Widespread use of antiretroviral therapy has caused a remarkable decline in rates of morbidity and death related to acquired immunodeficiency syndrome (AIDS) and has effectively made human immunodeficiency virus (HIV) infection a manageable—although not yet curable— chronic condition. And as the HIV-infected population on antiretroviral therapy ages, the prevalence of chronic conditions (eg, cardiovascular disease, hepatic disease, pulmonary disease, non-AIDS cancers) and deaths attributable to these conditions have also increased.¹

Many of the traditional risk factors for cardiovascular disease in the general population, including smoking, dyslipidemia, and diabetes, are common in HIV-infected patients, and HIV infection itself independently increases the risk of coronary heart disease. In addition, different antiretroviral combinations can contribute, in varying degrees, to changes in lipid levels and insulin resistance, further increasing coronary risk.

Ultimately, however, the immunologic benefits of antiretroviral therapy for individual patients far exceed the modest increase in cardiovascular risk associated with certain regimens. In most cases, careful selection of the initial antiretroviral regimen and the addition of lipid-lowering or glucose-controlling medications (with close attention to drug interactions) can effectively manage the metabolic changes associated with antiretroviral therapy and obviate any premature modification of virologically suppressive regimens.

TRADITIONAL CARDIAC RISK FACTORS IN HIV PATIENTS

The risk of coronary heart disease in HIV patients is influenced mostly by traditional factors such as age, smoking, diabetes, and dyslipidemia, including high levels of total cholesterol and low-density lipoprotein cholesterol (LDL-C) and low levels of high-density lipoprotein cholesterol (HDL-C).²

In various large cohorts, HIV-infected men had a higher prevalence of smoking,³ a lower mean HDL-C level,^3,4 and a higher mean triglyceride level^3,4 than men without HIV infection, placing them at greater risk of coronary heart disease. However, even after adjusting for traditional risk factors, rates of atherosclerosis are still higher in people who are infected with HIV than in those who are not.⁵

EFFECT OF HIV INFECTION ON CORONARY RISK

HIV infection has been shown to increase coronary risk.

In the Kaiser Permanente database,⁶ HIV-positive patients had a significantly higher rate of hospitalizations for coronary heart disease than did people who were not infected.

Similarly, in a cohort study of almost 4,000 HIV-infected patients and more than 1 million controls, the risk of acute myocardial infarction was 75% higher for HIV-positive patients than for HIV-negative patients, even after adjusting for sex, race, hypertension, diabetes, and dyslipidemia.⁵

The Fat Redistribution and Metabolism (FRAM) cross-sectional study⁷ showed that HIV infection was associated with greater carotid intima media thickness, an established marker of atherosclerosis, independently of traditional risk factors and to virtually the same degree as smoking and male sex.

Other studies of subclinical atherosclerosis in HIV patients have yielded disparate results, likely because of differences in study design, methods of measuring carotid thickness, and characteristics of the study populations (eg, prevalence of cardiovascular risk factors and stage of HIV disease). However, a meta-analysis of six prospective cohort studies, three case-control studies, and four cross-sectional studies confirmed that HIV patients had slightly but statistically significantly greater carotid intima media thickness than HIV-negative people.⁸

MECHANISMS BY WHICH HIV MAY PROMOTE CORONARY HEART DISEASE

The pathogenesis of coronary heart disease in HIV infection has not been fully elucidated, but the virus appears to contribute directly to the accelerated development of atherosclerosis. It may do so through direct effects on cholesterol processing and transport, attraction of monocytes to the intimal wall, and activation of monocytes to induce an inflammatory response and endothelial proliferation.

Effects on lipids

In early HIV infection, levels of total cholesterol and HDL-C are lower. In more advanced infection, lower CD4+ lymphocyte counts have been associated with lower levels of apolipoprotein B and with smaller LDL-C particles, suggesting that HIV affects lipid processing and delivery to vessel walls.⁹ HIV infection is also associated with reduced clearance of LDL-C.¹⁰ HIV appears to specifically inhibit the compensatory efflux of excess cholesterol from macrophages, thus promoting the formation of foam cells in atherosclerotic plaque.¹¹

Attraction of monocytes to the vessel wall

In vitro studies also suggest that HIV enhances migration of monocytes into the vascular intima during atherosclerotic plaque development by promoting secretion of the chemokine monocyte chemoattractant protein 1¹² and the expression of endothelial cell adhesion molecules such as intercellular adhesion molecule 1, vascular cell adhesion molecule 1 (VCAM-1), and E-selectin.¹³

Inflammation

A recent study suggests that chronic inflammation may be a key contributor to the accelerated development of atherosclerosis in HIV patients. Hsue et al¹⁴ compared carotid intima media thickness and levels of C-reactive protein (a marker of systemic inflammation) in HIV-positive and HIV-negative patients. The carotid intima media thickness was greater in all groups of HIV patients, irrespective of level of viremia or exposure to antiretroviral therapy, than in healthy controls. In addition, C-reactive protein levels remained elevated in HIV-infected participants regardless of their level of viremia.

These findings suggest not only that HIV-associated atherosclerosis is determined by advanced immunodeficiency, high-level viremia, and exposure to antiretroviral drugs, but also that persistent inflammation due to HIV infection may play an important role in accelerated atherosclerosis.

EFFECT OF ANTIRETROVIRAL THERAPY ON CORONARY RISK

Antiretroviral therapy is associated with a small but significant increase in coronary risk.

Medi-Cal,¹⁵ a retrospective study of 28,513 patients, found antiretroviral therapy to be associated with coronary heart disease among patients 18 to 33 years of age (relative risk 2.06, P < .001).

The Data Collection on Adverse Events of Anti-HIV Drugs study¹⁶ prospectively followed 23,437 patients for 94,469 person-years. Adjusted for exposure to nonnucleoside reverse transcriptase inhibitors and for hypertension and diabetes, the relative risk of myocardial infarction per year of protease inhibitor exposure was 1.16 (95% confidence interval [CI] 1.10–1.23). The relative risk was lower after adjusting for serum lipid levels but remained significant at 1.10 (95% CI 1.04–1.18).

Reports have been mixed regarding a possible association between myocardial infarction and the nucleoside reverse transcriptase inhibitor abacavir (Ziagen): several studies found a statistically significant association,^17–20 and others did not.^21–23 Differences in study design (observational cohort studies vs prospective randomized clinical trials), populations studied (differing in age, cardiovascular risk factor prevalence, and whether the patients had already been exposed to treatment), and outcome definition probably contributed to the different conclusions.

On the other hand, several studies have shown that suppression of HIV with antiretroviral therapy actually improves some of the surrogate markers of cardiovascular disease. For example:

• Markers of endothelial function such as flow-mediated vasodilation improve significantly within 4 weeks of a patient’s starting antiretroviral therapy, regardless of the class of antiretroviral drug used.²⁴
• After viral suppression is achieved, levels of the markers of endothelial activation VCAM-1 and P-selectin decline significantly, as do levels of the adipocyte activation marker leptin and the coagulation marker D-dimer.^25,26
• Levels of the anti-inflammatory markers adiponectin and interleukin 10 increase. ^25,26

Interrupting antiretroviral therapy may increase coronary risk

Not only is uncontrolled viral replication in untreated HIV infection associated with cardiovascular disease, but interrupting antiretroviral therapy may result in a supplementary increase in coronary risk.

In the 5,472-patient Strategies for Management of Antiretroviral Therapy (SMART) trial, the rate of cardiovascular disease events was higher if treatment was interrupted than with continuous treatment, with a hazard ratio of 1.57 (95% CI 1.0–2.46, P = .05).²⁷

This association between treatment interruption and coronary events does not appear to be related to the level of viremia.²⁸ Rather, development of cardiovascular disease in HIV-infected patients who interrupt antiretroviral therapy may be mediated, to a large extent, by chronic inflammation in the setting of viral replication. In the treatment-interruption group, levels of the inflammatory cytokine interleukin 6 (IL-6) and the coagulation marker D-dimer were significantly elevated 1 month after randomization, and these differences were strongly associated with death (odds ratio [OR] 12.6, P < .0001 for IL-6; OR 13.1, P < .0001 for D-dimer). Elevated IL-6 levels were also significantly associated with the development of cardiovascular disease (OR 2.8, P = .03).²⁹

METABOLIC COMPLICATIONS OF ANTIRETROVIRAL THERAPY

Persons with HIV infection may experience metabolic complications that are due to HIV itself or to its treatment.

Cross-sectional studies that included HIV-negative patients as controls have demonstrated changes in lipid processing that are known to promote atherosclerosis. For example, persons with HIV infection have smaller LDL-C particles³⁰ and higher levels of circulating oxidized LDL-C.³¹

In the Multicenter AIDS Cohort Study (MACS), after HIV seroconversion, nonfasting total cholesterol, LDL-C, and HDL-C levels declined, which is consistent with a chronic inflammatory state. After antiretroviral therapy was started, lipid levels returned to baseline levels or slightly higher except for HDL-C, which remained low.⁹ These changes may be due to a general “return to health,” or they may be direct medication effects.

Similar patterns were seen in the SMART study.²⁸ Participants randomized to receive intermittent antiretroviral therapy had overall decreases in all lipid levels, with a marked reduction in HDL-C, while those randomized to receive continuous therapy had increased levels of all lipids, including HDL-C, at 12 months. Overall, the ratio of total cholesterol to HDL-C actually increased for participants on episodic therapy, while it decreased in the continuous-treatment group. Along with continued vascular inflammation, the low HDL-C may have contributed to the worse cardiovascular outcomes in patients who received intermittent antiretroviral therapy.

Some lipid changes associated with antiretroviral therapy may actually be beneficial. For example, nonnucleoside reverse transcriptase inhibitors may raise HDL-C levels. However, such increases alone do not necessarily offset the other lipid changes or translate to an observed improvement in coronary risk.³²

The degree of dyslipidemia and specific lipid changes differ among the different classes of antiretroviral drugs and even among the individual drugs within each class. Furthermore, the magnitude of the observed lipid changes varies widely among patients on the same antiretroviral regimen, reflecting the likely important role of host genomics.

While the protease inhibitors and nonnucleoside reverse transcriptase inhibitors have well-described effects on lipids (described in greater detail in the following sections), there have been no reported significant changes in lipid profiles or cardiovascular risk associated with the newest classes, ie, fusion inhibitors such as enfuvirtide (Fuzeon), CC chemokine receptor type 5 (CCR5) receptor inhibitors such as maraviroc (Selzentry), or integrase inhibitors such as raltegravir (Isentress).

 

 

Impact of protease inhibitors on lipids

Ritonavir (Norvir) and ritonavir-boosted protease inhibitor combinations cause the most significant increases in lipids. Currently, ritonavir is used in low doses to boost the levels of most other protease inhibitors as the standard of care in protease inhibitor-based regimens. However, in most patients, giving ritonavir with protease inhibitors raises lipid levels, particularly triglycerides.

Most boosted protease inhibitor regimens have similar effects on lipid levels, with some exceptions.

Tipranavir (Aptivus) plus ritonavir, for example, markedly raises total cholesterol and triglyceride levels and would not be recommended for patients with dyslipidemia at baseline.³³

Atazanavir (Reyataz)^34,35 plus ritonavir and darunavir (Prezista)³⁶ plus ritonavir cause more modest lipid changes. Unboosted atazanavir raises lipid levels only minimally, if at all,^34,35 but it is no longer a preferred regimen according to US Department of Health and Human Services guidelines.⁴²

Impact of nonnucleoside reverse transcriptase inhibitors on lipids

Efavirenz (Sustiva), a nonnucleoside reverse transcriptase inhibitor, when added to a regimen of two or three nucleoside reverse transcriptase inhibitors, resulted in modest increases in all lipids, including HDL-C (a potentially beneficial change) at 96 weeks compared with a regimen of three nucleoside reverse transcriptase inhibitors only.⁴³

Nevirapine (Viramune), compared with efavirenz, results in a more favorable lipid profile in previously untreated patients, as shown by larger increases in HDL-C and smaller increases in triglycerides at 48 weeks.⁴⁴

Etravirine (Intelence), the newest nonnucleoside reverse transcriptase inhibitor, does not appear to cause any further increase in lipids when added to a regimen containing darunavir-ritonavir and nucleoside agents.⁴⁵

Impact of nucleoside reverse transcriptase inhibitors on lipids

As a class, nucleoside reverse transcriptase inhibitors have been associated with mitochondrial toxicity and insulin resistance,⁴⁶ but the lipid changes associated with them are generally less significant than those caused by protease inhibitors or nonnucleoside reverse transcriptase inhibitors. Nevertheless, within the class, there is considerable variability in lipid changes associated with specific agents.

Stavudine (Zerit), for example, is associated with hypertriglyceridemia.

Tenofovir (Viread), for another example, in combination with emtricitabine (Emtriva) and the nonnucleoside reverse transcriptase inhibitor efavirenz (the three drugs are contained in a formulation called Atripla) was associated with a smaller increase in fasting total cholesterol than with zidovudine-lamivudine and efavirenz at 96 weeks.⁴⁷

A recent placebo-controlled, crossover, pilot study of 17 HIV-infected patients suggested that tenofovir may actually have independent lipid-lowering properties.⁴⁸

Abacavir, as discussed above, has been reported to be associated with a higher risk of myocardial infarction, but this is debatable.

MANAGING CORONARY RISK FACTORS IN HIV-INFECTED PATIENTS

Cardiovascular risk assessment

In HIV patients, cardiovascular risk can be assessed using models derived from large epidemiologic studies such as the Framingham Heart Study.⁴⁹

Current guidelines from the Infectious Diseases Society of America and the AIDS Clinical Trials Group (ACTG) for evaluating and managing dyslipidemia in HIV-infected adults are based on the National Cholesterol Education Program Adult Treatment Panel III.⁵⁰ They recommend obtaining a fasting lipid profile before starting antiretroviral therapy and within 3 to 6 months after starting a new regimen.

The guidelines also recommend stratifying risk by counting the number of cardiovascular risk factors, as is done for the general population. If the patient has more than two factors, the Framingham equation should be used to calculate the 10-year risk of myocardial infarction or cardiac death. Interventions should be offered for modifiable cardiovascular risk factors such as smoking, hypertension, physical inactivity, and diabetes mellitus. LDL-C goals should be determined, and lipid-lowering drugs should be initiated accordingly. If triglyceride levels are 200 to 500 mg/dL and levels of “non-HDL-C” (total cholesterol minus the HDL-C level) are high, a statin is recommended. If the triglyceride level is higher than 500 mg/dL, a fibrate should be started.⁵¹

 

 

Dyslipidemia management

In HIV patients, statin and fibrate therapy must be considered cautiously, given the important drug interactions with protease inhibitors and especially ritonavir. Many statins are metabolized by cytochrome P3A4, which protease inhibitors inhibit.

Statins generally considered safe to use with most protease inhibitors:

• Pravastatin (Pravachol)
• Rosuvastatin (Crestor)
• Atorvastatin (Lipitor).

Exceptions and caveats:

• Pravastatin should not be prescribed with boosted darunavir.
• Data for fluvastatin (Lescol) in HIV-infected patients on antiretroviral therapy are limited.
• Lovastatin (Mevacor) and simvastatin (Zocor) are contraindicated with protease inhibitor therapy.⁵²
• In contrast to the increase in statin levels seen with protease inhibitors, efavirenz lowers levels of simvastatin, pravastatin, and atorvastatin.^53,54

Ezetimibe (Zetia), which is metabolized independently of the cytochrome P450 system, has been shown to be safe and effective when given to HIV-infected patients on antiretroviral therapy.⁵⁸

Fenofibrate (Lofibra) is recommended by current guidelines for patients with elevated triglyceride levels (> 500 mg/dL).⁵¹ In the ACTG 5087 study, a combination of fenofibrate plus pravastatin was found to be safe and effective in improving lipid profiles.⁵⁹

Long-acting niacin resulted in significant improvements in triglycerides, total cholesterol, HDL-C, and LDL-C after 48 weeks of use, although insulin sensitivity worsened.⁶⁰

Fish oil has been shown to be an effective alternative to fibrates, or it can be used in combination with them.⁶¹

Switching antiretroviral agents vs adding lipid-lowering agents. In some patients with significant dyslipidemia, switching antiretro viral agents may lower lipid levels without compromising virologic control.⁶² However, due to the multifactorial nature of dyslipidemia in HIV patients on antiretroviral therapy, switching the HIV therapy alone may not result in sufficient improvement in the lipid profile⁴⁵ and may be associated with virologic failure, particularly among patients who have underlying treatment-resistant HIV.⁶³

In many cases, adding lipid-lowering agents may be more beneficial than switching the antiretroviral therapy. For example, a randomized trial in HIV-infected patients with hyperlipidemia found that adding a lipid-lowering agent such as pravastatin or bezafibrate to the unchanged antiretroviral regimen resulted in greater improvement in total cholesterol, LDL-C, and triglyceride levels than switching from a protease inhibitor to either nevirapine or efavirenz.⁶⁴

Given the complexity of prescribing lipid-lowering therapies to patients on antiretroviral therapy, we recommend that providers check with a pharmacist or refer to package inserts and other medical literature if they are unfamiliar with these drug interactions and responses to lipid-lowering therapies.

Managing insulin resistance

Diabetes mellitus is a well-known risk factor for coronary heart disease. The Data Collection on Adverse Events of Anti-HIV Drugs study found a higher incidence of coronary heart disease in HIV-infected patients, with higher rates in those with longer duration of diabetes.⁶⁵ The prevalence of diabetes in HIV-infected populations varies, depending on demographic characteristics,^65,66 prevalence of coinfection with hepatitis C virus,⁶⁶ and prevalence of exposure to antiretroviral drugs⁶⁷ in the study population.

Drugs that lessen insulin resistance include the thiazolidinedione rosiglitazone (Avandia) and the biguanide metformin (Glucophage). In a randomized trial, both drugs, alone or in combination, improved insulin sensitivity in HIV-infected patients, but neither lessened the amount of visceral or subcutaneous fat.⁶⁸

Smoking cessation

Smoking is another well-known modifiable risk factor for coronary heart disease.

The prevalence of smoking is usually higher in HIV patients than in HIV-negative people. For example, a French cohort study reported smoking prevalence rates of 56.6% in HIV-infected men vs 32.7% in HIV-negative men; in women, the rates were 58% vs 28.1%. The 5-year relative risk of coronary heart disease in HIV-infected vs HIV-negative persons was 1.20 for men and 1.59 for women. The estimated attributable risk due to smoking was 65% for men and 29% for women.³

Therefore, smoking cessation should be a top priority in managing cardiovascular risk in HIV-infected patients. In fact, control of modifiable risk factors through lifestyle changes such as smoking cessation, dietary changes, and exercise is likely to have a significant impact on cardiovascular risk in this population.

Widespread use of antiretroviral therapy has caused a remarkable decline in rates of morbidity and death related to acquired immunodeficiency syndrome (AIDS) and has effectively made human immunodeficiency virus (HIV) infection a manageable—although not yet curable— chronic condition. And as the HIV-infected population on antiretroviral therapy ages, the prevalence of chronic conditions (eg, cardiovascular disease, hepatic disease, pulmonary disease, non-AIDS cancers) and deaths attributable to these conditions have also increased.¹

Many of the traditional risk factors for cardiovascular disease in the general population, including smoking, dyslipidemia, and diabetes, are common in HIV-infected patients, and HIV infection itself independently increases the risk of coronary heart disease. In addition, different antiretroviral combinations can contribute, in varying degrees, to changes in lipid levels and insulin resistance, further increasing coronary risk.

Ultimately, however, the immunologic benefits of antiretroviral therapy for individual patients far exceed the modest increase in cardiovascular risk associated with certain regimens. In most cases, careful selection of the initial antiretroviral regimen and the addition of lipid-lowering or glucose-controlling medications (with close attention to drug interactions) can effectively manage the metabolic changes associated with antiretroviral therapy and obviate any premature modification of virologically suppressive regimens.

TRADITIONAL CARDIAC RISK FACTORS IN HIV PATIENTS

The risk of coronary heart disease in HIV patients is influenced mostly by traditional factors such as age, smoking, diabetes, and dyslipidemia, including high levels of total cholesterol and low-density lipoprotein cholesterol (LDL-C) and low levels of high-density lipoprotein cholesterol (HDL-C).²

In various large cohorts, HIV-infected men had a higher prevalence of smoking,³ a lower mean HDL-C level,^3,4 and a higher mean triglyceride level^3,4 than men without HIV infection, placing them at greater risk of coronary heart disease. However, even after adjusting for traditional risk factors, rates of atherosclerosis are still higher in people who are infected with HIV than in those who are not.⁵

EFFECT OF HIV INFECTION ON CORONARY RISK

HIV infection has been shown to increase coronary risk.

In the Kaiser Permanente database,⁶ HIV-positive patients had a significantly higher rate of hospitalizations for coronary heart disease than did people who were not infected.

Similarly, in a cohort study of almost 4,000 HIV-infected patients and more than 1 million controls, the risk of acute myocardial infarction was 75% higher for HIV-positive patients than for HIV-negative patients, even after adjusting for sex, race, hypertension, diabetes, and dyslipidemia.⁵

The Fat Redistribution and Metabolism (FRAM) cross-sectional study⁷ showed that HIV infection was associated with greater carotid intima media thickness, an established marker of atherosclerosis, independently of traditional risk factors and to virtually the same degree as smoking and male sex.

