of the class, we discussed the doctor-patient relationship.

I asked my patient what was most important about our relationship. She said that when she was diagnosed with diabetes, I gave her my private home phone number.

I responded, “Mrs. E, in our 15 years together, how many times have you used that number?”

“None,” was her reply.

Med students, take note

I really don’t know if my retirement has been easier for my patients than for me. I certainly hope so. Part of my job was to encourage their independence and self-sufficiency. My emotional dependence on them is my problem and I suspect one that is not that uncommon among doctors. I am still teaching and doing some research. Some of my retired friends still go to grand rounds and travel to medical meetings, even though they don’t see any patients.

I have few regrets in retiring from my practice. It was the right thing to do at the right time. Do I miss it every day? Yes, but I also feel so lucky to have worked as a family physician for 42 years.

I once heard a British family physician define the family doctor as someone you can go to and talk to about anything you want. To me, the family doctor is someone who knows you—really knows you—in a way that no one else does. A family doctor is someone who can cry with a patient about a loss, not because the physician can appreciate the loss, but because the patient’s loss is the physician’s loss, too.

I wish more young medical students understood the depth of the connections we make as family physicians, and just how rewarding the work can be. If they did, there would certainly be more students choosing a career in family medicine.

Acknowledgement
I thank Nancy W. Merenstein, the first reader of everything I write and my constant supporter; Paula Preisach, manager and organizer of my academic career; and Jonathan Han, MD, David Loxterkamp, MD, Jennifer Middleton, MD, MPH, and Allen Shaughnessy, PharmD, for helpful comments and suggestions on earlier drafts of this paper.

 

CORRESPONDENCE
Joel H. Merenstein, MD, UPMC St. Margaret, 3937 Butler Street, Pittsburgh, PA 15201; [email protected]

As a family physician, you are better positioned than you might think to make a difference in the lives of patients with bipolar illness. Not only are you likely to be involved in monitoring such patients, but you may frequently be the first clinician patients with bipolar symptoms seek help from.

All it takes to provide that help is a heightened awareness of bipolar disorder, the ways in which bipolar patients present, and the signs and symptoms to look for. Yet evidence suggests that many physicians do not have adequate knowledge of this chronic and debilitating condition. While close to one-third of patients with bipolar disorder seek medical care within a year of the onset of bipolar symptoms, nearly 70% do not receive an accurate diagnosis until they have seen an average of 4 physicians.¹ Misdiagnosis—both underdetection¹ and over-inclusion²—often results in improper treatment. And even when the diagnosis is correct, patients with bipolar disease often receive inadequate or harmful treatment.³

Ongoing care for bipolar illness is best provided in collaboration with a psychiatrist. With the disorder affecting about 3% to 5% of the US population,⁴ family physicians will inevitably play a key role in diagnosis and treatment. The text, tables, and screening tool that follow will help with both.

Bipolar diagnosis hinges on this characteristic

The Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR) defines 4 types of bipolar illness: bipolar I, bipolar II, cyclothymia (the most mild form), and not otherwise specified (TABLE 1).⁵ The key feature of all 4 types—and the distinguishing characteristic that diagnosis typically hinges on—is a manic or hypomanic episode (TABLE 2).⁵

Although a full-blown manic episode may not be hard to identify, hypomania is easily missed. By definition, hypomania—with its heightened sense of well-being and productivity—is not problematic and is rarely a patient’s primary complaint.

Mixed mania, a feature of bipolar I, is the worst of both worlds: It is a state in which a full manic episode is superimposed on a full depressive episode—a depression with all the energy and force of a mania. Patients who have experienced one episode of mixed mania have a 12-fold increase in mixed states, 6.5 times more depression, and 1.7 times more dysthymia than those who experience manic episodes without the overlay of depression.⁶

TABLE 1
Types of bipolar disease: DSM-IV diagnoses⁵

Bipolar I	Bipolar II	Cyclothymia	Bipolar disorder not otherwise specified
≥1 manic or mixed lifetime episode, frequently accompanied by major depressive episodes	≥1 major depressive episode, accompanied by ≥1 lifetime hypomanic episode	≥2 years of numerous periods of hypomanic and subsyndromal depressive symptoms	Symptoms resemble, but do not meet, criteria for any specific bipolar disorder

TABLE 2
Mania and hypomania: DSM-IV criteria⁵

To identify an episode of mania or hypomania, all of the following criteria must be met. Of note: Hypomania has the same criteria as mania, with 2 notable exceptions: (1) the minimum duration of hypomania is 4 days, rather than 7;* and (2) hypomania is not significantly problematic. Euphoric, expansive, or irritable mood (not due to drugs) 3 or 4 of the following (4 if irritable mood): – Reduced need for sleep – Increased goal-directed activity or agitation – Increased involvement in pleasurable, but potentially destructive, activity – Pressured speech – Distractibility – Flight of ideas/racing thoughts – Grandiose/increased self-esteem

*There is no maximal duration, but the average manic episode lasts 1 to 2 months.