Other studies of subclinical atherosclerosis in HIV patients have yielded disparate results, likely because of differences in study design, methods of measuring carotid thickness, and characteristics of the study populations (eg, prevalence of cardiovascular risk factors and stage of HIV disease). However, a meta-analysis of six prospective cohort studies, three case-control studies, and four cross-sectional studies confirmed that HIV patients had slightly but statistically significantly greater carotid intima media thickness than HIV-negative people.⁸

MECHANISMS BY WHICH HIV MAY PROMOTE CORONARY HEART DISEASE

The pathogenesis of coronary heart disease in HIV infection has not been fully elucidated, but the virus appears to contribute directly to the accelerated development of atherosclerosis. It may do so through direct effects on cholesterol processing and transport, attraction of monocytes to the intimal wall, and activation of monocytes to induce an inflammatory response and endothelial proliferation.

Effects on lipids

In early HIV infection, levels of total cholesterol and HDL-C are lower. In more advanced infection, lower CD4+ lymphocyte counts have been associated with lower levels of apolipoprotein B and with smaller LDL-C particles, suggesting that HIV affects lipid processing and delivery to vessel walls.⁹ HIV infection is also associated with reduced clearance of LDL-C.¹⁰ HIV appears to specifically inhibit the compensatory efflux of excess cholesterol from macrophages, thus promoting the formation of foam cells in atherosclerotic plaque.¹¹

Attraction of monocytes to the vessel wall

In vitro studies also suggest that HIV enhances migration of monocytes into the vascular intima during atherosclerotic plaque development by promoting secretion of the chemokine monocyte chemoattractant protein 1¹² and the expression of endothelial cell adhesion molecules such as intercellular adhesion molecule 1, vascular cell adhesion molecule 1 (VCAM-1), and E-selectin.¹³

Inflammation

A recent study suggests that chronic inflammation may be a key contributor to the accelerated development of atherosclerosis in HIV patients. Hsue et al¹⁴ compared carotid intima media thickness and levels of C-reactive protein (a marker of systemic inflammation) in HIV-positive and HIV-negative patients. The carotid intima media thickness was greater in all groups of HIV patients, irrespective of level of viremia or exposure to antiretroviral therapy, than in healthy controls. In addition, C-reactive protein levels remained elevated in HIV-infected participants regardless of their level of viremia.

These findings suggest not only that HIV-associated atherosclerosis is determined by advanced immunodeficiency, high-level viremia, and exposure to antiretroviral drugs, but also that persistent inflammation due to HIV infection may play an important role in accelerated atherosclerosis.

EFFECT OF ANTIRETROVIRAL THERAPY ON CORONARY RISK

Antiretroviral therapy is associated with a small but significant increase in coronary risk.

Medi-Cal,¹⁵ a retrospective study of 28,513 patients, found antiretroviral therapy to be associated with coronary heart disease among patients 18 to 33 years of age (relative risk 2.06, P < .001).

The Data Collection on Adverse Events of Anti-HIV Drugs study¹⁶ prospectively followed 23,437 patients for 94,469 person-years. Adjusted for exposure to nonnucleoside reverse transcriptase inhibitors and for hypertension and diabetes, the relative risk of myocardial infarction per year of protease inhibitor exposure was 1.16 (95% confidence interval [CI] 1.10–1.23). The relative risk was lower after adjusting for serum lipid levels but remained significant at 1.10 (95% CI 1.04–1.18).

Reports have been mixed regarding a possible association between myocardial infarction and the nucleoside reverse transcriptase inhibitor abacavir (Ziagen): several studies found a statistically significant association,^17–20 and others did not.^21–23 Differences in study design (observational cohort studies vs prospective randomized clinical trials), populations studied (differing in age, cardiovascular risk factor prevalence, and whether the patients had already been exposed to treatment), and outcome definition probably contributed to the different conclusions.

On the other hand, several studies have shown that suppression of HIV with antiretroviral therapy actually improves some of the surrogate markers of cardiovascular disease. For example:

• Markers of endothelial function such as flow-mediated vasodilation improve significantly within 4 weeks of a patient’s starting antiretroviral therapy, regardless of the class of antiretroviral drug used.²⁴
• After viral suppression is achieved, levels of the markers of endothelial activation VCAM-1 and P-selectin decline significantly, as do levels of the adipocyte activation marker leptin and the coagulation marker D-dimer.^25,26
• Levels of the anti-inflammatory markers adiponectin and interleukin 10 increase. ^25,26

Interrupting antiretroviral therapy may increase coronary risk

Not only is uncontrolled viral replication in untreated HIV infection associated with cardiovascular disease, but interrupting antiretroviral therapy may result in a supplementary increase in coronary risk.

In the 5,472-patient Strategies for Management of Antiretroviral Therapy (SMART) trial, the rate of cardiovascular disease events was higher if treatment was interrupted than with continuous treatment, with a hazard ratio of 1.57 (95% CI 1.0–2.46, P = .05).²⁷

This association between treatment interruption and coronary events does not appear to be related to the level of viremia.²⁸ Rather, development of cardiovascular disease in HIV-infected patients who interrupt antiretroviral therapy may be mediated, to a large extent, by chronic inflammation in the setting of viral replication. In the treatment-interruption group, levels of the inflammatory cytokine interleukin 6 (IL-6) and the coagulation marker D-dimer were significantly elevated 1 month after randomization, and these differences were strongly associated with death (odds ratio [OR] 12.6, P < .0001 for IL-6; OR 13.1, P < .0001 for D-dimer). Elevated IL-6 levels were also significantly associated with the development of cardiovascular disease (OR 2.8, P = .03).²⁹

METABOLIC COMPLICATIONS OF ANTIRETROVIRAL THERAPY

Persons with HIV infection may experience metabolic complications that are due to HIV itself or to its treatment.

Cross-sectional studies that included HIV-negative patients as controls have demonstrated changes in lipid processing that are known to promote atherosclerosis. For example, persons with HIV infection have smaller LDL-C particles³⁰ and higher levels of circulating oxidized LDL-C.³¹

In the Multicenter AIDS Cohort Study (MACS), after HIV seroconversion, nonfasting total cholesterol, LDL-C, and HDL-C levels declined, which is consistent with a chronic inflammatory state. After antiretroviral therapy was started, lipid levels returned to baseline levels or slightly higher except for HDL-C, which remained low.⁹ These changes may be due to a general “return to health,” or they may be direct medication effects.

Similar patterns were seen in the SMART study.²⁸ Participants randomized to receive intermittent antiretroviral therapy had overall decreases in all lipid levels, with a marked reduction in HDL-C, while those randomized to receive continuous therapy had increased levels of all lipids, including HDL-C, at 12 months. Overall, the ratio of total cholesterol to HDL-C actually increased for participants on episodic therapy, while it decreased in the continuous-treatment group. Along with continued vascular inflammation, the low HDL-C may have contributed to the worse cardiovascular outcomes in patients who received intermittent antiretroviral therapy.

Some lipid changes associated with antiretroviral therapy may actually be beneficial. For example, nonnucleoside reverse transcriptase inhibitors may raise HDL-C levels. However, such increases alone do not necessarily offset the other lipid changes or translate to an observed improvement in coronary risk.³²

The degree of dyslipidemia and specific lipid changes differ among the different classes of antiretroviral drugs and even among the individual drugs within each class. Furthermore, the magnitude of the observed lipid changes varies widely among patients on the same antiretroviral regimen, reflecting the likely important role of host genomics.

While the protease inhibitors and nonnucleoside reverse transcriptase inhibitors have well-described effects on lipids (described in greater detail in the following sections), there have been no reported significant changes in lipid profiles or cardiovascular risk associated with the newest classes, ie, fusion inhibitors such as enfuvirtide (Fuzeon), CC chemokine receptor type 5 (CCR5) receptor inhibitors such as maraviroc (Selzentry), or integrase inhibitors such as raltegravir (Isentress).

 

 

Impact of protease inhibitors on lipids

Ritonavir (Norvir) and ritonavir-boosted protease inhibitor combinations cause the most significant increases in lipids. Currently, ritonavir is used in low doses to boost the levels of most other protease inhibitors as the standard of care in protease inhibitor-based regimens. However, in most patients, giving ritonavir with protease inhibitors raises lipid levels, particularly triglycerides.

Most boosted protease inhibitor regimens have similar effects on lipid levels, with some exceptions.

Tipranavir (Aptivus) plus ritonavir, for example, markedly raises total cholesterol and triglyceride levels and would not be recommended for patients with dyslipidemia at baseline.³³

Atazanavir (Reyataz)^34,35 plus ritonavir and darunavir (Prezista)³⁶ plus ritonavir cause more modest lipid changes. Unboosted atazanavir raises lipid levels only minimally, if at all,^34,35 but it is no longer a preferred regimen according to US Department of Health and Human Services guidelines.⁴²

Impact of nonnucleoside reverse transcriptase inhibitors on lipids

Efavirenz (Sustiva), a nonnucleoside reverse transcriptase inhibitor, when added to a regimen of two or three nucleoside reverse transcriptase inhibitors, resulted in modest increases in all lipids, including HDL-C (a potentially beneficial change) at 96 weeks compared with a regimen of three nucleoside reverse transcriptase inhibitors only.⁴³

Nevirapine (Viramune), compared with efavirenz, results in a more favorable lipid profile in previously untreated patients, as shown by larger increases in HDL-C and smaller increases in triglycerides at 48 weeks.⁴⁴

Etravirine (Intelence), the newest nonnucleoside reverse transcriptase inhibitor, does not appear to cause any further increase in lipids when added to a regimen containing darunavir-ritonavir and nucleoside agents.⁴⁵

Impact of nucleoside reverse transcriptase inhibitors on lipids

As a class, nucleoside reverse transcriptase inhibitors have been associated with mitochondrial toxicity and insulin resistance,⁴⁶ but the lipid changes associated with them are generally less significant than those caused by protease inhibitors or nonnucleoside reverse transcriptase inhibitors. Nevertheless, within the class, there is considerable variability in lipid changes associated with specific agents.

Stavudine (Zerit), for example, is associated with hypertriglyceridemia.

Tenofovir (Viread), for another example, in combination with emtricitabine (Emtriva) and the nonnucleoside reverse transcriptase inhibitor efavirenz (the three drugs are contained in a formulation called Atripla) was associated with a smaller increase in fasting total cholesterol than with zidovudine-lamivudine and efavirenz at 96 weeks.⁴⁷

A recent placebo-controlled, crossover, pilot study of 17 HIV-infected patients suggested that tenofovir may actually have independent lipid-lowering properties.⁴⁸

Abacavir, as discussed above, has been reported to be associated with a higher risk of myocardial infarction, but this is debatable.

MANAGING CORONARY RISK FACTORS IN HIV-INFECTED PATIENTS

Cardiovascular risk assessment

In HIV patients, cardiovascular risk can be assessed using models derived from large epidemiologic studies such as the Framingham Heart Study.⁴⁹

Current guidelines from the Infectious Diseases Society of America and the AIDS Clinical Trials Group (ACTG) for evaluating and managing dyslipidemia in HIV-infected adults are based on the National Cholesterol Education Program Adult Treatment Panel III.⁵⁰ They recommend obtaining a fasting lipid profile before starting antiretroviral therapy and within 3 to 6 months after starting a new regimen.

The guidelines also recommend stratifying risk by counting the number of cardiovascular risk factors, as is done for the general population. If the patient has more than two factors, the Framingham equation should be used to calculate the 10-year risk of myocardial infarction or cardiac death. Interventions should be offered for modifiable cardiovascular risk factors such as smoking, hypertension, physical inactivity, and diabetes mellitus. LDL-C goals should be determined, and lipid-lowering drugs should be initiated accordingly. If triglyceride levels are 200 to 500 mg/dL and levels of “non-HDL-C” (total cholesterol minus the HDL-C level) are high, a statin is recommended. If the triglyceride level is higher than 500 mg/dL, a fibrate should be started.⁵¹

 

 

Dyslipidemia management

In HIV patients, statin and fibrate therapy must be considered cautiously, given the important drug interactions with protease inhibitors and especially ritonavir. Many statins are metabolized by cytochrome P3A4, which protease inhibitors inhibit.

Statins generally considered safe to use with most protease inhibitors:

• Pravastatin (Pravachol)
• Rosuvastatin (Crestor)
• Atorvastatin (Lipitor).

Exceptions and caveats:

• Pravastatin should not be prescribed with boosted darunavir.
• Data for fluvastatin (Lescol) in HIV-infected patients on antiretroviral therapy are limited.
• Lovastatin (Mevacor) and simvastatin (Zocor) are contraindicated with protease inhibitor therapy.⁵²
• In contrast to the increase in statin levels seen with protease inhibitors, efavirenz lowers levels of simvastatin, pravastatin, and atorvastatin.^53,54

Ezetimibe (Zetia), which is metabolized independently of the cytochrome P450 system, has been shown to be safe and effective when given to HIV-infected patients on antiretroviral therapy.⁵⁸

Fenofibrate (Lofibra) is recommended by current guidelines for patients with elevated triglyceride levels (> 500 mg/dL).⁵¹ In the ACTG 5087 study, a combination of fenofibrate plus pravastatin was found to be safe and effective in improving lipid profiles.⁵⁹

Long-acting niacin resulted in significant improvements in triglycerides, total cholesterol, HDL-C, and LDL-C after 48 weeks of use, although insulin sensitivity worsened.⁶⁰

Fish oil has been shown to be an effective alternative to fibrates, or it can be used in combination with them.⁶¹

Switching antiretroviral agents vs adding lipid-lowering agents. In some patients with significant dyslipidemia, switching antiretro viral agents may lower lipid levels without compromising virologic control.⁶² However, due to the multifactorial nature of dyslipidemia in HIV patients on antiretroviral therapy, switching the HIV therapy alone may not result in sufficient improvement in the lipid profile⁴⁵ and may be associated with virologic failure, particularly among patients who have underlying treatment-resistant HIV.⁶³

In many cases, adding lipid-lowering agents may be more beneficial than switching the antiretroviral therapy. For example, a randomized trial in HIV-infected patients with hyperlipidemia found that adding a lipid-lowering agent such as pravastatin or bezafibrate to the unchanged antiretroviral regimen resulted in greater improvement in total cholesterol, LDL-C, and triglyceride levels than switching from a protease inhibitor to either nevirapine or efavirenz.⁶⁴

Given the complexity of prescribing lipid-lowering therapies to patients on antiretroviral therapy, we recommend that providers check with a pharmacist or refer to package inserts and other medical literature if they are unfamiliar with these drug interactions and responses to lipid-lowering therapies.

Managing insulin resistance

Diabetes mellitus is a well-known risk factor for coronary heart disease. The Data Collection on Adverse Events of Anti-HIV Drugs study found a higher incidence of coronary heart disease in HIV-infected patients, with higher rates in those with longer duration of diabetes.⁶⁵ The prevalence of diabetes in HIV-infected populations varies, depending on demographic characteristics,^65,66 prevalence of coinfection with hepatitis C virus,⁶⁶ and prevalence of exposure to antiretroviral drugs⁶⁷ in the study population.

Drugs that lessen insulin resistance include the thiazolidinedione rosiglitazone (Avandia) and the biguanide metformin (Glucophage). In a randomized trial, both drugs, alone or in combination, improved insulin sensitivity in HIV-infected patients, but neither lessened the amount of visceral or subcutaneous fat.⁶⁸

Smoking cessation

Smoking is another well-known modifiable risk factor for coronary heart disease.

The prevalence of smoking is usually higher in HIV patients than in HIV-negative people. For example, a French cohort study reported smoking prevalence rates of 56.6% in HIV-infected men vs 32.7% in HIV-negative men; in women, the rates were 58% vs 28.1%. The 5-year relative risk of coronary heart disease in HIV-infected vs HIV-negative persons was 1.20 for men and 1.59 for women. The estimated attributable risk due to smoking was 65% for men and 29% for women.³

Therefore, smoking cessation should be a top priority in managing cardiovascular risk in HIV-infected patients. In fact, control of modifiable risk factors through lifestyle changes such as smoking cessation, dietary changes, and exercise is likely to have a significant impact on cardiovascular risk in this population.

Widespread use of antiretroviral therapy has caused a remarkable decline in rates of morbidity and death related to acquired immunodeficiency syndrome (AIDS) and has effectively made human immunodeficiency virus (HIV) infection a manageable—although not yet curable— chronic condition. And as the HIV-infected population on antiretroviral therapy ages, the prevalence of chronic conditions (eg, cardiovascular disease, hepatic disease, pulmonary disease, non-AIDS cancers) and deaths attributable to these conditions have also increased.¹

Many of the traditional risk factors for cardiovascular disease in the general population, including smoking, dyslipidemia, and diabetes, are common in HIV-infected patients, and HIV infection itself independently increases the risk of coronary heart disease. In addition, different antiretroviral combinations can contribute, in varying degrees, to changes in lipid levels and insulin resistance, further increasing coronary risk.

Ultimately, however, the immunologic benefits of antiretroviral therapy for individual patients far exceed the modest increase in cardiovascular risk associated with certain regimens. In most cases, careful selection of the initial antiretroviral regimen and the addition of lipid-lowering or glucose-controlling medications (with close attention to drug interactions) can effectively manage the metabolic changes associated with antiretroviral therapy and obviate any premature modification of virologically suppressive regimens.

TRADITIONAL CARDIAC RISK FACTORS IN HIV PATIENTS

The risk of coronary heart disease in HIV patients is influenced mostly by traditional factors such as age, smoking, diabetes, and dyslipidemia, including high levels of total cholesterol and low-density lipoprotein cholesterol (LDL-C) and low levels of high-density lipoprotein cholesterol (HDL-C).²

In various large cohorts, HIV-infected men had a higher prevalence of smoking,³ a lower mean HDL-C level,^3,4 and a higher mean triglyceride level^3,4 than men without HIV infection, placing them at greater risk of coronary heart disease. However, even after adjusting for traditional risk factors, rates of atherosclerosis are still higher in people who are infected with HIV than in those who are not.⁵

EFFECT OF HIV INFECTION ON CORONARY RISK

HIV infection has been shown to increase coronary risk.

In the Kaiser Permanente database,⁶ HIV-positive patients had a significantly higher rate of hospitalizations for coronary heart disease than did people who were not infected.

Similarly, in a cohort study of almost 4,000 HIV-infected patients and more than 1 million controls, the risk of acute myocardial infarction was 75% higher for HIV-positive patients than for HIV-negative patients, even after adjusting for sex, race, hypertension, diabetes, and dyslipidemia.⁵

The Fat Redistribution and Metabolism (FRAM) cross-sectional study⁷ showed that HIV infection was associated with greater carotid intima media thickness, an established marker of atherosclerosis, independently of traditional risk factors and to virtually the same degree as smoking and male sex.

Other studies of subclinical atherosclerosis in HIV patients have yielded disparate results, likely because of differences in study design, methods of measuring carotid thickness, and characteristics of the study populations (eg, prevalence of cardiovascular risk factors and stage of HIV disease). However, a meta-analysis of six prospective cohort studies, three case-control studies, and four cross-sectional studies confirmed that HIV patients had slightly but statistically significantly greater carotid intima media thickness than HIV-negative people.⁸

MECHANISMS BY WHICH HIV MAY PROMOTE CORONARY HEART DISEASE

The pathogenesis of coronary heart disease in HIV infection has not been fully elucidated, but the virus appears to contribute directly to the accelerated development of atherosclerosis. It may do so through direct effects on cholesterol processing and transport, attraction of monocytes to the intimal wall, and activation of monocytes to induce an inflammatory response and endothelial proliferation.

Effects on lipids

In early HIV infection, levels of total cholesterol and HDL-C are lower. In more advanced infection, lower CD4+ lymphocyte counts have been associated with lower levels of apolipoprotein B and with smaller LDL-C particles, suggesting that HIV affects lipid processing and delivery to vessel walls.⁹ HIV infection is also associated with reduced clearance of LDL-C.¹⁰ HIV appears to specifically inhibit the compensatory efflux of excess cholesterol from macrophages, thus promoting the formation of foam cells in atherosclerotic plaque.¹¹

Attraction of monocytes to the vessel wall

In vitro studies also suggest that HIV enhances migration of monocytes into the vascular intima during atherosclerotic plaque development by promoting secretion of the chemokine monocyte chemoattractant protein 1¹² and the expression of endothelial cell adhesion molecules such as intercellular adhesion molecule 1, vascular cell adhesion molecule 1 (VCAM-1), and E-selectin.¹³

Inflammation

A recent study suggests that chronic inflammation may be a key contributor to the accelerated development of atherosclerosis in HIV patients. Hsue et al¹⁴ compared carotid intima media thickness and levels of C-reactive protein (a marker of systemic inflammation) in HIV-positive and HIV-negative patients. The carotid intima media thickness was greater in all groups of HIV patients, irrespective of level of viremia or exposure to antiretroviral therapy, than in healthy controls. In addition, C-reactive protein levels remained elevated in HIV-infected participants regardless of their level of viremia.

These findings suggest not only that HIV-associated atherosclerosis is determined by advanced immunodeficiency, high-level viremia, and exposure to antiretroviral drugs, but also that persistent inflammation due to HIV infection may play an important role in accelerated atherosclerosis.

EFFECT OF ANTIRETROVIRAL THERAPY ON CORONARY RISK

Antiretroviral therapy is associated with a small but significant increase in coronary risk.

Medi-Cal,¹⁵ a retrospective study of 28,513 patients, found antiretroviral therapy to be associated with coronary heart disease among patients 18 to 33 years of age (relative risk 2.06, P < .001).

The Data Collection on Adverse Events of Anti-HIV Drugs study¹⁶ prospectively followed 23,437 patients for 94,469 person-years. Adjusted for exposure to nonnucleoside reverse transcriptase inhibitors and for hypertension and diabetes, the relative risk of myocardial infarction per year of protease inhibitor exposure was 1.16 (95% confidence interval [CI] 1.10–1.23). The relative risk was lower after adjusting for serum lipid levels but remained significant at 1.10 (95% CI 1.04–1.18).

Reports have been mixed regarding a possible association between myocardial infarction and the nucleoside reverse transcriptase inhibitor abacavir (Ziagen): several studies found a statistically significant association,^17–20 and others did not.^21–23 Differences in study design (observational cohort studies vs prospective randomized clinical trials), populations studied (differing in age, cardiovascular risk factor prevalence, and whether the patients had already been exposed to treatment), and outcome definition probably contributed to the different conclusions.

On the other hand, several studies have shown that suppression of HIV with antiretroviral therapy actually improves some of the surrogate markers of cardiovascular disease. For example:

• Markers of endothelial function such as flow-mediated vasodilation improve significantly within 4 weeks of a patient’s starting antiretroviral therapy, regardless of the class of antiretroviral drug used.²⁴
• After viral suppression is achieved, levels of the markers of endothelial activation VCAM-1 and P-selectin decline significantly, as do levels of the adipocyte activation marker leptin and the coagulation marker D-dimer.^25,26
• Levels of the anti-inflammatory markers adiponectin and interleukin 10 increase. ^25,26

Interrupting antiretroviral therapy may increase coronary risk

Not only is uncontrolled viral replication in untreated HIV infection associated with cardiovascular disease, but interrupting antiretroviral therapy may result in a supplementary increase in coronary risk.

In the 5,472-patient Strategies for Management of Antiretroviral Therapy (SMART) trial, the rate of cardiovascular disease events was higher if treatment was interrupted than with continuous treatment, with a hazard ratio of 1.57 (95% CI 1.0–2.46, P = .05).²⁷

This association between treatment interruption and coronary events does not appear to be related to the level of viremia.²⁸ Rather, development of cardiovascular disease in HIV-infected patients who interrupt antiretroviral therapy may be mediated, to a large extent, by chronic inflammation in the setting of viral replication. In the treatment-interruption group, levels of the inflammatory cytokine interleukin 6 (IL-6) and the coagulation marker D-dimer were significantly elevated 1 month after randomization, and these differences were strongly associated with death (odds ratio [OR] 12.6, P < .0001 for IL-6; OR 13.1, P < .0001 for D-dimer). Elevated IL-6 levels were also significantly associated with the development of cardiovascular disease (OR 2.8, P = .03).²⁹

METABOLIC COMPLICATIONS OF ANTIRETROVIRAL THERAPY

Persons with HIV infection may experience metabolic complications that are due to HIV itself or to its treatment.

Cross-sectional studies that included HIV-negative patients as controls have demonstrated changes in lipid processing that are known to promote atherosclerosis. For example, persons with HIV infection have smaller LDL-C particles³⁰ and higher levels of circulating oxidized LDL-C.³¹

In the Multicenter AIDS Cohort Study (MACS), after HIV seroconversion, nonfasting total cholesterol, LDL-C, and HDL-C levels declined, which is consistent with a chronic inflammatory state. After antiretroviral therapy was started, lipid levels returned to baseline levels or slightly higher except for HDL-C, which remained low.⁹ These changes may be due to a general “return to health,” or they may be direct medication effects.

Similar patterns were seen in the SMART study.²⁸ Participants randomized to receive intermittent antiretroviral therapy had overall decreases in all lipid levels, with a marked reduction in HDL-C, while those randomized to receive continuous therapy had increased levels of all lipids, including HDL-C, at 12 months. Overall, the ratio of total cholesterol to HDL-C actually increased for participants on episodic therapy, while it decreased in the continuous-treatment group. Along with continued vascular inflammation, the low HDL-C may have contributed to the worse cardiovascular outcomes in patients who received intermittent antiretroviral therapy.

Some lipid changes associated with antiretroviral therapy may actually be beneficial. For example, nonnucleoside reverse transcriptase inhibitors may raise HDL-C levels. However, such increases alone do not necessarily offset the other lipid changes or translate to an observed improvement in coronary risk.³²

The degree of dyslipidemia and specific lipid changes differ among the different classes of antiretroviral drugs and even among the individual drugs within each class. Furthermore, the magnitude of the observed lipid changes varies widely among patients on the same antiretroviral regimen, reflecting the likely important role of host genomics.

While the protease inhibitors and nonnucleoside reverse transcriptase inhibitors have well-described effects on lipids (described in greater detail in the following sections), there have been no reported significant changes in lipid profiles or cardiovascular risk associated with the newest classes, ie, fusion inhibitors such as enfuvirtide (Fuzeon), CC chemokine receptor type 5 (CCR5) receptor inhibitors such as maraviroc (Selzentry), or integrase inhibitors such as raltegravir (Isentress).

 

 

Impact of protease inhibitors on lipids

Ritonavir (Norvir) and ritonavir-boosted protease inhibitor combinations cause the most significant increases in lipids. Currently, ritonavir is used in low doses to boost the levels of most other protease inhibitors as the standard of care in protease inhibitor-based regimens. However, in most patients, giving ritonavir with protease inhibitors raises lipid levels, particularly triglycerides.

Most boosted protease inhibitor regimens have similar effects on lipid levels, with some exceptions.

Tipranavir (Aptivus) plus ritonavir, for example, markedly raises total cholesterol and triglyceride levels and would not be recommended for patients with dyslipidemia at baseline.³³

Atazanavir (Reyataz)^34,35 plus ritonavir and darunavir (Prezista)³⁶ plus ritonavir cause more modest lipid changes. Unboosted atazanavir raises lipid levels only minimally, if at all,^34,35 but it is no longer a preferred regimen according to US Department of Health and Human Services guidelines.⁴²

Impact of nonnucleoside reverse transcriptase inhibitors on lipids

Efavirenz (Sustiva), a nonnucleoside reverse transcriptase inhibitor, when added to a regimen of two or three nucleoside reverse transcriptase inhibitors, resulted in modest increases in all lipids, including HDL-C (a potentially beneficial change) at 96 weeks compared with a regimen of three nucleoside reverse transcriptase inhibitors only.⁴³

Nevirapine (Viramune), compared with efavirenz, results in a more favorable lipid profile in previously untreated patients, as shown by larger increases in HDL-C and smaller increases in triglycerides at 48 weeks.⁴⁴

Etravirine (Intelence), the newest nonnucleoside reverse transcriptase inhibitor, does not appear to cause any further increase in lipids when added to a regimen containing darunavir-ritonavir and nucleoside agents.⁴⁵

Impact of nucleoside reverse transcriptase inhibitors on lipids

As a class, nucleoside reverse transcriptase inhibitors have been associated with mitochondrial toxicity and insulin resistance,⁴⁶ but the lipid changes associated with them are generally less significant than those caused by protease inhibitors or nonnucleoside reverse transcriptase inhibitors. Nevertheless, within the class, there is considerable variability in lipid changes associated with specific agents.

Stavudine (Zerit), for example, is associated with hypertriglyceridemia.

Tenofovir (Viread), for another example, in combination with emtricitabine (Emtriva) and the nonnucleoside reverse transcriptase inhibitor efavirenz (the three drugs are contained in a formulation called Atripla) was associated with a smaller increase in fasting total cholesterol than with zidovudine-lamivudine and efavirenz at 96 weeks.⁴⁷

A recent placebo-controlled, crossover, pilot study of 17 HIV-infected patients suggested that tenofovir may actually have independent lipid-lowering properties.⁴⁸

Abacavir, as discussed above, has been reported to be associated with a higher risk of myocardial infarction, but this is debatable.

MANAGING CORONARY RISK FACTORS IN HIV-INFECTED PATIENTS

Cardiovascular risk assessment

In HIV patients, cardiovascular risk can be assessed using models derived from large epidemiologic studies such as the Framingham Heart Study.⁴⁹

Current guidelines from the Infectious Diseases Society of America and the AIDS Clinical Trials Group (ACTG) for evaluating and managing dyslipidemia in HIV-infected adults are based on the National Cholesterol Education Program Adult Treatment Panel III.⁵⁰ They recommend obtaining a fasting lipid profile before starting antiretroviral therapy and within 3 to 6 months after starting a new regimen.

The guidelines also recommend stratifying risk by counting the number of cardiovascular risk factors, as is done for the general population. If the patient has more than two factors, the Framingham equation should be used to calculate the 10-year risk of myocardial infarction or cardiac death. Interventions should be offered for modifiable cardiovascular risk factors such as smoking, hypertension, physical inactivity, and diabetes mellitus. LDL-C goals should be determined, and lipid-lowering drugs should be initiated accordingly. If triglyceride levels are 200 to 500 mg/dL and levels of “non-HDL-C” (total cholesterol minus the HDL-C level) are high, a statin is recommended. If the triglyceride level is higher than 500 mg/dL, a fibrate should be started.⁵¹

 

 

Dyslipidemia management

In HIV patients, statin and fibrate therapy must be considered cautiously, given the important drug interactions with protease inhibitors and especially ritonavir. Many statins are metabolized by cytochrome P3A4, which protease inhibitors inhibit.

Statins generally considered safe to use with most protease inhibitors:

• Pravastatin (Pravachol)
• Rosuvastatin (Crestor)
• Atorvastatin (Lipitor).

Exceptions and caveats:

• Pravastatin should not be prescribed with boosted darunavir.
• Data for fluvastatin (Lescol) in HIV-infected patients on antiretroviral therapy are limited.
• Lovastatin (Mevacor) and simvastatin (Zocor) are contraindicated with protease inhibitor therapy.⁵²
• In contrast to the increase in statin levels seen with protease inhibitors, efavirenz lowers levels of simvastatin, pravastatin, and atorvastatin.^53,54

Ezetimibe (Zetia), which is metabolized independently of the cytochrome P450 system, has been shown to be safe and effective when given to HIV-infected patients on antiretroviral therapy.⁵⁸

Fenofibrate (Lofibra) is recommended by current guidelines for patients with elevated triglyceride levels (> 500 mg/dL).⁵¹ In the ACTG 5087 study, a combination of fenofibrate plus pravastatin was found to be safe and effective in improving lipid profiles.⁵⁹

Long-acting niacin resulted in significant improvements in triglycerides, total cholesterol, HDL-C, and LDL-C after 48 weeks of use, although insulin sensitivity worsened.⁶⁰

Fish oil has been shown to be an effective alternative to fibrates, or it can be used in combination with them.⁶¹

Switching antiretroviral agents vs adding lipid-lowering agents. In some patients with significant dyslipidemia, switching antiretro viral agents may lower lipid levels without compromising virologic control.⁶² However, due to the multifactorial nature of dyslipidemia in HIV patients on antiretroviral therapy, switching the HIV therapy alone may not result in sufficient improvement in the lipid profile⁴⁵ and may be associated with virologic failure, particularly among patients who have underlying treatment-resistant HIV.⁶³

In many cases, adding lipid-lowering agents may be more beneficial than switching the antiretroviral therapy. For example, a randomized trial in HIV-infected patients with hyperlipidemia found that adding a lipid-lowering agent such as pravastatin or bezafibrate to the unchanged antiretroviral regimen resulted in greater improvement in total cholesterol, LDL-C, and triglyceride levels than switching from a protease inhibitor to either nevirapine or efavirenz.⁶⁴

Given the complexity of prescribing lipid-lowering therapies to patients on antiretroviral therapy, we recommend that providers check with a pharmacist or refer to package inserts and other medical literature if they are unfamiliar with these drug interactions and responses to lipid-lowering therapies.

Managing insulin resistance

Diabetes mellitus is a well-known risk factor for coronary heart disease. The Data Collection on Adverse Events of Anti-HIV Drugs study found a higher incidence of coronary heart disease in HIV-infected patients, with higher rates in those with longer duration of diabetes.⁶⁵ The prevalence of diabetes in HIV-infected populations varies, depending on demographic characteristics,^65,66 prevalence of coinfection with hepatitis C virus,⁶⁶ and prevalence of exposure to antiretroviral drugs⁶⁷ in the study population.

Drugs that lessen insulin resistance include the thiazolidinedione rosiglitazone (Avandia) and the biguanide metformin (Glucophage). In a randomized trial, both drugs, alone or in combination, improved insulin sensitivity in HIV-infected patients, but neither lessened the amount of visceral or subcutaneous fat.⁶⁸

Smoking cessation

Smoking is another well-known modifiable risk factor for coronary heart disease.

The prevalence of smoking is usually higher in HIV patients than in HIV-negative people. For example, a French cohort study reported smoking prevalence rates of 56.6% in HIV-infected men vs 32.7% in HIV-negative men; in women, the rates were 58% vs 28.1%. The 5-year relative risk of coronary heart disease in HIV-infected vs HIV-negative persons was 1.20 for men and 1.59 for women. The estimated attributable risk due to smoking was 65% for men and 29% for women.³

Therefore, smoking cessation should be a top priority in managing cardiovascular risk in HIV-infected patients. In fact, control of modifiable risk factors through lifestyle changes such as smoking cessation, dietary changes, and exercise is likely to have a significant impact on cardiovascular risk in this population.

Although glucocorticoid drugs such as prednisone, methylprednisolone, and dexamethasone have many benefits, they are the number-one cause of secondary osteoporosis. ¹ When prescribing them for long-term therapy, physicians should take steps to prevent bone loss and fractures.

Being inexpensive and potent anti-inflammatory drugs, glucocorticoids are widely used to treat many diseases affecting millions of Americans, such as dermatologic conditions, inflammatory bowel disease, pulmonary diseases (eg, asthma, chronic obstructive pulmonary disease, interstitial lung disease), renal diseases (eg, glomerulonephritis), rheumatologic disorders (eg, rheumatoid arthritis, lupus, vasculitis, polymyalgia rheumatica), and transplant rejection.

This article discusses the mechanisms of glucocorticoid-induced bone loss and guidelines for preventing and treating it.

GLUCOCORTICOIDS PROMOTE BONE LOSS DIRECTLY AND INDIRECTLY

The pathophysiology of glucocorticoid-induced osteoporosis is much more complicated than was previously thought.

The older view was that these drugs mostly affect bone indirectly by inhibiting calcium absorption, causing secondary hyperparathyroidism. Indeed, they do inhibit calcium absorption from the gastrointestinal tract and induce renal calcium loss. However, most patients do not have elevated levels of parathyroid hormone.

Now, reduced bone formation rather than increased bone resorption is thought to be the predominant effect of glucocorticoids on bone turnover, as these drugs suppress the number and the activity of osteoblasts.

Direct effects on bone

Glucocorticoids directly affect bone cells in a number of ways—eg, by stimulating osteoclastogenesis, decreasing osteoblast function and life span, increasing osteoblast apoptosis, and impairing preosteoblast formation.²

Glucocorticoids also increase osteocyte apoptosis.³ Osteocytes, the most numerous bone cells, are thought to be an integral part of the “nervous system” of bone, directing bone-remodeling units to locations where repair of bone microfractures or removal of bone is needed. Osteocyte apoptosis caused by glucocorticoids may disrupt the signaling process, resulting in increased osteoclast activity in an area of apoptotic osteocytes and the inability to directly repair bone, thus impairing the bone’s ability to preserve its strength and architecture. Such disruption may affect bone quality and increase the risk of fracture independent of any decrease in bone mineral density. ⁴

Direct molecular effects

Glucocorticoids have been found to:

• Block the stimulatory effect of insulin-like growth factor 1 on bone formation⁵
• Oppose Wnt/beta-catenin signaling, resulting in decreased bone formation⁶
• Affect stromal cell differentiation, shunting cell formation towards more adipocyte formation so that fewer osteoblasts and chondrocytes are formed, resulting in less bone formation
• Increase levels of receptor activator of nuclear factor kappa (RANK) ligand and macrophage colony-stimulating factor and decrease levels of osteoprotegerin, resulting in increased osteoclastogenesis and increased bone resorption⁷
• Decrease estrogen, testosterone, and adrenal androgen levels, which also have adverse effects on bone cells.⁸

Inflammatory diseases also affect bone

Furthermore, many patients taking glucocorticoids are already at risk of osteoporosis because many of the diseases that require these drugs for treatment are associated with bone loss due to their inflammatory nature. In rheumatoid arthritis, RANK ligand, one of the cytokines involved in inflammation, causes bony erosions and also causes localized osteopenia. The malabsorption of calcium and vitamin D in inflammatory bowel disease is a cause of secondary osteoporosis.

Trabecular bone is affected first

The degree of bone loss in patients receiving glucocorticoids can vary markedly, depending on the skeletal site. Initially, these drugs affect trabecular bone because of its higher metabolic activity, but with prolonged use cortical bone is also affected.² Greater trabecular thinning is seen in glucocorticoid-induced osteoporosis than in postmenopausal osteoporosis, in which more trabecular perforations are seen.⁹

Bone loss occurs rapidly during the first few months of glucocorticoid therapy, followed by a slower but continued loss with ongoing use.

FRACTURE RISK INCREASES RAPIDLY

With this decrease in bone mass comes a rapid increase in fracture risk, which correlates with the dose of glucocorticoids and the duration of use.¹⁰ Vertebral fractures resulting from prolonged cortisone use were first described in 1954.¹¹

A dosage of 5 mg or more of prednisolone or its equivalent per day decreases bone mineral density and rapidly increases the risk of fracture over 3 to 6 months. The relative risks¹²:

• Any fracture—1.33 to 1.91
• Hip fracture—1.61 to 2.01
• Vertebral fracture—2.60 to 2.86
• Forearm fracture—1.09 to 1.13.

These risks are independent of age, sex, and underlying disease.¹²

Patients receiving glucocorticoids may suffer vertebral and hip fractures at higher bone mineral density values than patients with postmenopausal osteoporosis. In 2003, van Staa et al¹³ reported that, at any given bone mineral density, the incidence of new vertebral fracture in postmenopausal women receiving glucocorticoids was higher than in nonusers. This suggests that glucocorticoids have both a qualitative and a quantitative effect on bone.

Glucocorticoids also cause a form of myopathy, which increases the propensity to fall, further increasing the risk of fractures.

Fracture risk declines after oral glucocorticoids are stopped, reaching a relative risk of 1 approximately 2 years later.¹² However, keep in mind that the underlying conditions being treated by the glucocorticoids also increase the patient’s fracture risk. Therefore, the patient’s risk of fracture needs to be evaluated even after stopping the glucocorticoid.

INHALED STEROIDS IN HIGH DOSES MAY ALSO INCREASE RISK

Although inhaled glucocorticoids are generally believed not to affect bone, some evidence suggests that in high doses (> 2,000 μg/day) they may result in significant osteoporosis over several years.^14,15

In a retrospective cohort study, van Staa et al¹⁵ compared the risk of fracture in 171,000 patients taking the inhaled glucocorticoids fluticasone (Flovent), budesonide (Pulmicort), or beclomethasone (Beconase); 109,000 patients taking inhaled nonglucocorticoid bronchodilators; and 171,000 controls not using inhalers. They found no differences between the inhaled glucocorticoid and nonglucocorticoid bronchodilator groups in the risk of nonvertebral fracture. Users of inhaled glucocorticoids had a higher risk of fracture, particularly of the hip and spine, than did controls, but this may have been related more to the severity of the underlying respiratory disease than to the inhaled glucocorticoids.

Weldon et al¹⁶ suggested preventive measures to prevent glucocorticoid-induced effects on bone metabolism when prescribing inhaled glucocorticoids to children. They stated that prophylaxis against osteoporosis requires suspicion, assessment of bone density, supplemental calcium and vitamin D, and, if indicated, bisphosphonates to prevent bone fractures that could compromise the patient’s quality of life.

PREVENTING AND TREATING BONE LOSS DUE TO GLUCOCORTICOIDS

Effective options are available to prevent the deleterious effects of glucocorticoids on bone.

A plethora of guidelines offer direction on how to reduce fracture risk—ie, how to maintain bone mineral density while preventing additional bone loss, alleviating pain associated with existing fractures, maintaining and increasing muscle strength, and initiating lifestyle changes as needed.^17,18 Guidelines from the American College of Rheumatology (ACR),¹⁷ published in 2001, are being updated. United Kingdom (UK) guidelines,¹⁸ published in December 2002, differ slightly from those of the ACR.

Limit exposure to glucocorticoids

Oral glucocorticoids should be given in the lowest effective dose for the shortest possible time. However, there is no safe oral glucocorticoid dose with respect to bone. Alternate-day dosing suppresses the adrenal axis less but has the same effect as daily dosing with regard to bone.

Recommend lifestyle measures from day 1

All guidelines recommend that as soon as a patient is prescribed a glucocorticoid, the clinician should prescribe certain preventive measures, including:

• Smoking cessation
• Weight-bearing and strength-building exercises
• Calcium intake of 1,000 to 1,500 mg per day
• Vitamin D 800 to 1,000 IU per day.

Calcium and vitamin D for all

The Cochrane Database of Systematic Reviews¹⁹ evaluated the data supporting the recommendation to use calcium and vitamin D as preventive therapy in patients receiving glucocorticoids. Five trials with 274 patients were included in the meta-analysis. At 2 years after starting calcium and vitamin D, there was a significant weighted mean difference of 2.6% (95% confidence interval [CI] 0.7–4.5) between the treatment and control groups in lumbar spine bone mineral density.

The authors concluded that because calcium and vitamin D have low toxicity and are inexpensive, all patients starting glucocorticoids should also take a calcium and a vitamin D supplement prophylactically.

Bisphosphonates are effective and recommended

The ACR¹⁷ and UK¹⁸ guidelines said that bisphosphonates are effective for preventing and treating bone loss in patients receiving glucocorticoids.

More recently, Stoch et al²⁰ evaluated the efficacy and safety of alendronate (Fosamax) 70 mg weekly for preventing and treating bone loss in patients on glucocorticoid therapy. At 12 months, bone mineral density in the lumbar spine, trochanter, and total hip had increased from baseline in the alendronate group and was significantly higher than in the placebo group. At the same time, levels of biochemical markers of bone remodeling were significantly lower than at baseline in the alendronate group.