Complicating matters: Numerous comorbidities

Bipolar illness predisposes patients to multiple medical and psychiatric comorbidities. Cardiovascular, cerebrovascular, and metabolic disorders and sleep disturbances are common in those with bipolar disorder.⁷ So is obesity, which affects about 50% of patients with bipolar disease.⁸

Bipolar patients also suffer from an extremely high rate of comorbid psychiatric conditions. Overall, 93% of those with bipolar I also have an anxiety disorder, 71% suffer from drug or alcohol dependence, and 50% suffer from dysthymia, according to the National Comorbidity Survey.⁹ In addition, about two-thirds of bipolar patients suffer from various personality disorders¹⁰—a comorbidity that is particularly disturbing because it is associated with a chronically dysfunctional pattern of problem-solving.

 

Even without comorbidities, the impact of bipolar disorder is significant: In a study of 1468 patients with bipolar disorder, complaints of difficulties with work, leisure activities, and family and social interactions were common.¹¹ Women were more likely to cite disruption of social and family life, while men often reported having been convicted of crimes. Younger patients reported a greater number of symptomatic days compared with their older counterparts.¹¹

Suicide risk. Patients with bipolar disorder also face an increased risk of suicide, particularly in the depressive phase of the illness. Among 12,662 Oregon Medicaid patients diagnosed with, and treated for, bipolar disorder between 1998 and 2003, there were 11 deaths by suicide and 79 significant suicide attempts.¹²

Suspect bipolar disorder?

One of the best ways by which family physicians can speed up and improve the accuracy of bipolar diagnosis is to utilize the Mood Disorder Questionnaire (MDQ) (TABLE 3).¹³ Patients with any mood complaint are its target population. Within that group, the MDQ has been found to have excellent specificity (0.90) and acceptable sensitivity (0.73).¹³ (For more on identifying patients with bipolar disease, see “A blood test for bipolar disorder?”.)

TABLE 3
The Mood Disorder Questionnaire bipolar screening tool

Please answer each question to the best of your ability.
1. Has there ever been a period of time when you were not your usual self and …
	YES	NO
you felt so good or so hyper that other people thought you were not your normal self or you were so hyper that you got into trouble?
you were so irritable that you shouted at people or started fights or arguments?
you felt much more self-confident than usual?
you got much less sleep than usual and found you didn’t really miss it?
you were much more talkative or spoke much faster than usual?
thoughts raced through your head or you couldn’t slow your mind down?
you were so easily distracted by things around you that you had trouble concentrating or staying on track?
you had much more energy than usual?
you were much more active or did many more things than usual?
you were much more social or outgoing than usual; for example, you telephoned friends in the middle of the night?
you were much more interested in sex than usual?
you did things that were unusual for you or that other people might have thought were excessive, foolish, or risky?
spending money got you or your family into trouble?
2. If you checked YES to more than one of the above, have several of these ever happened during the same period of time?
3. How much of a problem did any of these cause you—like being unable to work; having family, money, or legal troubles; getting into arguments or fights? Please circle one response only. No Problem Minor problem Moderate problem Serious problem
Have any of your blood relatives (ie, children, siblings, parents, grandparents, aunts, uncles) had manic-depressive illness or bipolar disorder?
For a positive screen, 7 of the 13 items in No. 1 must be Yes, No. 2 must be Yes, and No. 3 must be moderate or serious. Source: Hirschfeld RM, et al. Am J Psychiatry. 2000.13 Reprinted with permission.

When to administer the MDQ
Because patients with bipolar disease are more likely to seek help when they are suffering from a depressive episode, it is important to maintain a high index of suspicion. Before ruling out bipolar disease, take a complete medical history, inquiring about comorbidities, family history, and whether the patient can recall any episodes of agitation, intense irritation, or other manifestations of mania or hypomania (TABLE 2).⁵ If, based on the history, you continue to suspect bipolar disorder, administer the MDQ.

If the patient has a positive screen, your next step would be to initiate treatment for bipolar disorder, even if depression is the presenting symptom. A referral to a psychiatrist would be indicated, as well.

Complexities of bipolar treatment

In recent years, numerous agents have been approved by the US Food and Drug Administration (FDA) for the treatment of bipolar illness in general, and for acute mania in particular. Nearly all of the second-generation, or atypical, antipsychotics have been approved for use in acute mania.¹⁴ (Mixed states should be treated the same as mania.) Most of these agents have also been found to be useful as maintenance medications, to prevent relapse (TABLE 4).

 

Considerable evidence suggests that lithium significantly reduces the risk of relapse, particularly in classic euphoric mania. Other agents that are approved for maintenance therapy include aripiprazole, lamotrigine, and olanzapine as monotherapy, and olanzapine, quetiapine, and ziprasidone as addon agents to lithium or divalproex. Combining a mood stabilizer and an antipsychotic agent generally leads to better outcomes, both in acute mania¹⁵ and relapse prevention,¹⁶ compared with a mood stabilizer alone. However, bipolar depression, which is more common than either mania¹⁷ or hypomania,¹⁸ is the major clinical challenge.