For premenopausal women, postmenopausal women on estrogen replacement therapy, and men, the ACR¹⁷ recommends risedronate (Actonel) 5 mg per day or alendronate 5 mg per day; for postmenopausal women not on estrogen, risedronate 5 mg per day or alendronate 10 mg per day is recommended.

 

 

Who should receive a bisphosphonate?

In men and postmenopausal women, the ACR¹⁷ recommends a bisphosphonate for patients starting long-term glucocorticoid treatment (ie, expected to last 3 months or more) in doses of 5 mg or more per day of prednisone or its equivalent, irrespective of bone mineral density values.

In patients already taking glucocorticoids, a bisphosphonate should be started if the bone mineral density is below a certain threshold. The rationale for using bone mineral thresholds instead of giving bisphosphonates to all is that these drugs have potentially significant side effects and so should not be prescribed if not needed. The appropriate threshold at which intervention should be considered in glucocorticoid-treated patients is a matter of controversy. Based on evidence that fractures occur at a higher bone mineral density in glucocorticoid-treated patients than in postmenopausal women, the UK guidelines¹⁸ recommend starting a bisphosphonate if the T score is less than −1.5 at the spine or hip, but the ACR¹⁷ guidelines propose a T-score cutoff of −1.0. Whichever cutoff is chosen, its significance in terms of absolute fracture risk will differ according to the age of the patient. Therefore, use of T scores as an intervention threshold is not advisable.

The ACR and the UK guidelines both recommend measuring the bone mineral density by dual-energy x-ray absorptiometry at baseline (even though preventive therapy is not based on this value) and repeating it 6 months later and then yearly.

In premenopausal women, bisphosphonates should be used with caution, as they cross the placenta and are teratogenic in animals. Nevertheless, the ACR guidelines¹⁷ state they can be given after appropriate counseling and instruction about contraception.

The UK guidelines¹⁸ note that in the large clinical trials of alendronate and risedronate, the incidence of vertebral fractures was low in premenopausal women, indicating a very low fracture risk. Therefore, the UK guidelines state that bone-active drugs should be reserved for premenopausal women who have very low bone mineral density or who suffer fragility fractures or who have other strong risk factors for fracture.

In children and adolescents, the data are insufficient to produce evidence-based guidelines for the prevention and treatment of glucocorticoid-induced osteoporosis. General measures include using the lowest effective dose of glucocorticoids for the shortest period of time, and considering alternate therapies, calcium and vitamin D supplementation, weight-bearing exercise, and proper nutrition.

Bisphosphonates are recommended when bone mineral density is falling despite these general measures and when “high-dose” glucocorticoids are likely to be used for a “prolonged” time, or in patients who have already had a fracture.²¹

Weekly doses may improve compliance

Risedronate is approved by the US Food and Drug Administration (FDA) for the prevention of glucocorticoid-induced osteoporosis, and both risedronate and alendronate are approved for its treatment.

The ACR guidelines recommend the FDA-approved (ie, daily) doses of alendronate and risedronate for glucocorticoid-induced osteoporosis. Most patients, however, are pre-scribed weekly doses of these two agents, as compliance is much greater with this schedule of administration.

Estrogen is being used more selectively

The 2001 ACR guidelines said that, although there were no randomized controlled trials of hormone replacement (or testosterone) therapy to prevent glucocorticoid-induced bone loss, patients receiving long-term glucocorticoid therapy who are hypogonadal should be offered hormone replacement therapy.¹⁷

In 2002, the principal results of the Women’s Health Initiative²² showed that hormone replacement therapy with estrogen and progesterone was associated with a higher risk of breast cancer. Since then, the consensus has been that hormone replacement therapy should be restricted to women with menopausal symptoms or to older women who cannot tolerate other therapies or who express a strong preference for hormone replacement therapy despite being informed about potential adverse events.²³

A role for testosterone?

Since a daily dose of more than 5 to 7.5 mg of prednisone increases the risk of gonadotropin and testosterone suppression,²⁴ testosterone replacement therapy has been used to treat glucocorticoid-induced osteoporosis in men.

In two placebo-controlled trials in men receiving glucocorticoid therapy for bronchial asthma or chronic obstructive pulmonary disease, testosterone therapy was associated with a significant 4% increase (95% CI 2–7) in bone mineral density in the lumbar spine.^25,26

While these studies cannot be considered conclusive in view of their small size and the lack of fracture data, the Endocrine Society currently recommends that men with chronic obstructive pulmonary disease who are receiving glucocorticoids, are hypogonadal, and have no contraindications to androgen replacement therapy (eg, prostate cancer) be offered testosterone therapy to preserve lean body mass and bone mineral density.²⁷

Calcitonin is not a first-line therapy

Neither the ACR nor the UK guidelines recommended calcitonin as first-line therapy.

A Cochrane systematic review²⁸ evaluated the data on the use of calcitonin to prevent and treat glucocorticoid-induced osteoporosis. Nine trials met the inclusion criteria, and included 221 patients randomized to receive calcitonin and 220 patients who received placebo. Calcitonin was more effective than placebo in preserving bone density in the lumbar spine, with a weighted mean difference of 2.8% (95% CI 1.4–4.3) at 6 months and 3.2% (95% CI 0.3–6.1) at 12 months. However, at 24 months, the lumbar spine bone mineral density was not statistically different between groups, nor was the relative risk of fractures. Calcitonin was given subcutaneously in one trial, in which it showed a substantially greater degree of prevention of bone loss than in the other trials, in which it was given nasally.

NEWLY APPROVED AND INVESTIGATIONAL AGENTS

Zoledronic acid once a year

Zoledronic acid (Reclast), a bisphosphonate given intravenously once a year, was approved for glucocorticoid-induced osteoporosis after the ACR and UK guidelines were published.

Zoledronic acid underwent a randomized multicenter, double-blind, active control trial²⁹ in 833 men and women, age range 18 to 85 years, who had glucocorticoid-induced osteoporosis (they had been treated with 7.5 mg per day or more of prednisone or its equivalent). Of these patients, 416 received a single infusion of 5 mg of zoledronic acid and daily oral placebo, and 417 received a single placebo infusion and daily oral risedronate 5 mg as an active control. All patients also received 1,000 mg of calcium and 400 to 1,000 IU of vitamin D per day. The study duration was 1 year.

Of those who had received a glucocorticoid for more than 3 months, those who received zoledronic acid had a significantly greater mean increase in lumbar spine bone mineral density compared with those in the oral risedronate group: 4.1% vs 2.7%, an absolute difference of 1.4% (P < .0001).

In those who had received a glucocorticoid for 3 months or less, those who received zoledronic acid also had a significantly greater mean increase in lumbar spine bone mineral density compared with those in the risedronate group at 1 year: 2.6% vs 0.6%, a treatment difference of 2% (P < .0001).

Bone biopsy specimens were obtained from 23 patients, 12 in the zoledronic acid group and 11 in the risedronate group.³⁰ Qualitative assessment showed normal bone architecture and quality without mineralization defects. Apparent reductions in activation frequency and remodeling rates were seen when compared with the histomorphometric results in the zoledronic acid postmenopausal osteoporosis population.³¹ The long-term consequences of this degree of suppression of bone remodeling in the glucocorticoid-treated patients are unknown.

The overall safety and tolerability of zoledronic acid in the glucocorticoid-induced osteoporosis population was similar to that in the postmenopausal osteoporosis clinical trial.^29,31 Adverse reactions reported in at least 2% of patients that were either not reported in the postmenopausal osteoporosis trial or were reported more frequently in the glucocorticoid-induced trial included the following: abdominal pain, musculoskeletal pain, nausea, and dyspepsia. The incidence of serious adverse events was similar in the zoledronic acid and the active control groups. In the zoledronic acid group, 2.2% of the patients withdrew from the study due to adverse events vs 1.4% in the active control group.

Teriparatide, a parathyroid hormone drug

Teriparatide (Forteo) consists of a fragment of the human parathyroid hormone molecule. It is given once daily by subcutaneous injection. It was also approved for treating glucocorticoid-induced osteoporosis after the current guidelines were written.

Teriparatide was compared with alendronate in a randomized, double-blind trial in patients with glucocorticoid-induced osteoporosis. ³² Entry criteria were treatment with at least 5 mg of prednisone per day for at least 3 months before screening and a T score of −2.0 or less in the lumbar spine, total hip, or femoral neck, or −1.0 or less plus one or more fragility fractures.

Eighty-three men and 345 women ages 21 or older were enrolled and randomized to receive injectable teriparatide 20 μg per day plus oral placebo or oral alendronate 10 mg per day plus injectable placebo. All of them also received calcium 1,000 mg per day and vitamin D 800 IU per day.

At 18 months, the bone mineral density had increased significantly more in the teriparatide group than in the alendronate group in the lumbar spine (P < .001) and in the total hip (P < .01). As expected, markers of bone turnover were suppressed in the alendronate group but were increased in the teriparatide group.

New vertebral fractures were found on radiography in 10 of 165 patients in the alendronate group vs 1 of 171 patients in the teriparatide group (P = .004). Clinical vertebral fractures occurred in 3 of 165 patients treated with alendronate but in none of the teriparatide-treated patients (P = .07). Nonvertebral fractures occurred in 8 of 214 patients treated with alendronate and 12 of 214 patients treated with teriparatide (P = .362). Three of 214 patients treated with alendronate suffered nonvertebral fragility fractures, compared with 5 of 214 patients treated with teriparatide (P = .455).

Denosumab, an antibody to RANK ligand

Denosumab (Prolia) is a fully human monoclonal antibody to RANK ligand. (Recall that glucocorticoids are associated with increases in RANK ligand and decreases in osteoprotegerin.) Denosumab is given subcutaneously in a dosage of 60 mg every 6 months. It was recently approved for the treatment of postmenopausal osteoporosis.

In a phase 2 study of denosumab³³ in men and women with rheumatoid arthritis (an independent risk factor for bone loss), the bone mineral density of the lumbar spine increased irrespective of whether the patients were treated with bisphosphonates and glucocorticoids.

ADHERENCE TO GUIDELINES IS POOR

Unfortunately, prevention and treatment in actual clinical practice still lag behind what is recommended in the current guidelines, even though multiple therapies are available.

In 2005, Blalock et al³⁴ expressed concerns about patients’ knowledge, beliefs, and behavior and the prevention and treatment of glucocorticoid-induced osteoporosis. They found that most patients taking oral glucocorticoids are not adequately educated about the prevention of osteoporosis, stating that “patients either are not being counseled or they are being counseled in a manner that is not sufficient to promote subsequent recall and behavior change.”³⁴ They concluded that research is needed to develop effective ways to educate patients about how to prevent glucocorticoid-induced osteoporosis.

Also in 2005, Curtis et al³⁵ reviewed the records of managed-care patients taking glucocorticoids, comparing the prescription of antiresorptive therapy and the use of over-the-counter calcium or vitamin D or both in the periods 2001 to 2003 vs 1995 to 1998. The frequency of bone mineral density measurement in 2001 to 2003 had increased threefold compared with 1995 to 1998, and the use of a prescription antiresorptive drug had increased approximately twofold. However, only 42% of the patients underwent bone mineral density testing or were prescribed bone-protective medicine. The rates were lowest for men, at 25%.

A CALL TO ACTION

Evidenced-based guidelines exist to guide the clinician in an attempt to prevent the deleterious effects of glucocorticoids on bone. Physicians, physician assistants, nurse practitioners, and pharmacists need to coordinate their effects to ensure that adherence to these guidelines improves. Only then will the bone health of patients treated with glucocorticoids improve.

Although glucocorticoid drugs such as prednisone, methylprednisolone, and dexamethasone have many benefits, they are the number-one cause of secondary osteoporosis. ¹ When prescribing them for long-term therapy, physicians should take steps to prevent bone loss and fractures.

Being inexpensive and potent anti-inflammatory drugs, glucocorticoids are widely used to treat many diseases affecting millions of Americans, such as dermatologic conditions, inflammatory bowel disease, pulmonary diseases (eg, asthma, chronic obstructive pulmonary disease, interstitial lung disease), renal diseases (eg, glomerulonephritis), rheumatologic disorders (eg, rheumatoid arthritis, lupus, vasculitis, polymyalgia rheumatica), and transplant rejection.

This article discusses the mechanisms of glucocorticoid-induced bone loss and guidelines for preventing and treating it.

GLUCOCORTICOIDS PROMOTE BONE LOSS DIRECTLY AND INDIRECTLY

The pathophysiology of glucocorticoid-induced osteoporosis is much more complicated than was previously thought.

The older view was that these drugs mostly affect bone indirectly by inhibiting calcium absorption, causing secondary hyperparathyroidism. Indeed, they do inhibit calcium absorption from the gastrointestinal tract and induce renal calcium loss. However, most patients do not have elevated levels of parathyroid hormone.

Now, reduced bone formation rather than increased bone resorption is thought to be the predominant effect of glucocorticoids on bone turnover, as these drugs suppress the number and the activity of osteoblasts.

Direct effects on bone

Glucocorticoids directly affect bone cells in a number of ways—eg, by stimulating osteoclastogenesis, decreasing osteoblast function and life span, increasing osteoblast apoptosis, and impairing preosteoblast formation.²

Glucocorticoids also increase osteocyte apoptosis.³ Osteocytes, the most numerous bone cells, are thought to be an integral part of the “nervous system” of bone, directing bone-remodeling units to locations where repair of bone microfractures or removal of bone is needed. Osteocyte apoptosis caused by glucocorticoids may disrupt the signaling process, resulting in increased osteoclast activity in an area of apoptotic osteocytes and the inability to directly repair bone, thus impairing the bone’s ability to preserve its strength and architecture. Such disruption may affect bone quality and increase the risk of fracture independent of any decrease in bone mineral density. ⁴

Direct molecular effects

Glucocorticoids have been found to:

• Block the stimulatory effect of insulin-like growth factor 1 on bone formation⁵
• Oppose Wnt/beta-catenin signaling, resulting in decreased bone formation⁶
• Affect stromal cell differentiation, shunting cell formation towards more adipocyte formation so that fewer osteoblasts and chondrocytes are formed, resulting in less bone formation
• Increase levels of receptor activator of nuclear factor kappa (RANK) ligand and macrophage colony-stimulating factor and decrease levels of osteoprotegerin, resulting in increased osteoclastogenesis and increased bone resorption⁷
• Decrease estrogen, testosterone, and adrenal androgen levels, which also have adverse effects on bone cells.⁸

Inflammatory diseases also affect bone

Furthermore, many patients taking glucocorticoids are already at risk of osteoporosis because many of the diseases that require these drugs for treatment are associated with bone loss due to their inflammatory nature. In rheumatoid arthritis, RANK ligand, one of the cytokines involved in inflammation, causes bony erosions and also causes localized osteopenia. The malabsorption of calcium and vitamin D in inflammatory bowel disease is a cause of secondary osteoporosis.

Trabecular bone is affected first

The degree of bone loss in patients receiving glucocorticoids can vary markedly, depending on the skeletal site. Initially, these drugs affect trabecular bone because of its higher metabolic activity, but with prolonged use cortical bone is also affected.² Greater trabecular thinning is seen in glucocorticoid-induced osteoporosis than in postmenopausal osteoporosis, in which more trabecular perforations are seen.⁹

Bone loss occurs rapidly during the first few months of glucocorticoid therapy, followed by a slower but continued loss with ongoing use.

FRACTURE RISK INCREASES RAPIDLY

With this decrease in bone mass comes a rapid increase in fracture risk, which correlates with the dose of glucocorticoids and the duration of use.¹⁰ Vertebral fractures resulting from prolonged cortisone use were first described in 1954.¹¹

A dosage of 5 mg or more of prednisolone or its equivalent per day decreases bone mineral density and rapidly increases the risk of fracture over 3 to 6 months. The relative risks¹²:

• Any fracture—1.33 to 1.91
• Hip fracture—1.61 to 2.01
• Vertebral fracture—2.60 to 2.86
• Forearm fracture—1.09 to 1.13.

These risks are independent of age, sex, and underlying disease.¹²

Patients receiving glucocorticoids may suffer vertebral and hip fractures at higher bone mineral density values than patients with postmenopausal osteoporosis. In 2003, van Staa et al¹³ reported that, at any given bone mineral density, the incidence of new vertebral fracture in postmenopausal women receiving glucocorticoids was higher than in nonusers. This suggests that glucocorticoids have both a qualitative and a quantitative effect on bone.

Glucocorticoids also cause a form of myopathy, which increases the propensity to fall, further increasing the risk of fractures.

Fracture risk declines after oral glucocorticoids are stopped, reaching a relative risk of 1 approximately 2 years later.¹² However, keep in mind that the underlying conditions being treated by the glucocorticoids also increase the patient’s fracture risk. Therefore, the patient’s risk of fracture needs to be evaluated even after stopping the glucocorticoid.

INHALED STEROIDS IN HIGH DOSES MAY ALSO INCREASE RISK

Although inhaled glucocorticoids are generally believed not to affect bone, some evidence suggests that in high doses (> 2,000 μg/day) they may result in significant osteoporosis over several years.^14,15

In a retrospective cohort study, van Staa et al¹⁵ compared the risk of fracture in 171,000 patients taking the inhaled glucocorticoids fluticasone (Flovent), budesonide (Pulmicort), or beclomethasone (Beconase); 109,000 patients taking inhaled nonglucocorticoid bronchodilators; and 171,000 controls not using inhalers. They found no differences between the inhaled glucocorticoid and nonglucocorticoid bronchodilator groups in the risk of nonvertebral fracture. Users of inhaled glucocorticoids had a higher risk of fracture, particularly of the hip and spine, than did controls, but this may have been related more to the severity of the underlying respiratory disease than to the inhaled glucocorticoids.

Weldon et al¹⁶ suggested preventive measures to prevent glucocorticoid-induced effects on bone metabolism when prescribing inhaled glucocorticoids to children. They stated that prophylaxis against osteoporosis requires suspicion, assessment of bone density, supplemental calcium and vitamin D, and, if indicated, bisphosphonates to prevent bone fractures that could compromise the patient’s quality of life.

PREVENTING AND TREATING BONE LOSS DUE TO GLUCOCORTICOIDS

Effective options are available to prevent the deleterious effects of glucocorticoids on bone.

A plethora of guidelines offer direction on how to reduce fracture risk—ie, how to maintain bone mineral density while preventing additional bone loss, alleviating pain associated with existing fractures, maintaining and increasing muscle strength, and initiating lifestyle changes as needed.^17,18 Guidelines from the American College of Rheumatology (ACR),¹⁷ published in 2001, are being updated. United Kingdom (UK) guidelines,¹⁸ published in December 2002, differ slightly from those of the ACR.

Limit exposure to glucocorticoids

Oral glucocorticoids should be given in the lowest effective dose for the shortest possible time. However, there is no safe oral glucocorticoid dose with respect to bone. Alternate-day dosing suppresses the adrenal axis less but has the same effect as daily dosing with regard to bone.

Recommend lifestyle measures from day 1

All guidelines recommend that as soon as a patient is prescribed a glucocorticoid, the clinician should prescribe certain preventive measures, including:

• Smoking cessation
• Weight-bearing and strength-building exercises
• Calcium intake of 1,000 to 1,500 mg per day
• Vitamin D 800 to 1,000 IU per day.

Calcium and vitamin D for all

The Cochrane Database of Systematic Reviews¹⁹ evaluated the data supporting the recommendation to use calcium and vitamin D as preventive therapy in patients receiving glucocorticoids. Five trials with 274 patients were included in the meta-analysis. At 2 years after starting calcium and vitamin D, there was a significant weighted mean difference of 2.6% (95% confidence interval [CI] 0.7–4.5) between the treatment and control groups in lumbar spine bone mineral density.

The authors concluded that because calcium and vitamin D have low toxicity and are inexpensive, all patients starting glucocorticoids should also take a calcium and a vitamin D supplement prophylactically.

Bisphosphonates are effective and recommended

The ACR¹⁷ and UK¹⁸ guidelines said that bisphosphonates are effective for preventing and treating bone loss in patients receiving glucocorticoids.

More recently, Stoch et al²⁰ evaluated the efficacy and safety of alendronate (Fosamax) 70 mg weekly for preventing and treating bone loss in patients on glucocorticoid therapy. At 12 months, bone mineral density in the lumbar spine, trochanter, and total hip had increased from baseline in the alendronate group and was significantly higher than in the placebo group. At the same time, levels of biochemical markers of bone remodeling were significantly lower than at baseline in the alendronate group.

For premenopausal women, postmenopausal women on estrogen replacement therapy, and men, the ACR¹⁷ recommends risedronate (Actonel) 5 mg per day or alendronate 5 mg per day; for postmenopausal women not on estrogen, risedronate 5 mg per day or alendronate 10 mg per day is recommended.

 

 

Who should receive a bisphosphonate?

In men and postmenopausal women, the ACR¹⁷ recommends a bisphosphonate for patients starting long-term glucocorticoid treatment (ie, expected to last 3 months or more) in doses of 5 mg or more per day of prednisone or its equivalent, irrespective of bone mineral density values.

In patients already taking glucocorticoids, a bisphosphonate should be started if the bone mineral density is below a certain threshold. The rationale for using bone mineral thresholds instead of giving bisphosphonates to all is that these drugs have potentially significant side effects and so should not be prescribed if not needed. The appropriate threshold at which intervention should be considered in glucocorticoid-treated patients is a matter of controversy. Based on evidence that fractures occur at a higher bone mineral density in glucocorticoid-treated patients than in postmenopausal women, the UK guidelines¹⁸ recommend starting a bisphosphonate if the T score is less than −1.5 at the spine or hip, but the ACR¹⁷ guidelines propose a T-score cutoff of −1.0. Whichever cutoff is chosen, its significance in terms of absolute fracture risk will differ according to the age of the patient. Therefore, use of T scores as an intervention threshold is not advisable.

The ACR and the UK guidelines both recommend measuring the bone mineral density by dual-energy x-ray absorptiometry at baseline (even though preventive therapy is not based on this value) and repeating it 6 months later and then yearly.

In premenopausal women, bisphosphonates should be used with caution, as they cross the placenta and are teratogenic in animals. Nevertheless, the ACR guidelines¹⁷ state they can be given after appropriate counseling and instruction about contraception.

The UK guidelines¹⁸ note that in the large clinical trials of alendronate and risedronate, the incidence of vertebral fractures was low in premenopausal women, indicating a very low fracture risk. Therefore, the UK guidelines state that bone-active drugs should be reserved for premenopausal women who have very low bone mineral density or who suffer fragility fractures or who have other strong risk factors for fracture.

In children and adolescents, the data are insufficient to produce evidence-based guidelines for the prevention and treatment of glucocorticoid-induced osteoporosis. General measures include using the lowest effective dose of glucocorticoids for the shortest period of time, and considering alternate therapies, calcium and vitamin D supplementation, weight-bearing exercise, and proper nutrition.

Bisphosphonates are recommended when bone mineral density is falling despite these general measures and when “high-dose” glucocorticoids are likely to be used for a “prolonged” time, or in patients who have already had a fracture.²¹

Weekly doses may improve compliance

Risedronate is approved by the US Food and Drug Administration (FDA) for the prevention of glucocorticoid-induced osteoporosis, and both risedronate and alendronate are approved for its treatment.

The ACR guidelines recommend the FDA-approved (ie, daily) doses of alendronate and risedronate for glucocorticoid-induced osteoporosis. Most patients, however, are pre-scribed weekly doses of these two agents, as compliance is much greater with this schedule of administration.

Estrogen is being used more selectively

The 2001 ACR guidelines said that, although there were no randomized controlled trials of hormone replacement (or testosterone) therapy to prevent glucocorticoid-induced bone loss, patients receiving long-term glucocorticoid therapy who are hypogonadal should be offered hormone replacement therapy.¹⁷

In 2002, the principal results of the Women’s Health Initiative²² showed that hormone replacement therapy with estrogen and progesterone was associated with a higher risk of breast cancer. Since then, the consensus has been that hormone replacement therapy should be restricted to women with menopausal symptoms or to older women who cannot tolerate other therapies or who express a strong preference for hormone replacement therapy despite being informed about potential adverse events.²³

A role for testosterone?

Since a daily dose of more than 5 to 7.5 mg of prednisone increases the risk of gonadotropin and testosterone suppression,²⁴ testosterone replacement therapy has been used to treat glucocorticoid-induced osteoporosis in men.

In two placebo-controlled trials in men receiving glucocorticoid therapy for bronchial asthma or chronic obstructive pulmonary disease, testosterone therapy was associated with a significant 4% increase (95% CI 2–7) in bone mineral density in the lumbar spine.^25,26

While these studies cannot be considered conclusive in view of their small size and the lack of fracture data, the Endocrine Society currently recommends that men with chronic obstructive pulmonary disease who are receiving glucocorticoids, are hypogonadal, and have no contraindications to androgen replacement therapy (eg, prostate cancer) be offered testosterone therapy to preserve lean body mass and bone mineral density.²⁷

Calcitonin is not a first-line therapy

Neither the ACR nor the UK guidelines recommended calcitonin as first-line therapy.

A Cochrane systematic review²⁸ evaluated the data on the use of calcitonin to prevent and treat glucocorticoid-induced osteoporosis. Nine trials met the inclusion criteria, and included 221 patients randomized to receive calcitonin and 220 patients who received placebo. Calcitonin was more effective than placebo in preserving bone density in the lumbar spine, with a weighted mean difference of 2.8% (95% CI 1.4–4.3) at 6 months and 3.2% (95% CI 0.3–6.1) at 12 months. However, at 24 months, the lumbar spine bone mineral density was not statistically different between groups, nor was the relative risk of fractures. Calcitonin was given subcutaneously in one trial, in which it showed a substantially greater degree of prevention of bone loss than in the other trials, in which it was given nasally.

NEWLY APPROVED AND INVESTIGATIONAL AGENTS

Zoledronic acid once a year

Zoledronic acid (Reclast), a bisphosphonate given intravenously once a year, was approved for glucocorticoid-induced osteoporosis after the ACR and UK guidelines were published.

Zoledronic acid underwent a randomized multicenter, double-blind, active control trial²⁹ in 833 men and women, age range 18 to 85 years, who had glucocorticoid-induced osteoporosis (they had been treated with 7.5 mg per day or more of prednisone or its equivalent). Of these patients, 416 received a single infusion of 5 mg of zoledronic acid and daily oral placebo, and 417 received a single placebo infusion and daily oral risedronate 5 mg as an active control. All patients also received 1,000 mg of calcium and 400 to 1,000 IU of vitamin D per day. The study duration was 1 year.

Of those who had received a glucocorticoid for more than 3 months, those who received zoledronic acid had a significantly greater mean increase in lumbar spine bone mineral density compared with those in the oral risedronate group: 4.1% vs 2.7%, an absolute difference of 1.4% (P < .0001).

In those who had received a glucocorticoid for 3 months or less, those who received zoledronic acid also had a significantly greater mean increase in lumbar spine bone mineral density compared with those in the risedronate group at 1 year: 2.6% vs 0.6%, a treatment difference of 2% (P < .0001).

Bone biopsy specimens were obtained from 23 patients, 12 in the zoledronic acid group and 11 in the risedronate group.³⁰ Qualitative assessment showed normal bone architecture and quality without mineralization defects. Apparent reductions in activation frequency and remodeling rates were seen when compared with the histomorphometric results in the zoledronic acid postmenopausal osteoporosis population.³¹ The long-term consequences of this degree of suppression of bone remodeling in the glucocorticoid-treated patients are unknown.

The overall safety and tolerability of zoledronic acid in the glucocorticoid-induced osteoporosis population was similar to that in the postmenopausal osteoporosis clinical trial.^29,31 Adverse reactions reported in at least 2% of patients that were either not reported in the postmenopausal osteoporosis trial or were reported more frequently in the glucocorticoid-induced trial included the following: abdominal pain, musculoskeletal pain, nausea, and dyspepsia. The incidence of serious adverse events was similar in the zoledronic acid and the active control groups. In the zoledronic acid group, 2.2% of the patients withdrew from the study due to adverse events vs 1.4% in the active control group.

Teriparatide, a parathyroid hormone drug

Teriparatide (Forteo) consists of a fragment of the human parathyroid hormone molecule. It is given once daily by subcutaneous injection. It was also approved for treating glucocorticoid-induced osteoporosis after the current guidelines were written.

Teriparatide was compared with alendronate in a randomized, double-blind trial in patients with glucocorticoid-induced osteoporosis. ³² Entry criteria were treatment with at least 5 mg of prednisone per day for at least 3 months before screening and a T score of −2.0 or less in the lumbar spine, total hip, or femoral neck, or −1.0 or less plus one or more fragility fractures.

Eighty-three men and 345 women ages 21 or older were enrolled and randomized to receive injectable teriparatide 20 μg per day plus oral placebo or oral alendronate 10 mg per day plus injectable placebo. All of them also received calcium 1,000 mg per day and vitamin D 800 IU per day.

At 18 months, the bone mineral density had increased significantly more in the teriparatide group than in the alendronate group in the lumbar spine (P < .001) and in the total hip (P < .01). As expected, markers of bone turnover were suppressed in the alendronate group but were increased in the teriparatide group.

New vertebral fractures were found on radiography in 10 of 165 patients in the alendronate group vs 1 of 171 patients in the teriparatide group (P = .004). Clinical vertebral fractures occurred in 3 of 165 patients treated with alendronate but in none of the teriparatide-treated patients (P = .07). Nonvertebral fractures occurred in 8 of 214 patients treated with alendronate and 12 of 214 patients treated with teriparatide (P = .362). Three of 214 patients treated with alendronate suffered nonvertebral fragility fractures, compared with 5 of 214 patients treated with teriparatide (P = .455).

Denosumab, an antibody to RANK ligand

Denosumab (Prolia) is a fully human monoclonal antibody to RANK ligand. (Recall that glucocorticoids are associated with increases in RANK ligand and decreases in osteoprotegerin.) Denosumab is given subcutaneously in a dosage of 60 mg every 6 months. It was recently approved for the treatment of postmenopausal osteoporosis.

In a phase 2 study of denosumab³³ in men and women with rheumatoid arthritis (an independent risk factor for bone loss), the bone mineral density of the lumbar spine increased irrespective of whether the patients were treated with bisphosphonates and glucocorticoids.

ADHERENCE TO GUIDELINES IS POOR

Unfortunately, prevention and treatment in actual clinical practice still lag behind what is recommended in the current guidelines, even though multiple therapies are available.

In 2005, Blalock et al³⁴ expressed concerns about patients’ knowledge, beliefs, and behavior and the prevention and treatment of glucocorticoid-induced osteoporosis. They found that most patients taking oral glucocorticoids are not adequately educated about the prevention of osteoporosis, stating that “patients either are not being counseled or they are being counseled in a manner that is not sufficient to promote subsequent recall and behavior change.”³⁴ They concluded that research is needed to develop effective ways to educate patients about how to prevent glucocorticoid-induced osteoporosis.

Also in 2005, Curtis et al³⁵ reviewed the records of managed-care patients taking glucocorticoids, comparing the prescription of antiresorptive therapy and the use of over-the-counter calcium or vitamin D or both in the periods 2001 to 2003 vs 1995 to 1998. The frequency of bone mineral density measurement in 2001 to 2003 had increased threefold compared with 1995 to 1998, and the use of a prescription antiresorptive drug had increased approximately twofold. However, only 42% of the patients underwent bone mineral density testing or were prescribed bone-protective medicine. The rates were lowest for men, at 25%.

A CALL TO ACTION

Evidenced-based guidelines exist to guide the clinician in an attempt to prevent the deleterious effects of glucocorticoids on bone. Physicians, physician assistants, nurse practitioners, and pharmacists need to coordinate their effects to ensure that adherence to these guidelines improves. Only then will the bone health of patients treated with glucocorticoids improve.

Although glucocorticoid drugs such as prednisone, methylprednisolone, and dexamethasone have many benefits, they are the number-one cause of secondary osteoporosis. ¹ When prescribing them for long-term therapy, physicians should take steps to prevent bone loss and fractures.

Being inexpensive and potent anti-inflammatory drugs, glucocorticoids are widely used to treat many diseases affecting millions of Americans, such as dermatologic conditions, inflammatory bowel disease, pulmonary diseases (eg, asthma, chronic obstructive pulmonary disease, interstitial lung disease), renal diseases (eg, glomerulonephritis), rheumatologic disorders (eg, rheumatoid arthritis, lupus, vasculitis, polymyalgia rheumatica), and transplant rejection.

This article discusses the mechanisms of glucocorticoid-induced bone loss and guidelines for preventing and treating it.

GLUCOCORTICOIDS PROMOTE BONE LOSS DIRECTLY AND INDIRECTLY

The pathophysiology of glucocorticoid-induced osteoporosis is much more complicated than was previously thought.

The older view was that these drugs mostly affect bone indirectly by inhibiting calcium absorption, causing secondary hyperparathyroidism. Indeed, they do inhibit calcium absorption from the gastrointestinal tract and induce renal calcium loss. However, most patients do not have elevated levels of parathyroid hormone.

Now, reduced bone formation rather than increased bone resorption is thought to be the predominant effect of glucocorticoids on bone turnover, as these drugs suppress the number and the activity of osteoblasts.

Direct effects on bone

Glucocorticoids directly affect bone cells in a number of ways—eg, by stimulating osteoclastogenesis, decreasing osteoblast function and life span, increasing osteoblast apoptosis, and impairing preosteoblast formation.²

Glucocorticoids also increase osteocyte apoptosis.³ Osteocytes, the most numerous bone cells, are thought to be an integral part of the “nervous system” of bone, directing bone-remodeling units to locations where repair of bone microfractures or removal of bone is needed. Osteocyte apoptosis caused by glucocorticoids may disrupt the signaling process, resulting in increased osteoclast activity in an area of apoptotic osteocytes and the inability to directly repair bone, thus impairing the bone’s ability to preserve its strength and architecture. Such disruption may affect bone quality and increase the risk of fracture independent of any decrease in bone mineral density. ⁴

Direct molecular effects

Glucocorticoids have been found to:

• Block the stimulatory effect of insulin-like growth factor 1 on bone formation⁵
• Oppose Wnt/beta-catenin signaling, resulting in decreased bone formation⁶
• Affect stromal cell differentiation, shunting cell formation towards more adipocyte formation so that fewer osteoblasts and chondrocytes are formed, resulting in less bone formation
• Increase levels of receptor activator of nuclear factor kappa (RANK) ligand and macrophage colony-stimulating factor and decrease levels of osteoprotegerin, resulting in increased osteoclastogenesis and increased bone resorption⁷
• Decrease estrogen, testosterone, and adrenal androgen levels, which also have adverse effects on bone cells.⁸

Inflammatory diseases also affect bone

Furthermore, many patients taking glucocorticoids are already at risk of osteoporosis because many of the diseases that require these drugs for treatment are associated with bone loss due to their inflammatory nature. In rheumatoid arthritis, RANK ligand, one of the cytokines involved in inflammation, causes bony erosions and also causes localized osteopenia. The malabsorption of calcium and vitamin D in inflammatory bowel disease is a cause of secondary osteoporosis.

Trabecular bone is affected first

The degree of bone loss in patients receiving glucocorticoids can vary markedly, depending on the skeletal site. Initially, these drugs affect trabecular bone because of its higher metabolic activity, but with prolonged use cortical bone is also affected.² Greater trabecular thinning is seen in glucocorticoid-induced osteoporosis than in postmenopausal osteoporosis, in which more trabecular perforations are seen.⁹

Bone loss occurs rapidly during the first few months of glucocorticoid therapy, followed by a slower but continued loss with ongoing use.

FRACTURE RISK INCREASES RAPIDLY

With this decrease in bone mass comes a rapid increase in fracture risk, which correlates with the dose of glucocorticoids and the duration of use.¹⁰ Vertebral fractures resulting from prolonged cortisone use were first described in 1954.¹¹

A dosage of 5 mg or more of prednisolone or its equivalent per day decreases bone mineral density and rapidly increases the risk of fracture over 3 to 6 months. The relative risks¹²:

• Any fracture—1.33 to 1.91
• Hip fracture—1.61 to 2.01
• Vertebral fracture—2.60 to 2.86
• Forearm fracture—1.09 to 1.13.

These risks are independent of age, sex, and underlying disease.¹²

Patients receiving glucocorticoids may suffer vertebral and hip fractures at higher bone mineral density values than patients with postmenopausal osteoporosis. In 2003, van Staa et al¹³ reported that, at any given bone mineral density, the incidence of new vertebral fracture in postmenopausal women receiving glucocorticoids was higher than in nonusers. This suggests that glucocorticoids have both a qualitative and a quantitative effect on bone.

Glucocorticoids also cause a form of myopathy, which increases the propensity to fall, further increasing the risk of fractures.

Fracture risk declines after oral glucocorticoids are stopped, reaching a relative risk of 1 approximately 2 years later.¹² However, keep in mind that the underlying conditions being treated by the glucocorticoids also increase the patient’s fracture risk. Therefore, the patient’s risk of fracture needs to be evaluated even after stopping the glucocorticoid.

INHALED STEROIDS IN HIGH DOSES MAY ALSO INCREASE RISK

Although inhaled glucocorticoids are generally believed not to affect bone, some evidence suggests that in high doses (> 2,000 μg/day) they may result in significant osteoporosis over several years.^14,15

In a retrospective cohort study, van Staa et al¹⁵ compared the risk of fracture in 171,000 patients taking the inhaled glucocorticoids fluticasone (Flovent), budesonide (Pulmicort), or beclomethasone (Beconase); 109,000 patients taking inhaled nonglucocorticoid bronchodilators; and 171,000 controls not using inhalers. They found no differences between the inhaled glucocorticoid and nonglucocorticoid bronchodilator groups in the risk of nonvertebral fracture. Users of inhaled glucocorticoids had a higher risk of fracture, particularly of the hip and spine, than did controls, but this may have been related more to the severity of the underlying respiratory disease than to the inhaled glucocorticoids.

Weldon et al¹⁶ suggested preventive measures to prevent glucocorticoid-induced effects on bone metabolism when prescribing inhaled glucocorticoids to children. They stated that prophylaxis against osteoporosis requires suspicion, assessment of bone density, supplemental calcium and vitamin D, and, if indicated, bisphosphonates to prevent bone fractures that could compromise the patient’s quality of life.

PREVENTING AND TREATING BONE LOSS DUE TO GLUCOCORTICOIDS

Effective options are available to prevent the deleterious effects of glucocorticoids on bone.

A plethora of guidelines offer direction on how to reduce fracture risk—ie, how to maintain bone mineral density while preventing additional bone loss, alleviating pain associated with existing fractures, maintaining and increasing muscle strength, and initiating lifestyle changes as needed.^17,18 Guidelines from the American College of Rheumatology (ACR),¹⁷ published in 2001, are being updated. United Kingdom (UK) guidelines,¹⁸ published in December 2002, differ slightly from those of the ACR.

Limit exposure to glucocorticoids

Oral glucocorticoids should be given in the lowest effective dose for the shortest possible time. However, there is no safe oral glucocorticoid dose with respect to bone. Alternate-day dosing suppresses the adrenal axis less but has the same effect as daily dosing with regard to bone.

Recommend lifestyle measures from day 1

All guidelines recommend that as soon as a patient is prescribed a glucocorticoid, the clinician should prescribe certain preventive measures, including:

• Smoking cessation
• Weight-bearing and strength-building exercises
• Calcium intake of 1,000 to 1,500 mg per day
• Vitamin D 800 to 1,000 IU per day.

Calcium and vitamin D for all

The Cochrane Database of Systematic Reviews¹⁹ evaluated the data supporting the recommendation to use calcium and vitamin D as preventive therapy in patients receiving glucocorticoids. Five trials with 274 patients were included in the meta-analysis. At 2 years after starting calcium and vitamin D, there was a significant weighted mean difference of 2.6% (95% confidence interval [CI] 0.7–4.5) between the treatment and control groups in lumbar spine bone mineral density.

The authors concluded that because calcium and vitamin D have low toxicity and are inexpensive, all patients starting glucocorticoids should also take a calcium and a vitamin D supplement prophylactically.

Bisphosphonates are effective and recommended

The ACR¹⁷ and UK¹⁸ guidelines said that bisphosphonates are effective for preventing and treating bone loss in patients receiving glucocorticoids.

More recently, Stoch et al²⁰ evaluated the efficacy and safety of alendronate (Fosamax) 70 mg weekly for preventing and treating bone loss in patients on glucocorticoid therapy. At 12 months, bone mineral density in the lumbar spine, trochanter, and total hip had increased from baseline in the alendronate group and was significantly higher than in the placebo group. At the same time, levels of biochemical markers of bone remodeling were significantly lower than at baseline in the alendronate group.

For premenopausal women, postmenopausal women on estrogen replacement therapy, and men, the ACR¹⁷ recommends risedronate (Actonel) 5 mg per day or alendronate 5 mg per day; for postmenopausal women not on estrogen, risedronate 5 mg per day or alendronate 10 mg per day is recommended.

 

 

Who should receive a bisphosphonate?

In men and postmenopausal women, the ACR¹⁷ recommends a bisphosphonate for patients starting long-term glucocorticoid treatment (ie, expected to last 3 months or more) in doses of 5 mg or more per day of prednisone or its equivalent, irrespective of bone mineral density values.

In patients already taking glucocorticoids, a bisphosphonate should be started if the bone mineral density is below a certain threshold. The rationale for using bone mineral thresholds instead of giving bisphosphonates to all is that these drugs have potentially significant side effects and so should not be prescribed if not needed. The appropriate threshold at which intervention should be considered in glucocorticoid-treated patients is a matter of controversy. Based on evidence that fractures occur at a higher bone mineral density in glucocorticoid-treated patients than in postmenopausal women, the UK guidelines¹⁸ recommend starting a bisphosphonate if the T score is less than −1.5 at the spine or hip, but the ACR¹⁷ guidelines propose a T-score cutoff of −1.0. Whichever cutoff is chosen, its significance in terms of absolute fracture risk will differ according to the age of the patient. Therefore, use of T scores as an intervention threshold is not advisable.

The ACR and the UK guidelines both recommend measuring the bone mineral density by dual-energy x-ray absorptiometry at baseline (even though preventive therapy is not based on this value) and repeating it 6 months later and then yearly.

In premenopausal women, bisphosphonates should be used with caution, as they cross the placenta and are teratogenic in animals. Nevertheless, the ACR guidelines¹⁷ state they can be given after appropriate counseling and instruction about contraception.

The UK guidelines¹⁸ note that in the large clinical trials of alendronate and risedronate, the incidence of vertebral fractures was low in premenopausal women, indicating a very low fracture risk. Therefore, the UK guidelines state that bone-active drugs should be reserved for premenopausal women who have very low bone mineral density or who suffer fragility fractures or who have other strong risk factors for fracture.

In children and adolescents, the data are insufficient to produce evidence-based guidelines for the prevention and treatment of glucocorticoid-induced osteoporosis. General measures include using the lowest effective dose of glucocorticoids for the shortest period of time, and considering alternate therapies, calcium and vitamin D supplementation, weight-bearing exercise, and proper nutrition.