TABLE 4
FDA-approved treatments for bipolar disorder^32,33

Treatment	Mania	Bipolar depression	Maintenance
Aripiprazole	√		√
Asenapine	√
Carbamazepine ER	√
Chlorpromazine	√
Divalproex; divalproex ER	√
Lamotrigine			√
Lithium	√*		√
Olanzapine	√	√†	√
Quetiapine; quetiapine XR	√	√	√
Risperidone	√
Ziprasidone	√		√
ER, extended release; FDA, US Food and Drug Administration; XR, extended release. *Not approved for mixed mania. † Approved for bipolar depression in combination with fluoxetine.

What’s best for bipolar depression?
For the acutely depressed bipolar patient, optimizing mood stabilization therapy is typically the first step. If the depression doesn’t resolve in 4 or 5 weeks, adding an agent with relapse prevention properties is a preferred approach. Antidepressants may be harmful to patients with bipolar disorder (possibly triggering manic episodes, rapid cycling, or a chronic dysphoric state),^3,19 and are usually tried only after other options have been exhausted.

Quetiapine, which is effective for the treatment of mania at doses around 600 mg daily, appears to also be effective for the treatment of acute bipolar depression at doses around 300 mg/d.²⁰ In 2-year studies in which quetiapine was added to either lithium or divalproex, the 2-drug combination was found to reduce the risk for relapse approximately 3-fold compared with the mood stabilizer alone.¹⁶

Olanzapine/fluoxetine. Besides quetiapine, this drug combination is the only other agent with FDA approval for the treatment of bipolar depression. A 24-week open extension trial found that the risk for a manic episode due to the coadministration of fluoxetine was low, but 27% of those studied relapsed into depression.²¹

Drugs that do not have FDA approval specifically for bipolar depression may also be used to treat it.

Lithium, which has antidepressant activity, particularly at levels exceeding 0.8 mEq/L, is one such drug. In addition to its effectiveness in treating bipolar depression, lithium appears to have an antisuicide effect.¹²

In a recent study of patients with bipolar disorder, lithium was found to be more protective than other mood stabilizers. The hazard ratio (HR) for suicide attempts was significantly greater for patients taking divalproex (HR=2.7; P<.001) or carbamazepine (HR=2.8; P<.001) compared with patients taking lithium.¹²

Modafinil, a nonstimulant used to increase alertness in patients with daytime sleepiness due to a variety of conditions, has been tested as an adjunctive agent in depressed bipolar patients. In a blinded study, patients were randomly assigned to have modafinil (n=41) or placebo (n=44) added to their existing treatment regimen.²² Response, defined as ≥50% improvement in mood, occurred at twice the rate in those treated with modafinil (44%) compared with those on placebo (23%; P<.05).²² In the brief (6 week) study, modafinil did not appear to cause an increase in manic or hypomanic episodes.²²

Pramipexole, a dopamine agonist used for early-stage Parkinson’s disease, has been tested in patients with bipolar depression in 2 small, short-term placebo-controlled trials. A total of 15 patients with type I disease and 28 patients with type II disease were studied for a 6-week period. The results: 60% to 67% of patients taking pramipexole responded, vs 9% to 20% of those on placebo.^23,24

Electroconvulsive therapy (ECT) is an underutilized treatment that is effective for depressed patients who are resistant to pharmacological treatment. In fact, bipolar depression may improve more rapidly than unipolar depression with ultra-brief pulse treatment—a therapy in which the pulse width of the electrical stimulus is much briefer (<0.5 msec) than that of standard ECT.²⁵ ECT has also been shown to be effective for mixed states, in which depression and mania coexist.²⁶ The cognitive adverse effects associated with ECT can be reduced while maintaining the same efficacy by using bifrontal (instead of the typical bitemporal) electrode replacement.²⁷

 

Predicting the course of disease, preventing relapse

Generally, the polarity of the current episode predicts that of future episodes. Studies have found that, independent of whether patients were on effective mood-stabilizing agents or placebo, those who relapsed had an episode like their most recent one by a ratio of more than 2 to 1.²⁸

Research suggests a link between age at onset of illness and cycling time and response to particular agents. In 1 trial, those with early-onset bipolar disorder (in adolescence) had briefer euthymic periods and responded better to carbamazepine compared with those who developed symptoms of bipolar disorder at a later age.²⁹ Late-onset bipolar illness (in the 30s or older) was characterized by longer euthymic periods and manic episodes that responded well to lithium.²⁹ The average age of onset is about 25 years.³⁰

Regardless of patient age or age of onset of symptoms, however, prevention of relapse is the goal of ongoing treatment. You can help by assessing the patient’s mood, reviewing the medication regimen and level of compliance, and offering support at every visit—and by consulting with the patient’s psychiatrist, as needed.

CORRESPONDENCE
Rif S. El-Mallakh, MD, Mood Disorders Research Program, Department of Psychiatry and Behavioral Sciences, University of Louisville School of Medicine, MedCenter One, 501 East Broadway, Suite 340, Louisville, KY 40202; [email protected]