Bisphosphonates are recommended when bone mineral density is falling despite these general measures and when “high-dose” glucocorticoids are likely to be used for a “prolonged” time, or in patients who have already had a fracture.²¹

Weekly doses may improve compliance

Risedronate is approved by the US Food and Drug Administration (FDA) for the prevention of glucocorticoid-induced osteoporosis, and both risedronate and alendronate are approved for its treatment.

The ACR guidelines recommend the FDA-approved (ie, daily) doses of alendronate and risedronate for glucocorticoid-induced osteoporosis. Most patients, however, are pre-scribed weekly doses of these two agents, as compliance is much greater with this schedule of administration.

Estrogen is being used more selectively

The 2001 ACR guidelines said that, although there were no randomized controlled trials of hormone replacement (or testosterone) therapy to prevent glucocorticoid-induced bone loss, patients receiving long-term glucocorticoid therapy who are hypogonadal should be offered hormone replacement therapy.¹⁷

In 2002, the principal results of the Women’s Health Initiative²² showed that hormone replacement therapy with estrogen and progesterone was associated with a higher risk of breast cancer. Since then, the consensus has been that hormone replacement therapy should be restricted to women with menopausal symptoms or to older women who cannot tolerate other therapies or who express a strong preference for hormone replacement therapy despite being informed about potential adverse events.²³

A role for testosterone?

Since a daily dose of more than 5 to 7.5 mg of prednisone increases the risk of gonadotropin and testosterone suppression,²⁴ testosterone replacement therapy has been used to treat glucocorticoid-induced osteoporosis in men.

In two placebo-controlled trials in men receiving glucocorticoid therapy for bronchial asthma or chronic obstructive pulmonary disease, testosterone therapy was associated with a significant 4% increase (95% CI 2–7) in bone mineral density in the lumbar spine.^25,26

While these studies cannot be considered conclusive in view of their small size and the lack of fracture data, the Endocrine Society currently recommends that men with chronic obstructive pulmonary disease who are receiving glucocorticoids, are hypogonadal, and have no contraindications to androgen replacement therapy (eg, prostate cancer) be offered testosterone therapy to preserve lean body mass and bone mineral density.²⁷

Calcitonin is not a first-line therapy

Neither the ACR nor the UK guidelines recommended calcitonin as first-line therapy.

A Cochrane systematic review²⁸ evaluated the data on the use of calcitonin to prevent and treat glucocorticoid-induced osteoporosis. Nine trials met the inclusion criteria, and included 221 patients randomized to receive calcitonin and 220 patients who received placebo. Calcitonin was more effective than placebo in preserving bone density in the lumbar spine, with a weighted mean difference of 2.8% (95% CI 1.4–4.3) at 6 months and 3.2% (95% CI 0.3–6.1) at 12 months. However, at 24 months, the lumbar spine bone mineral density was not statistically different between groups, nor was the relative risk of fractures. Calcitonin was given subcutaneously in one trial, in which it showed a substantially greater degree of prevention of bone loss than in the other trials, in which it was given nasally.

NEWLY APPROVED AND INVESTIGATIONAL AGENTS

Zoledronic acid once a year

Zoledronic acid (Reclast), a bisphosphonate given intravenously once a year, was approved for glucocorticoid-induced osteoporosis after the ACR and UK guidelines were published.

Zoledronic acid underwent a randomized multicenter, double-blind, active control trial²⁹ in 833 men and women, age range 18 to 85 years, who had glucocorticoid-induced osteoporosis (they had been treated with 7.5 mg per day or more of prednisone or its equivalent). Of these patients, 416 received a single infusion of 5 mg of zoledronic acid and daily oral placebo, and 417 received a single placebo infusion and daily oral risedronate 5 mg as an active control. All patients also received 1,000 mg of calcium and 400 to 1,000 IU of vitamin D per day. The study duration was 1 year.

Of those who had received a glucocorticoid for more than 3 months, those who received zoledronic acid had a significantly greater mean increase in lumbar spine bone mineral density compared with those in the oral risedronate group: 4.1% vs 2.7%, an absolute difference of 1.4% (P < .0001).

In those who had received a glucocorticoid for 3 months or less, those who received zoledronic acid also had a significantly greater mean increase in lumbar spine bone mineral density compared with those in the risedronate group at 1 year: 2.6% vs 0.6%, a treatment difference of 2% (P < .0001).

Bone biopsy specimens were obtained from 23 patients, 12 in the zoledronic acid group and 11 in the risedronate group.³⁰ Qualitative assessment showed normal bone architecture and quality without mineralization defects. Apparent reductions in activation frequency and remodeling rates were seen when compared with the histomorphometric results in the zoledronic acid postmenopausal osteoporosis population.³¹ The long-term consequences of this degree of suppression of bone remodeling in the glucocorticoid-treated patients are unknown.

The overall safety and tolerability of zoledronic acid in the glucocorticoid-induced osteoporosis population was similar to that in the postmenopausal osteoporosis clinical trial.^29,31 Adverse reactions reported in at least 2% of patients that were either not reported in the postmenopausal osteoporosis trial or were reported more frequently in the glucocorticoid-induced trial included the following: abdominal pain, musculoskeletal pain, nausea, and dyspepsia. The incidence of serious adverse events was similar in the zoledronic acid and the active control groups. In the zoledronic acid group, 2.2% of the patients withdrew from the study due to adverse events vs 1.4% in the active control group.

Teriparatide, a parathyroid hormone drug

Teriparatide (Forteo) consists of a fragment of the human parathyroid hormone molecule. It is given once daily by subcutaneous injection. It was also approved for treating glucocorticoid-induced osteoporosis after the current guidelines were written.

Teriparatide was compared with alendronate in a randomized, double-blind trial in patients with glucocorticoid-induced osteoporosis. ³² Entry criteria were treatment with at least 5 mg of prednisone per day for at least 3 months before screening and a T score of −2.0 or less in the lumbar spine, total hip, or femoral neck, or −1.0 or less plus one or more fragility fractures.

Eighty-three men and 345 women ages 21 or older were enrolled and randomized to receive injectable teriparatide 20 μg per day plus oral placebo or oral alendronate 10 mg per day plus injectable placebo. All of them also received calcium 1,000 mg per day and vitamin D 800 IU per day.

At 18 months, the bone mineral density had increased significantly more in the teriparatide group than in the alendronate group in the lumbar spine (P < .001) and in the total hip (P < .01). As expected, markers of bone turnover were suppressed in the alendronate group but were increased in the teriparatide group.

New vertebral fractures were found on radiography in 10 of 165 patients in the alendronate group vs 1 of 171 patients in the teriparatide group (P = .004). Clinical vertebral fractures occurred in 3 of 165 patients treated with alendronate but in none of the teriparatide-treated patients (P = .07). Nonvertebral fractures occurred in 8 of 214 patients treated with alendronate and 12 of 214 patients treated with teriparatide (P = .362). Three of 214 patients treated with alendronate suffered nonvertebral fragility fractures, compared with 5 of 214 patients treated with teriparatide (P = .455).

Denosumab, an antibody to RANK ligand

Denosumab (Prolia) is a fully human monoclonal antibody to RANK ligand. (Recall that glucocorticoids are associated with increases in RANK ligand and decreases in osteoprotegerin.) Denosumab is given subcutaneously in a dosage of 60 mg every 6 months. It was recently approved for the treatment of postmenopausal osteoporosis.

In a phase 2 study of denosumab³³ in men and women with rheumatoid arthritis (an independent risk factor for bone loss), the bone mineral density of the lumbar spine increased irrespective of whether the patients were treated with bisphosphonates and glucocorticoids.

ADHERENCE TO GUIDELINES IS POOR

Unfortunately, prevention and treatment in actual clinical practice still lag behind what is recommended in the current guidelines, even though multiple therapies are available.

In 2005, Blalock et al³⁴ expressed concerns about patients’ knowledge, beliefs, and behavior and the prevention and treatment of glucocorticoid-induced osteoporosis. They found that most patients taking oral glucocorticoids are not adequately educated about the prevention of osteoporosis, stating that “patients either are not being counseled or they are being counseled in a manner that is not sufficient to promote subsequent recall and behavior change.”³⁴ They concluded that research is needed to develop effective ways to educate patients about how to prevent glucocorticoid-induced osteoporosis.

Also in 2005, Curtis et al³⁵ reviewed the records of managed-care patients taking glucocorticoids, comparing the prescription of antiresorptive therapy and the use of over-the-counter calcium or vitamin D or both in the periods 2001 to 2003 vs 1995 to 1998. The frequency of bone mineral density measurement in 2001 to 2003 had increased threefold compared with 1995 to 1998, and the use of a prescription antiresorptive drug had increased approximately twofold. However, only 42% of the patients underwent bone mineral density testing or were prescribed bone-protective medicine. The rates were lowest for men, at 25%.

A CALL TO ACTION

Evidenced-based guidelines exist to guide the clinician in an attempt to prevent the deleterious effects of glucocorticoids on bone. Physicians, physician assistants, nurse practitioners, and pharmacists need to coordinate their effects to ensure that adherence to these guidelines improves. Only then will the bone health of patients treated with glucocorticoids improve.

CASE: Jeff, a 15-year-old high school ice hockey player, asks you to write a note for his coach, stating that he has recovered from his concussion and can return to play. He says that 2 days ago he collided with another player and was knocked unconscious for roughly 10 seconds. He had a headache for the rest of that evening, and complained that the light was hurting his eyes. Now he has no symptoms at rest, but activity gives him a slight headache.

How would you evaluate this patient to determine whether he can return to play?

Concussions like Jeff’s are common in sports-related activities, and family physicians are frequently asked to manage the condition and decide when the injured athlete can safely return to play.

Concussions occur in both helmeted and nonhelmeted sports, and are most common in collision sports.¹ A 2007 estimate from the Centers for Disease Control and Prevention (CDC) suggests that 1.1 million people are seen in emergency departments in the United States each year for concussion-related injuries, while nearly another 235,000 people are hospitalized.² As astounding as these numbers are, many experts believe they underestimate the true incidence of concussion, given the propensity for athletes not to report symptoms for fear of being held out of sporting events.^3,4

Further complicating matters: There has historically been a lack of agreement over what, exactly, constitutes a concussion and how to manage these injuries.

Refining concussion terminology
Concussion has often been referred to as mild traumatic brain injury (MTBI), although more recent expert opinion suggests the terms refer to different injury constructs and should not be used interchangeably.⁵ Over the years there has been little agreement on the definition, grading, and treatment of these injuries.^6-8 On 3 occasions in the last decade, the sports medicine community has held symposia designed to refine an expert consensus on these issues: in 2001 in Vienna, in 2004 in Prague, and in 2008 in Zurich.^5,9,10 These recommendations provide a useful framework for caring for patients like Jeff.

A definition. According to the consensus statement that emerged from the most recent Zurich conference, sports concussion can be defined as a “complex pathophysiological process affecting the brain, induced by traumatic biomechanical forces.” Common features may include:⁵

• A direct blow to the head or elsewhere in the body with an impulsive force transmitted to the head.
• Rapid onset of neurological impairments that resolve spontaneously over time.
• Possible neuropathological changes, although the clinical symptoms reflect a functional disturbance rather than structural injury.
• A graded set of clinical symptoms that may or may not involve loss of consciousness.
• No abnormality on standard structural neuroimaging studies.

Athletes with concussion show a range of signs and symptoms

Athletes who suffer from a concussion may show signs of being dazed or disoriented, or experience retrograde amnesia (where they can’t remember things that happened before the traumatic event) or anterograde amnesia (where they can’t remember things that happened after the event). They may also suffer from poor coordination, decreased attention span, emotional lability, or loss of consciousness. After the traumatic event, they may complain of headache, dizziness, nausea or vomiting, photophobia, phonophobia, inability to concentrate, sleep disturbances, fatigue, and memory disturbances. Academic performance can also be severely impaired during the postconcussive period.

Symptoms of concussion may be short-lived or persist for many weeks. Postconcussive syndrome is a term used to describe the condition of prolonged and persistent concussive symptoms. Recent studies in military personal have also shown a strong association between post-traumatic stress disorder (PTSD) and clinical depression in soldiers who have suffered from a traumatic brain injury.¹¹

Start with the ABCs, then check the spine

If you are a team physician on the spot when the injury occurs, you can do the initial assessment on the field of play. A certified athletic trainer can also do this first assessment. Start by checking the basics: airway, breathing, and circulation. Once the ABCs have been completed, palpate the head and neck to rule out a head or cervical spine injury. If the player complains of neck pain or you can palpate bony tenderness or step-off over the spinous processes, suspect a possible cervical spine injury. Make sure the player is put onto a spine board with cervical spine precautions and transported to the nearest medical facility.

Look for neurologic deficits
If the cervical spine is cleared, you can do the rest of the assessment in a quiet location either on the sideline or in your office. Your history should include a narrative of how the injury occurred, an estimate of the force involved, the duration of any symptoms, and any previous concussions. The physical examination comes next, and should include a neurologic assessment and a full cognitive evaluation. Reassess frequently after the traumatic event to monitor for any signs of neurologic decline. If any neurologic deficits are found, the patient should be transported to the nearest medical facility for neuroimaging studies to rule out a structural brain injury.

The SCAT2: A convenient assessment tool
Standardized tools now exist to help you evaluate patients with concussion. The Pocket Sport Concussion Assessment Tool (SCAT2) on page 430 has been endorsed by the Zurich conference.⁵ It is a condensed version of the conference recommendations, suitable for use on the field of play. The SCAT2 includes a symptom scale, mental status tests, instructions on neurologic screening, and guidelines for return to play.

Pocket Sports Concussion Assessment Tool (SCAT2)

Adapted from: Pocket SCAT2. Available at: http://bjsm.bmj.com/content/43/Suppl_1/i89.full.pdf. Accessed July 7, 2010.

No system for grading severity is recommended

Many different classification systems for grading the severity of concussion have been proposed, but none of them is endorsed by the Zurich conference.^5,7,12-15 The classification schemes that have been proposed are complex, not evidence-based, and unable to encompass the full range of concussion symptoms. Thus, the 3rd International Conference on Concussion in Sport abandoned all attempts to use or create classification systems, but recommended that each case be treated clinically on the basis of the symptoms displayed and the duration of the impairment.⁵ Athletes with severe impairment or prolonged symptoms may require referral to a sport medicine specialist with expertise in the management of concussion.

The third conference did agree on a range of “modifying factors” that may influence management and possibly predict the potential for prolonged or persistent symptoms (TABLE). The conference participants endorsed that any athlete displaying these features should be managed in a multidisciplinary manner coordinated by a physician with specific expertise in the management of concussive injuries.

TABLE
"Modifying factors” that may influence concussion management

Return to play is the crucial decision

Just as multiple systems for classifying severity have been proposed, so have guidelines for return to play.^13-15 Again, each of the proposed guidelines has been based on expert opinion and no single set of guidelines has ever been proven to be accurate.¹⁰ There is, therefore, no universally accepted guide for making the decision of when an athlete can safely return to play. It is universally accepted, however, that no athlete should return to play if he or she is still symptomatic at rest or with any exertional maneuvers.^3,7,16 Additionally, the athlete should not be taking any medication that could minimize any of the signs or symptoms of concussion when the physician is determining whether he or she can return to activity.

Once you are assured that the player has no symptoms at rest, you can start him or her on a graded, step-by-step regimen for returning to play. Athletes should spend 24 to 48 hours at each level before progressing to the next. If symptoms return at any point, instruct the athlete to drop back down a step for 24 hours and then proceed with the progression as tolerated.^9,10 The stages of activity are: ^3,10

• Light aerobic exercise
• Moderate to intense aerobic exercise
• Sport-specific activities/noncontact training drills
• Full contact activities
• Game play.

Neuropsychological testing can help you decide

In 1989, Barth and colleagues evaluated 2300 college football players, 200 of whom had suspected concussion.¹⁷ Neuropsychological testing at 24 hours, 5 days, and 10 days showed a decline from baseline following a concussion, with the majority of the athletes returning to baseline by 10 days postconcussion. This finding led researchers to believe that testing could help identify concussions, and several computer-based testing products were developed.^11,18

Neuropsychological testing should include measures of concentration, motor dexterity, information processing, visual and verbal memory, executive function, and brain stem function.¹⁹ Testing can be performed in the athletic setting with a Web-based computer program, by a sports medicine specialist with an interest in concussion, or by a neuro-psychologist with expertise in concussion.

Improvement in cognitive function as a concussion resolves may come prior to, or follow, the resolution of clinical symptoms. Therefore, it is important to properly assess cognition and symptoms before you make a recommendation about returning to play.^3,10 Baseline performance parameters must be established before the season starts.

Neuropsychological testing can provide both an objective measure of the neuro-cognitive effects of concussion and the ability to track recovery. It may also assist in making return-to-play recommendations in complicated cases, but bear in mind that no data are available to suggest that return to play is safe once neuropsychological testing has returned to normal.^3,9 Test results can aid clinical decision making, but cannot substitute for it. Testing may be most helpful in athletes with repeated concussions or those with persistent symptoms.¹⁰

Educating athletes, parents, and coaches in prevention
No foolproof method exists for preventing concussion in sports. Sports medicine research has focused on designing and testing safer equipment and on devising new rules to make play safer.^20-22 At present, there is no evidence that protective equipment will prevent concussions, but recent studies by Collins and Viano suggest that newer football helmets may assist in decreasing the incidence of concussions.^20,22,23

The Zurich consensus statement warns that protective equipment can have a paradoxical effect, influencing athletes to take risks that they might otherwise avoid, thus increasing injury rates.⁵ Trials of rule changes in different sports have been and continue to be conducted, such as barring spearing in football and restricting helmet-to-helmet hits. Given the frequency of concussion, further research is clearly needed. In the meantime, family physicians can play a major role in educating players, parents, and coaches about the seriousness of concussive injury and the need for identifying concussion promptly and allowing adequate time for recovery.

What do you tell Jeff?
Your answer for Jeff is, “You’re not ready to go back to practice or play. You feel OK when you’re resting, but when you get up, your headache returns. Come back to the office in a day or 2, and I’ll re-evaluate you. If you don’t have any symptoms then, you can start a program of graduated activity, beginning with some light aerobic exercise. If you feel all right with that, you can go on to a moderate and then an intense aerobic workout. If you still feel good, you can go on to sports-specific activities with no contact training, and then full contact training.

“At each stage, you will need to be re-evaluated by me or by your team trainer. Once you’ve finished the program without any reactivation of symptoms, I’ll clear you for play.”

CORRESPONDENCE Shawn M. Ferullo, MD, One Boston Medical Center Place, Boston, MA 02118; [email protected]

CASE: Jeff, a 15-year-old high school ice hockey player, asks you to write a note for his coach, stating that he has recovered from his concussion and can return to play. He says that 2 days ago he collided with another player and was knocked unconscious for roughly 10 seconds. He had a headache for the rest of that evening, and complained that the light was hurting his eyes. Now he has no symptoms at rest, but activity gives him a slight headache.

How would you evaluate this patient to determine whether he can return to play?

Concussions like Jeff’s are common in sports-related activities, and family physicians are frequently asked to manage the condition and decide when the injured athlete can safely return to play.

Concussions occur in both helmeted and nonhelmeted sports, and are most common in collision sports.¹ A 2007 estimate from the Centers for Disease Control and Prevention (CDC) suggests that 1.1 million people are seen in emergency departments in the United States each year for concussion-related injuries, while nearly another 235,000 people are hospitalized.² As astounding as these numbers are, many experts believe they underestimate the true incidence of concussion, given the propensity for athletes not to report symptoms for fear of being held out of sporting events.^3,4

Further complicating matters: There has historically been a lack of agreement over what, exactly, constitutes a concussion and how to manage these injuries.

Refining concussion terminology
Concussion has often been referred to as mild traumatic brain injury (MTBI), although more recent expert opinion suggests the terms refer to different injury constructs and should not be used interchangeably.⁵ Over the years there has been little agreement on the definition, grading, and treatment of these injuries.^6-8 On 3 occasions in the last decade, the sports medicine community has held symposia designed to refine an expert consensus on these issues: in 2001 in Vienna, in 2004 in Prague, and in 2008 in Zurich.^5,9,10 These recommendations provide a useful framework for caring for patients like Jeff.

A definition. According to the consensus statement that emerged from the most recent Zurich conference, sports concussion can be defined as a “complex pathophysiological process affecting the brain, induced by traumatic biomechanical forces.” Common features may include:⁵

• A direct blow to the head or elsewhere in the body with an impulsive force transmitted to the head.
• Rapid onset of neurological impairments that resolve spontaneously over time.
• Possible neuropathological changes, although the clinical symptoms reflect a functional disturbance rather than structural injury.
• A graded set of clinical symptoms that may or may not involve loss of consciousness.
• No abnormality on standard structural neuroimaging studies.

Athletes with concussion show a range of signs and symptoms

Athletes who suffer from a concussion may show signs of being dazed or disoriented, or experience retrograde amnesia (where they can’t remember things that happened before the traumatic event) or anterograde amnesia (where they can’t remember things that happened after the event). They may also suffer from poor coordination, decreased attention span, emotional lability, or loss of consciousness. After the traumatic event, they may complain of headache, dizziness, nausea or vomiting, photophobia, phonophobia, inability to concentrate, sleep disturbances, fatigue, and memory disturbances. Academic performance can also be severely impaired during the postconcussive period.

Symptoms of concussion may be short-lived or persist for many weeks. Postconcussive syndrome is a term used to describe the condition of prolonged and persistent concussive symptoms. Recent studies in military personal have also shown a strong association between post-traumatic stress disorder (PTSD) and clinical depression in soldiers who have suffered from a traumatic brain injury.¹¹

Start with the ABCs, then check the spine

If you are a team physician on the spot when the injury occurs, you can do the initial assessment on the field of play. A certified athletic trainer can also do this first assessment. Start by checking the basics: airway, breathing, and circulation. Once the ABCs have been completed, palpate the head and neck to rule out a head or cervical spine injury. If the player complains of neck pain or you can palpate bony tenderness or step-off over the spinous processes, suspect a possible cervical spine injury. Make sure the player is put onto a spine board with cervical spine precautions and transported to the nearest medical facility.

Look for neurologic deficits
If the cervical spine is cleared, you can do the rest of the assessment in a quiet location either on the sideline or in your office. Your history should include a narrative of how the injury occurred, an estimate of the force involved, the duration of any symptoms, and any previous concussions. The physical examination comes next, and should include a neurologic assessment and a full cognitive evaluation. Reassess frequently after the traumatic event to monitor for any signs of neurologic decline. If any neurologic deficits are found, the patient should be transported to the nearest medical facility for neuroimaging studies to rule out a structural brain injury.

The SCAT2: A convenient assessment tool
Standardized tools now exist to help you evaluate patients with concussion. The Pocket Sport Concussion Assessment Tool (SCAT2) on page 430 has been endorsed by the Zurich conference.⁵ It is a condensed version of the conference recommendations, suitable for use on the field of play. The SCAT2 includes a symptom scale, mental status tests, instructions on neurologic screening, and guidelines for return to play.

Pocket Sports Concussion Assessment Tool (SCAT2)

Adapted from: Pocket SCAT2. Available at: http://bjsm.bmj.com/content/43/Suppl_1/i89.full.pdf. Accessed July 7, 2010.

No system for grading severity is recommended

Many different classification systems for grading the severity of concussion have been proposed, but none of them is endorsed by the Zurich conference.^5,7,12-15 The classification schemes that have been proposed are complex, not evidence-based, and unable to encompass the full range of concussion symptoms. Thus, the 3rd International Conference on Concussion in Sport abandoned all attempts to use or create classification systems, but recommended that each case be treated clinically on the basis of the symptoms displayed and the duration of the impairment.⁵ Athletes with severe impairment or prolonged symptoms may require referral to a sport medicine specialist with expertise in the management of concussion.

The third conference did agree on a range of “modifying factors” that may influence management and possibly predict the potential for prolonged or persistent symptoms (TABLE). The conference participants endorsed that any athlete displaying these features should be managed in a multidisciplinary manner coordinated by a physician with specific expertise in the management of concussive injuries.

TABLE
"Modifying factors” that may influence concussion management

Return to play is the crucial decision

Just as multiple systems for classifying severity have been proposed, so have guidelines for return to play.^13-15 Again, each of the proposed guidelines has been based on expert opinion and no single set of guidelines has ever been proven to be accurate.¹⁰ There is, therefore, no universally accepted guide for making the decision of when an athlete can safely return to play. It is universally accepted, however, that no athlete should return to play if he or she is still symptomatic at rest or with any exertional maneuvers.^3,7,16 Additionally, the athlete should not be taking any medication that could minimize any of the signs or symptoms of concussion when the physician is determining whether he or she can return to activity.

Once you are assured that the player has no symptoms at rest, you can start him or her on a graded, step-by-step regimen for returning to play. Athletes should spend 24 to 48 hours at each level before progressing to the next. If symptoms return at any point, instruct the athlete to drop back down a step for 24 hours and then proceed with the progression as tolerated.^9,10 The stages of activity are: ^3,10

• Light aerobic exercise
• Moderate to intense aerobic exercise
• Sport-specific activities/noncontact training drills
• Full contact activities
• Game play.

Neuropsychological testing can help you decide

In 1989, Barth and colleagues evaluated 2300 college football players, 200 of whom had suspected concussion.¹⁷ Neuropsychological testing at 24 hours, 5 days, and 10 days showed a decline from baseline following a concussion, with the majority of the athletes returning to baseline by 10 days postconcussion. This finding led researchers to believe that testing could help identify concussions, and several computer-based testing products were developed.^11,18

Neuropsychological testing should include measures of concentration, motor dexterity, information processing, visual and verbal memory, executive function, and brain stem function.¹⁹ Testing can be performed in the athletic setting with a Web-based computer program, by a sports medicine specialist with an interest in concussion, or by a neuro-psychologist with expertise in concussion.

Improvement in cognitive function as a concussion resolves may come prior to, or follow, the resolution of clinical symptoms. Therefore, it is important to properly assess cognition and symptoms before you make a recommendation about returning to play.^3,10 Baseline performance parameters must be established before the season starts.

Neuropsychological testing can provide both an objective measure of the neuro-cognitive effects of concussion and the ability to track recovery. It may also assist in making return-to-play recommendations in complicated cases, but bear in mind that no data are available to suggest that return to play is safe once neuropsychological testing has returned to normal.^3,9 Test results can aid clinical decision making, but cannot substitute for it. Testing may be most helpful in athletes with repeated concussions or those with persistent symptoms.¹⁰

Educating athletes, parents, and coaches in prevention
No foolproof method exists for preventing concussion in sports. Sports medicine research has focused on designing and testing safer equipment and on devising new rules to make play safer.^20-22 At present, there is no evidence that protective equipment will prevent concussions, but recent studies by Collins and Viano suggest that newer football helmets may assist in decreasing the incidence of concussions.^20,22,23

The Zurich consensus statement warns that protective equipment can have a paradoxical effect, influencing athletes to take risks that they might otherwise avoid, thus increasing injury rates.⁵ Trials of rule changes in different sports have been and continue to be conducted, such as barring spearing in football and restricting helmet-to-helmet hits. Given the frequency of concussion, further research is clearly needed. In the meantime, family physicians can play a major role in educating players, parents, and coaches about the seriousness of concussive injury and the need for identifying concussion promptly and allowing adequate time for recovery.

What do you tell Jeff?
Your answer for Jeff is, “You’re not ready to go back to practice or play. You feel OK when you’re resting, but when you get up, your headache returns. Come back to the office in a day or 2, and I’ll re-evaluate you. If you don’t have any symptoms then, you can start a program of graduated activity, beginning with some light aerobic exercise. If you feel all right with that, you can go on to a moderate and then an intense aerobic workout. If you still feel good, you can go on to sports-specific activities with no contact training, and then full contact training.

“At each stage, you will need to be re-evaluated by me or by your team trainer. Once you’ve finished the program without any reactivation of symptoms, I’ll clear you for play.”

CORRESPONDENCE Shawn M. Ferullo, MD, One Boston Medical Center Place, Boston, MA 02118; [email protected]

CASE: Jeff, a 15-year-old high school ice hockey player, asks you to write a note for his coach, stating that he has recovered from his concussion and can return to play. He says that 2 days ago he collided with another player and was knocked unconscious for roughly 10 seconds. He had a headache for the rest of that evening, and complained that the light was hurting his eyes. Now he has no symptoms at rest, but activity gives him a slight headache.

How would you evaluate this patient to determine whether he can return to play?

Concussions like Jeff’s are common in sports-related activities, and family physicians are frequently asked to manage the condition and decide when the injured athlete can safely return to play.

Concussions occur in both helmeted and nonhelmeted sports, and are most common in collision sports.¹ A 2007 estimate from the Centers for Disease Control and Prevention (CDC) suggests that 1.1 million people are seen in emergency departments in the United States each year for concussion-related injuries, while nearly another 235,000 people are hospitalized.² As astounding as these numbers are, many experts believe they underestimate the true incidence of concussion, given the propensity for athletes not to report symptoms for fear of being held out of sporting events.^3,4

Further complicating matters: There has historically been a lack of agreement over what, exactly, constitutes a concussion and how to manage these injuries.

Refining concussion terminology
Concussion has often been referred to as mild traumatic brain injury (MTBI), although more recent expert opinion suggests the terms refer to different injury constructs and should not be used interchangeably.⁵ Over the years there has been little agreement on the definition, grading, and treatment of these injuries.^6-8 On 3 occasions in the last decade, the sports medicine community has held symposia designed to refine an expert consensus on these issues: in 2001 in Vienna, in 2004 in Prague, and in 2008 in Zurich.^5,9,10 These recommendations provide a useful framework for caring for patients like Jeff.

A definition. According to the consensus statement that emerged from the most recent Zurich conference, sports concussion can be defined as a “complex pathophysiological process affecting the brain, induced by traumatic biomechanical forces.” Common features may include:⁵

• A direct blow to the head or elsewhere in the body with an impulsive force transmitted to the head.
• Rapid onset of neurological impairments that resolve spontaneously over time.
• Possible neuropathological changes, although the clinical symptoms reflect a functional disturbance rather than structural injury.
• A graded set of clinical symptoms that may or may not involve loss of consciousness.
• No abnormality on standard structural neuroimaging studies.

Athletes with concussion show a range of signs and symptoms

Athletes who suffer from a concussion may show signs of being dazed or disoriented, or experience retrograde amnesia (where they can’t remember things that happened before the traumatic event) or anterograde amnesia (where they can’t remember things that happened after the event). They may also suffer from poor coordination, decreased attention span, emotional lability, or loss of consciousness. After the traumatic event, they may complain of headache, dizziness, nausea or vomiting, photophobia, phonophobia, inability to concentrate, sleep disturbances, fatigue, and memory disturbances. Academic performance can also be severely impaired during the postconcussive period.

Symptoms of concussion may be short-lived or persist for many weeks. Postconcussive syndrome is a term used to describe the condition of prolonged and persistent concussive symptoms. Recent studies in military personal have also shown a strong association between post-traumatic stress disorder (PTSD) and clinical depression in soldiers who have suffered from a traumatic brain injury.¹¹

Start with the ABCs, then check the spine

If you are a team physician on the spot when the injury occurs, you can do the initial assessment on the field of play. A certified athletic trainer can also do this first assessment. Start by checking the basics: airway, breathing, and circulation. Once the ABCs have been completed, palpate the head and neck to rule out a head or cervical spine injury. If the player complains of neck pain or you can palpate bony tenderness or step-off over the spinous processes, suspect a possible cervical spine injury. Make sure the player is put onto a spine board with cervical spine precautions and transported to the nearest medical facility.

Look for neurologic deficits
If the cervical spine is cleared, you can do the rest of the assessment in a quiet location either on the sideline or in your office. Your history should include a narrative of how the injury occurred, an estimate of the force involved, the duration of any symptoms, and any previous concussions. The physical examination comes next, and should include a neurologic assessment and a full cognitive evaluation. Reassess frequently after the traumatic event to monitor for any signs of neurologic decline. If any neurologic deficits are found, the patient should be transported to the nearest medical facility for neuroimaging studies to rule out a structural brain injury.

The SCAT2: A convenient assessment tool
Standardized tools now exist to help you evaluate patients with concussion. The Pocket Sport Concussion Assessment Tool (SCAT2) on page 430 has been endorsed by the Zurich conference.⁵ It is a condensed version of the conference recommendations, suitable for use on the field of play. The SCAT2 includes a symptom scale, mental status tests, instructions on neurologic screening, and guidelines for return to play.

Pocket Sports Concussion Assessment Tool (SCAT2)

Adapted from: Pocket SCAT2. Available at: http://bjsm.bmj.com/content/43/Suppl_1/i89.full.pdf. Accessed July 7, 2010.

No system for grading severity is recommended

Many different classification systems for grading the severity of concussion have been proposed, but none of them is endorsed by the Zurich conference.^5,7,12-15 The classification schemes that have been proposed are complex, not evidence-based, and unable to encompass the full range of concussion symptoms. Thus, the 3rd International Conference on Concussion in Sport abandoned all attempts to use or create classification systems, but recommended that each case be treated clinically on the basis of the symptoms displayed and the duration of the impairment.⁵ Athletes with severe impairment or prolonged symptoms may require referral to a sport medicine specialist with expertise in the management of concussion.

The third conference did agree on a range of “modifying factors” that may influence management and possibly predict the potential for prolonged or persistent symptoms (TABLE). The conference participants endorsed that any athlete displaying these features should be managed in a multidisciplinary manner coordinated by a physician with specific expertise in the management of concussive injuries.

TABLE
"Modifying factors” that may influence concussion management

Return to play is the crucial decision

Just as multiple systems for classifying severity have been proposed, so have guidelines for return to play.^13-15 Again, each of the proposed guidelines has been based on expert opinion and no single set of guidelines has ever been proven to be accurate.¹⁰ There is, therefore, no universally accepted guide for making the decision of when an athlete can safely return to play. It is universally accepted, however, that no athlete should return to play if he or she is still symptomatic at rest or with any exertional maneuvers.^3,7,16 Additionally, the athlete should not be taking any medication that could minimize any of the signs or symptoms of concussion when the physician is determining whether he or she can return to activity.

Once you are assured that the player has no symptoms at rest, you can start him or her on a graded, step-by-step regimen for returning to play. Athletes should spend 24 to 48 hours at each level before progressing to the next. If symptoms return at any point, instruct the athlete to drop back down a step for 24 hours and then proceed with the progression as tolerated.^9,10 The stages of activity are: ^3,10

• Light aerobic exercise
• Moderate to intense aerobic exercise
• Sport-specific activities/noncontact training drills
• Full contact activities
• Game play.

Neuropsychological testing can help you decide

In 1989, Barth and colleagues evaluated 2300 college football players, 200 of whom had suspected concussion.¹⁷ Neuropsychological testing at 24 hours, 5 days, and 10 days showed a decline from baseline following a concussion, with the majority of the athletes returning to baseline by 10 days postconcussion. This finding led researchers to believe that testing could help identify concussions, and several computer-based testing products were developed.^11,18

Neuropsychological testing should include measures of concentration, motor dexterity, information processing, visual and verbal memory, executive function, and brain stem function.¹⁹ Testing can be performed in the athletic setting with a Web-based computer program, by a sports medicine specialist with an interest in concussion, or by a neuro-psychologist with expertise in concussion.

Improvement in cognitive function as a concussion resolves may come prior to, or follow, the resolution of clinical symptoms. Therefore, it is important to properly assess cognition and symptoms before you make a recommendation about returning to play.^3,10 Baseline performance parameters must be established before the season starts.

Neuropsychological testing can provide both an objective measure of the neuro-cognitive effects of concussion and the ability to track recovery. It may also assist in making return-to-play recommendations in complicated cases, but bear in mind that no data are available to suggest that return to play is safe once neuropsychological testing has returned to normal.^3,9 Test results can aid clinical decision making, but cannot substitute for it. Testing may be most helpful in athletes with repeated concussions or those with persistent symptoms.¹⁰

Educating athletes, parents, and coaches in prevention
No foolproof method exists for preventing concussion in sports. Sports medicine research has focused on designing and testing safer equipment and on devising new rules to make play safer.^20-22 At present, there is no evidence that protective equipment will prevent concussions, but recent studies by Collins and Viano suggest that newer football helmets may assist in decreasing the incidence of concussions.^20,22,23

The Zurich consensus statement warns that protective equipment can have a paradoxical effect, influencing athletes to take risks that they might otherwise avoid, thus increasing injury rates.⁵ Trials of rule changes in different sports have been and continue to be conducted, such as barring spearing in football and restricting helmet-to-helmet hits. Given the frequency of concussion, further research is clearly needed. In the meantime, family physicians can play a major role in educating players, parents, and coaches about the seriousness of concussive injury and the need for identifying concussion promptly and allowing adequate time for recovery.

What do you tell Jeff?
Your answer for Jeff is, “You’re not ready to go back to practice or play. You feel OK when you’re resting, but when you get up, your headache returns. Come back to the office in a day or 2, and I’ll re-evaluate you. If you don’t have any symptoms then, you can start a program of graduated activity, beginning with some light aerobic exercise. If you feel all right with that, you can go on to a moderate and then an intense aerobic workout. If you still feel good, you can go on to sports-specific activities with no contact training, and then full contact training.

“At each stage, you will need to be re-evaluated by me or by your team trainer. Once you’ve finished the program without any reactivation of symptoms, I’ll clear you for play.”

CORRESPONDENCE Shawn M. Ferullo, MD, One Boston Medical Center Place, Boston, MA 02118; [email protected]

Dysmenorrhea and menorrhagia beyond the norm often overlap in adolescents and can occur in up to 15% of these young women.

The normal time period from breast development (thelarche) and development of pubic hair to menses in young girls is about 2 years. A longer time course is cause for investigation.

The maturation of the hypothalamic-pituitary-ovarian axis occurs over approximately 5 years. After initiation of menses (menarche), some adolescents have anovulatory cycles, i.e., no luteinizing hormone surge with subsequent lack of ovulation and dysfunctional estrogen effect on the uterine endometrial lining. This can present with irregular bleeding that can be very heavy when the endometrial lining sheds in an unsynchronized manner. If no other cause for this bleeding is established (for example, endocrine, anatomic, or underlying chronic disease), then it is considered dysfunctional uterine bleeding (DUB).

In the same time period of 5 years from menarche, an estimated 15%-30% of young women will have primary dysmenorrhea strong enough to require pain medication, including nonsteroidal anti-inflammatory drugs (NSAIDs).

The vast majority of young adolescent girls experience some pain with their periods, ranging from discomfort to pain requiring medication to being unable to go to school.

When the pain is severe, these patients either miss school or just make it through the school day, but their attention and performance suffer. These girls with significant pain need more assistance because their dysmenorrhea may not subside for several years, and a referral to a subspecialist is warranted.

In terms of differential diagnosis, menstrual pain (dysmenorrhea) is a crampy, focal phenomenon in the mid-lower quadrant, sometimes with radiation to the back and the lower extremities. It starts with the onset of menses. If the pain precedes menses, it may be endometriosis and not primary dysmenorrhea, although there is an overlap in the pain symptoms between these two entities. A nonleading question to ask is whether the patient experiences pain before, during, or after her cycle.

A gastrointestinal etiology is more likely if the pain is nonfocal and present in all four quadrants. Ruling out other GI etiologies, particularly constipation, is important. A trial of Miralax over 2-3 weeks with a cessation in the pain easily confirms constipation as the underlying cause. Constipation is very common in children and adolescents, and the pain is not related to the menstrual cycle.

Dysmenorrhea is a clinical diagnosis. Laboratory tests for this condition are not needed. Instead, a good history, detailed description of the pain, and ultrasound examination (transabdominal, not transvaginal) aid the differential diagnosis. Ultrasound is reassuring, as it can show normal uterine development and no ovarian masses, including no benign childhood ovarian tumors. Rarely is a pelvic examination necessary.

Pediatricians are instrumental in terms of educating patients, encouraging these patients to keep a detailed menstrual and pain diary, and advocating appropriate use of NSAIDs. However, if the diagnosis and management of teenagers with dysmenorrhea are outside your comfort zone, or your focus is primarily on younger children, you can refer the patient to a pediatric and adolescent gynecologist or other adolescent medicine specialist.

One problem for these patients is the use of Tylenol, which does not work on the elevated prostaglandins in primary dysmenorrhea. Instead, recommend an NSAID such as ibuprofen (Motrin, Advil), naproxen (Naprosyn), or mefenamic acid (Ponstel).

If pain relief is inadequate, switch classes of NSAIDs instead of switching between drugs in the same class.

Birth control pills are another option for controlling painful periods. For most girls with menses painful enough to impair their activities of daily living, birth control pills are a huge benefit. Oral contraceptives for 1-2 years for irregular bleeding and dysmenorrhea can make a big difference, and then you can try a trial period without them. Prescription of birth control pills requires a lot of education, particularly because these young patients need to be compliant. Create a routine for them—such as suggesting their pills be stored in a secure location with their toothbrush.

Parents also need to be vested in this approach, and some will be resistant. I recommend that you discuss birth control pills as a strategy to control pain and bleeding when the parents and the patient are both present. Educate parents that birth control pills will not give their daughters breast cancer or cause them to become sexually active. Any generic monophasic oral contraceptive with 30 mcg of estradiol can be used.

If you add birth control pills to NSAIDs, 95% of patients experience no pain or bearable pain. It can take up to 6 months for maximum relief, however, and these teenagers need to keep a menstrual and pain diary to track and appreciate the improvements over time.

Heating pads can be a comforting, nonpharmacologic strategy for managing dysmenorrhea. Some girls who use them report taking fewer NSAIDs. There also is some literature on the benefits of acupuncture, but it is not always practical in the United States.

DUB is a diagnosis of exclusion. In your differential diagnosis, rule out thyroid dysfunction, prolactinoma (a rare brain tumor), or any underlying chronic diseases (such as lupus) that affect the menstrual cycle. If you suspect anatomic abnormalities, a transabdominal ultrasound examination is indicated. You also have to consider polycystic ovarian syndrome (PCOS), because teenagers with this syndrome can present with irregular bleeding.

Laboratory tests for DUB are thyroid function, prolactin, and markers for PCOS. These assays include free and total testosterone, sex hormone–binding globulin, and androstenedione.

Most pediatricians know this, but if the first menses (menarche) is very heavy, you have to think of a bleeding disorder. This is an important diagnostic sign that additional work-up is warranted, and early intervention may be possible. If there is a bleeding disorder, early diagnosis could mean a lesser chance of hemorrhage during childbirth. Awareness among pediatricians is important because young girls rarely see gynecologists.

Classic DUB is related to menstrual cycle irregularities. There is a cohort of eggs recruited in the first half of the cycle (follicular phase). One follicle emerges that will rupture and release the egg at midcycle after luteinizing hormone levels spike in the body. If this sequence does not occur, the menstrual cycle is affected. The endometrial lining has proliferated under the effect of estrogen, and unsynchronized shedding with irregular bleeding occurs.

Again, you can take control of the menstrual cycle with birth control pills.

Dysmenorrhea and menorrhagia beyond the norm often overlap in adolescents and can occur in up to 15% of these young women.

The normal time period from breast development (thelarche) and development of pubic hair to menses in young girls is about 2 years. A longer time course is cause for investigation.

The maturation of the hypothalamic-pituitary-ovarian axis occurs over approximately 5 years. After initiation of menses (menarche), some adolescents have anovulatory cycles, i.e., no luteinizing hormone surge with subsequent lack of ovulation and dysfunctional estrogen effect on the uterine endometrial lining. This can present with irregular bleeding that can be very heavy when the endometrial lining sheds in an unsynchronized manner. If no other cause for this bleeding is established (for example, endocrine, anatomic, or underlying chronic disease), then it is considered dysfunctional uterine bleeding (DUB).

In the same time period of 5 years from menarche, an estimated 15%-30% of young women will have primary dysmenorrhea strong enough to require pain medication, including nonsteroidal anti-inflammatory drugs (NSAIDs).

The vast majority of young adolescent girls experience some pain with their periods, ranging from discomfort to pain requiring medication to being unable to go to school.

When the pain is severe, these patients either miss school or just make it through the school day, but their attention and performance suffer. These girls with significant pain need more assistance because their dysmenorrhea may not subside for several years, and a referral to a subspecialist is warranted.

In terms of differential diagnosis, menstrual pain (dysmenorrhea) is a crampy, focal phenomenon in the mid-lower quadrant, sometimes with radiation to the back and the lower extremities. It starts with the onset of menses. If the pain precedes menses, it may be endometriosis and not primary dysmenorrhea, although there is an overlap in the pain symptoms between these two entities. A nonleading question to ask is whether the patient experiences pain before, during, or after her cycle.

A gastrointestinal etiology is more likely if the pain is nonfocal and present in all four quadrants. Ruling out other GI etiologies, particularly constipation, is important. A trial of Miralax over 2-3 weeks with a cessation in the pain easily confirms constipation as the underlying cause. Constipation is very common in children and adolescents, and the pain is not related to the menstrual cycle.

Dysmenorrhea is a clinical diagnosis. Laboratory tests for this condition are not needed. Instead, a good history, detailed description of the pain, and ultrasound examination (transabdominal, not transvaginal) aid the differential diagnosis. Ultrasound is reassuring, as it can show normal uterine development and no ovarian masses, including no benign childhood ovarian tumors. Rarely is a pelvic examination necessary.

Pediatricians are instrumental in terms of educating patients, encouraging these patients to keep a detailed menstrual and pain diary, and advocating appropriate use of NSAIDs. However, if the diagnosis and management of teenagers with dysmenorrhea are outside your comfort zone, or your focus is primarily on younger children, you can refer the patient to a pediatric and adolescent gynecologist or other adolescent medicine specialist.

One problem for these patients is the use of Tylenol, which does not work on the elevated prostaglandins in primary dysmenorrhea. Instead, recommend an NSAID such as ibuprofen (Motrin, Advil), naproxen (Naprosyn), or mefenamic acid (Ponstel).

If pain relief is inadequate, switch classes of NSAIDs instead of switching between drugs in the same class.

Birth control pills are another option for controlling painful periods. For most girls with menses painful enough to impair their activities of daily living, birth control pills are a huge benefit. Oral contraceptives for 1-2 years for irregular bleeding and dysmenorrhea can make a big difference, and then you can try a trial period without them. Prescription of birth control pills requires a lot of education, particularly because these young patients need to be compliant. Create a routine for them—such as suggesting their pills be stored in a secure location with their toothbrush.

Parents also need to be vested in this approach, and some will be resistant. I recommend that you discuss birth control pills as a strategy to control pain and bleeding when the parents and the patient are both present. Educate parents that birth control pills will not give their daughters breast cancer or cause them to become sexually active. Any generic monophasic oral contraceptive with 30 mcg of estradiol can be used.

If you add birth control pills to NSAIDs, 95% of patients experience no pain or bearable pain. It can take up to 6 months for maximum relief, however, and these teenagers need to keep a menstrual and pain diary to track and appreciate the improvements over time.

Heating pads can be a comforting, nonpharmacologic strategy for managing dysmenorrhea. Some girls who use them report taking fewer NSAIDs. There also is some literature on the benefits of acupuncture, but it is not always practical in the United States.

DUB is a diagnosis of exclusion. In your differential diagnosis, rule out thyroid dysfunction, prolactinoma (a rare brain tumor), or any underlying chronic diseases (such as lupus) that affect the menstrual cycle. If you suspect anatomic abnormalities, a transabdominal ultrasound examination is indicated. You also have to consider polycystic ovarian syndrome (PCOS), because teenagers with this syndrome can present with irregular bleeding.

Laboratory tests for DUB are thyroid function, prolactin, and markers for PCOS. These assays include free and total testosterone, sex hormone–binding globulin, and androstenedione.

Most pediatricians know this, but if the first menses (menarche) is very heavy, you have to think of a bleeding disorder. This is an important diagnostic sign that additional work-up is warranted, and early intervention may be possible. If there is a bleeding disorder, early diagnosis could mean a lesser chance of hemorrhage during childbirth. Awareness among pediatricians is important because young girls rarely see gynecologists.

Classic DUB is related to menstrual cycle irregularities. There is a cohort of eggs recruited in the first half of the cycle (follicular phase). One follicle emerges that will rupture and release the egg at midcycle after luteinizing hormone levels spike in the body. If this sequence does not occur, the menstrual cycle is affected. The endometrial lining has proliferated under the effect of estrogen, and unsynchronized shedding with irregular bleeding occurs.

Again, you can take control of the menstrual cycle with birth control pills.

Dysmenorrhea and menorrhagia beyond the norm often overlap in adolescents and can occur in up to 15% of these young women.

The normal time period from breast development (thelarche) and development of pubic hair to menses in young girls is about 2 years. A longer time course is cause for investigation.

The maturation of the hypothalamic-pituitary-ovarian axis occurs over approximately 5 years. After initiation of menses (menarche), some adolescents have anovulatory cycles, i.e., no luteinizing hormone surge with subsequent lack of ovulation and dysfunctional estrogen effect on the uterine endometrial lining. This can present with irregular bleeding that can be very heavy when the endometrial lining sheds in an unsynchronized manner. If no other cause for this bleeding is established (for example, endocrine, anatomic, or underlying chronic disease), then it is considered dysfunctional uterine bleeding (DUB).

In the same time period of 5 years from menarche, an estimated 15%-30% of young women will have primary dysmenorrhea strong enough to require pain medication, including nonsteroidal anti-inflammatory drugs (NSAIDs).

The vast majority of young adolescent girls experience some pain with their periods, ranging from discomfort to pain requiring medication to being unable to go to school.

When the pain is severe, these patients either miss school or just make it through the school day, but their attention and performance suffer. These girls with significant pain need more assistance because their dysmenorrhea may not subside for several years, and a referral to a subspecialist is warranted.

In terms of differential diagnosis, menstrual pain (dysmenorrhea) is a crampy, focal phenomenon in the mid-lower quadrant, sometimes with radiation to the back and the lower extremities. It starts with the onset of menses. If the pain precedes menses, it may be endometriosis and not primary dysmenorrhea, although there is an overlap in the pain symptoms between these two entities. A nonleading question to ask is whether the patient experiences pain before, during, or after her cycle.

A gastrointestinal etiology is more likely if the pain is nonfocal and present in all four quadrants. Ruling out other GI etiologies, particularly constipation, is important. A trial of Miralax over 2-3 weeks with a cessation in the pain easily confirms constipation as the underlying cause. Constipation is very common in children and adolescents, and the pain is not related to the menstrual cycle.

Dysmenorrhea is a clinical diagnosis. Laboratory tests for this condition are not needed. Instead, a good history, detailed description of the pain, and ultrasound examination (transabdominal, not transvaginal) aid the differential diagnosis. Ultrasound is reassuring, as it can show normal uterine development and no ovarian masses, including no benign childhood ovarian tumors. Rarely is a pelvic examination necessary.

Pediatricians are instrumental in terms of educating patients, encouraging these patients to keep a detailed menstrual and pain diary, and advocating appropriate use of NSAIDs. However, if the diagnosis and management of teenagers with dysmenorrhea are outside your comfort zone, or your focus is primarily on younger children, you can refer the patient to a pediatric and adolescent gynecologist or other adolescent medicine specialist.

One problem for these patients is the use of Tylenol, which does not work on the elevated prostaglandins in primary dysmenorrhea. Instead, recommend an NSAID such as ibuprofen (Motrin, Advil), naproxen (Naprosyn), or mefenamic acid (Ponstel).

If pain relief is inadequate, switch classes of NSAIDs instead of switching between drugs in the same class.

Birth control pills are another option for controlling painful periods. For most girls with menses painful enough to impair their activities of daily living, birth control pills are a huge benefit. Oral contraceptives for 1-2 years for irregular bleeding and dysmenorrhea can make a big difference, and then you can try a trial period without them. Prescription of birth control pills requires a lot of education, particularly because these young patients need to be compliant. Create a routine for them—such as suggesting their pills be stored in a secure location with their toothbrush.

Parents also need to be vested in this approach, and some will be resistant. I recommend that you discuss birth control pills as a strategy to control pain and bleeding when the parents and the patient are both present. Educate parents that birth control pills will not give their daughters breast cancer or cause them to become sexually active. Any generic monophasic oral contraceptive with 30 mcg of estradiol can be used.

If you add birth control pills to NSAIDs, 95% of patients experience no pain or bearable pain. It can take up to 6 months for maximum relief, however, and these teenagers need to keep a menstrual and pain diary to track and appreciate the improvements over time.

Heating pads can be a comforting, nonpharmacologic strategy for managing dysmenorrhea. Some girls who use them report taking fewer NSAIDs. There also is some literature on the benefits of acupuncture, but it is not always practical in the United States.

DUB is a diagnosis of exclusion. In your differential diagnosis, rule out thyroid dysfunction, prolactinoma (a rare brain tumor), or any underlying chronic diseases (such as lupus) that affect the menstrual cycle. If you suspect anatomic abnormalities, a transabdominal ultrasound examination is indicated. You also have to consider polycystic ovarian syndrome (PCOS), because teenagers with this syndrome can present with irregular bleeding.

Laboratory tests for DUB are thyroid function, prolactin, and markers for PCOS. These assays include free and total testosterone, sex hormone–binding globulin, and androstenedione.

Most pediatricians know this, but if the first menses (menarche) is very heavy, you have to think of a bleeding disorder. This is an important diagnostic sign that additional work-up is warranted, and early intervention may be possible. If there is a bleeding disorder, early diagnosis could mean a lesser chance of hemorrhage during childbirth. Awareness among pediatricians is important because young girls rarely see gynecologists.

Classic DUB is related to menstrual cycle irregularities. There is a cohort of eggs recruited in the first half of the cycle (follicular phase). One follicle emerges that will rupture and release the egg at midcycle after luteinizing hormone levels spike in the body. If this sequence does not occur, the menstrual cycle is affected. The endometrial lining has proliferated under the effect of estrogen, and unsynchronized shedding with irregular bleeding occurs.

Again, you can take control of the menstrual cycle with birth control pills.

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Stress is nothing new to American families, who—over the generations—have endured wars, epidemics, natural disasters, and numerous economic downturns.

Today's dismal economic climate with continuing unemployment poses real challenges for families.

You should be especially attuned to warning signs that more children in your practice may be at risk for hunger, displacement from their homes and schools, and poverty-associated trauma, both physical and psychological.

The statistics are sobering.

In June 2010, unemployment stood at 14.6 million people, or 9.5% of the working-age population nationwide. Even more people are jobless in some unfortunate states and cities—more than 14% in Nevada, for instance; 14.5% in Las Vegas, Nev.; and 27.6% in tiny El Centro, Calif.

Homelessness among American families is growing, with 170,000 families seeking shelter in 2009, up from 159,000 the year before, according to the U.S. Department of Housing and Urban Development.

Every 3 months, another 250,000 families' homes enter foreclosure, putting one child in every classroom at risk of losing his or her home, according to the Mortgage Bankers Association. That statistic is so stunning—home foreclosures impacting one child in every classroom—that it bears repeating as it indicates every pediatric practice has more red flags in terms of psychosocial stressors then at any time in most pediatrician's career.

Families, as always, face crises unrelated to the economy as well: illness, marital discord, substance abuse, and intergenerational pressures, but economic downturns increase the prevalence of almost all of the crises on this list.

Poverty is the elephant in the room, exposing children to a host of contributors to an unstable environment that sets the stage for poor academic performance, increased mental health disorders, conduct problems, substance abuse, and difficulties in relationships.

The first red flag raised by a family in economic trouble probably isn't even seen in the examining room, but in your billing department, where reimbursements are likely down and delinquent accounts are likely up.

A family may be unable to produce a copay for a visit, or may have lost health insurance along with mom or dad's job. They may report multiple changes in their address. Mail from your office may be returned as undeliverable.

This is, of course, an economic problem for you and your practice, but it likely heralds medical and psychosocial problems as well. A child whose family cannot pay for your services may be twice as likely as a financially secure child to have depression, anxiety, and learning problems at school.

Your office staff may want to alert you to financial red flags not only as they appear on the office balance sheet, but as they relate to your care of the child as well.

Moving, for example, has many implications for a child's development and well-being.

A new address may mean changes in a child's school and after-school activities, the loss of friends and close access to extended family members, and a shattering of the security of familiar places and routines. If the move was involuntary, say, a forced exit from a foreclosed home, parents may be so distracted and emotionally spent, they may not have devoted time to calmly explaining to the child what will change and what will stay the same.

I always think it's a good idea, but especially so in hard times, for you to ask one screening question of every family during routine office visits.

That bushel basket question is, “Are there any ongoing tensions affecting the family?”

Answers can potentially cover a lot of ground, and may open the door to a family sharing financial concerns, as well as any other issues that may be troubling them: a recent move, concern about a family member, or signs of domestic strife.

Red flags may appear during your examination as well. Immunizations may not be up to date, problems are suddenly arising at school, or a there may be a change in trajectory of the child's weight curve due to a lack of nutritious food.

Fatigue and stress associated with family troubles may be cloaked in somatic diagnoses: headaches, stomachaches, chest pain, weakness, or dizziness in a child who never had such complaints before or where these symptoms previously have signaled stress.

Take a good look at the parent accompanying your patient as well. Does the mother or father seem more withdrawn, sadder, or more anxious than expected?

Often, you have an internal red flag, a vaguely unsettled feeling that something is not right. Do not underestimate the value of this clinical sixth sense. Listen to it. It may not be anything specific that you can put your finger on or diagnose, but if you're getting that signal from within, sit down and take the pulse of the family in these troubling times.

[email protected]

Stress is nothing new to American families, who—over the generations—have endured wars, epidemics, natural disasters, and numerous economic downturns.

Today's dismal economic climate with continuing unemployment poses real challenges for families.

You should be especially attuned to warning signs that more children in your practice may be at risk for hunger, displacement from their homes and schools, and poverty-associated trauma, both physical and psychological.

The statistics are sobering.

In June 2010, unemployment stood at 14.6 million people, or 9.5% of the working-age population nationwide. Even more people are jobless in some unfortunate states and cities—more than 14% in Nevada, for instance; 14.5% in Las Vegas, Nev.; and 27.6% in tiny El Centro, Calif.

Homelessness among American families is growing, with 170,000 families seeking shelter in 2009, up from 159,000 the year before, according to the U.S. Department of Housing and Urban Development.

Every 3 months, another 250,000 families' homes enter foreclosure, putting one child in every classroom at risk of losing his or her home, according to the Mortgage Bankers Association. That statistic is so stunning—home foreclosures impacting one child in every classroom—that it bears repeating as it indicates every pediatric practice has more red flags in terms of psychosocial stressors then at any time in most pediatrician's career.

Families, as always, face crises unrelated to the economy as well: illness, marital discord, substance abuse, and intergenerational pressures, but economic downturns increase the prevalence of almost all of the crises on this list.

Poverty is the elephant in the room, exposing children to a host of contributors to an unstable environment that sets the stage for poor academic performance, increased mental health disorders, conduct problems, substance abuse, and difficulties in relationships.

The first red flag raised by a family in economic trouble probably isn't even seen in the examining room, but in your billing department, where reimbursements are likely down and delinquent accounts are likely up.

A family may be unable to produce a copay for a visit, or may have lost health insurance along with mom or dad's job. They may report multiple changes in their address. Mail from your office may be returned as undeliverable.

This is, of course, an economic problem for you and your practice, but it likely heralds medical and psychosocial problems as well. A child whose family cannot pay for your services may be twice as likely as a financially secure child to have depression, anxiety, and learning problems at school.

Your office staff may want to alert you to financial red flags not only as they appear on the office balance sheet, but as they relate to your care of the child as well.

Moving, for example, has many implications for a child's development and well-being.

A new address may mean changes in a child's school and after-school activities, the loss of friends and close access to extended family members, and a shattering of the security of familiar places and routines. If the move was involuntary, say, a forced exit from a foreclosed home, parents may be so distracted and emotionally spent, they may not have devoted time to calmly explaining to the child what will change and what will stay the same.

I always think it's a good idea, but especially so in hard times, for you to ask one screening question of every family during routine office visits.

That bushel basket question is, “Are there any ongoing tensions affecting the family?”

Answers can potentially cover a lot of ground, and may open the door to a family sharing financial concerns, as well as any other issues that may be troubling them: a recent move, concern about a family member, or signs of domestic strife.

Red flags may appear during your examination as well. Immunizations may not be up to date, problems are suddenly arising at school, or a there may be a change in trajectory of the child's weight curve due to a lack of nutritious food.

Fatigue and stress associated with family troubles may be cloaked in somatic diagnoses: headaches, stomachaches, chest pain, weakness, or dizziness in a child who never had such complaints before or where these symptoms previously have signaled stress.

Take a good look at the parent accompanying your patient as well. Does the mother or father seem more withdrawn, sadder, or more anxious than expected?

Often, you have an internal red flag, a vaguely unsettled feeling that something is not right. Do not underestimate the value of this clinical sixth sense. Listen to it. It may not be anything specific that you can put your finger on or diagnose, but if you're getting that signal from within, sit down and take the pulse of the family in these troubling times.

[email protected]

Stress is nothing new to American families, who—over the generations—have endured wars, epidemics, natural disasters, and numerous economic downturns.

Today's dismal economic climate with continuing unemployment poses real challenges for families.

You should be especially attuned to warning signs that more children in your practice may be at risk for hunger, displacement from their homes and schools, and poverty-associated trauma, both physical and psychological.

The statistics are sobering.

In June 2010, unemployment stood at 14.6 million people, or 9.5% of the working-age population nationwide. Even more people are jobless in some unfortunate states and cities—more than 14% in Nevada, for instance; 14.5% in Las Vegas, Nev.; and 27.6% in tiny El Centro, Calif.

Homelessness among American families is growing, with 170,000 families seeking shelter in 2009, up from 159,000 the year before, according to the U.S. Department of Housing and Urban Development.

Every 3 months, another 250,000 families' homes enter foreclosure, putting one child in every classroom at risk of losing his or her home, according to the Mortgage Bankers Association. That statistic is so stunning—home foreclosures impacting one child in every classroom—that it bears repeating as it indicates every pediatric practice has more red flags in terms of psychosocial stressors then at any time in most pediatrician's career.

Families, as always, face crises unrelated to the economy as well: illness, marital discord, substance abuse, and intergenerational pressures, but economic downturns increase the prevalence of almost all of the crises on this list.

Poverty is the elephant in the room, exposing children to a host of contributors to an unstable environment that sets the stage for poor academic performance, increased mental health disorders, conduct problems, substance abuse, and difficulties in relationships.

The first red flag raised by a family in economic trouble probably isn't even seen in the examining room, but in your billing department, where reimbursements are likely down and delinquent accounts are likely up.

A family may be unable to produce a copay for a visit, or may have lost health insurance along with mom or dad's job. They may report multiple changes in their address. Mail from your office may be returned as undeliverable.

This is, of course, an economic problem for you and your practice, but it likely heralds medical and psychosocial problems as well. A child whose family cannot pay for your services may be twice as likely as a financially secure child to have depression, anxiety, and learning problems at school.

Your office staff may want to alert you to financial red flags not only as they appear on the office balance sheet, but as they relate to your care of the child as well.

Moving, for example, has many implications for a child's development and well-being.

A new address may mean changes in a child's school and after-school activities, the loss of friends and close access to extended family members, and a shattering of the security of familiar places and routines. If the move was involuntary, say, a forced exit from a foreclosed home, parents may be so distracted and emotionally spent, they may not have devoted time to calmly explaining to the child what will change and what will stay the same.

I always think it's a good idea, but especially so in hard times, for you to ask one screening question of every family during routine office visits.

That bushel basket question is, “Are there any ongoing tensions affecting the family?”

Answers can potentially cover a lot of ground, and may open the door to a family sharing financial concerns, as well as any other issues that may be troubling them: a recent move, concern about a family member, or signs of domestic strife.

Red flags may appear during your examination as well. Immunizations may not be up to date, problems are suddenly arising at school, or a there may be a change in trajectory of the child's weight curve due to a lack of nutritious food.

Fatigue and stress associated with family troubles may be cloaked in somatic diagnoses: headaches, stomachaches, chest pain, weakness, or dizziness in a child who never had such complaints before or where these symptoms previously have signaled stress.

Take a good look at the parent accompanying your patient as well. Does the mother or father seem more withdrawn, sadder, or more anxious than expected?

Often, you have an internal red flag, a vaguely unsettled feeling that something is not right. Do not underestimate the value of this clinical sixth sense. Listen to it. It may not be anything specific that you can put your finger on or diagnose, but if you're getting that signal from within, sit down and take the pulse of the family in these troubling times.