Cleveland Clinic Journal of Medicine

Editor's note: This paper was posted online prior to publication in print. To expedite publication, the paper was peer-reviewed by a CCJM physician editor.

The unexpected and well-publicized appearance of swine-origin influenza A (H1N1) virus (S-OIV, informally known as swine flu) has both physicians and the general public on edge. The health care system is mobilizing while the world watches to see if S-OIV will become a pandemic or will just fade away, like the swine flu outbreak of 1976.

In this update, written in mid-May 2009, I try to provide an overview of our current understanding of S-OIV, its diagnosis, treatment, and prevention, knowing that the information about the outbreak is being updated almost daily. To stay abreast of the latest developments, physicians should also consult Web sites of the US Centers for Disease Control and Prevention (CDC) and the World Health Organization (WHO).

IS IT REALLY ‘SWINE’?

An unexpected surge in influenza A cases toward the end of the 2008–2009 influenza season occurring in and around Mexico City alerted health authorities to a type of influenza virus infection that does not commonly affect humans.

In most years, the annual influenza epidemics in the Northern Hemisphere wane by the end of April. S-OIV infection first appeared in Mexico in April 2009 and shortly after in California and Texas.

In the first few days, the specific viral genetic origin of the epidemic was unclear. But genetic analysis of the virus isolated from a patient in California found that this virus was a recent reassortant of previous triple-reassortants of viruses from pigs, humans, and birds, called triple-reassortant swine influenza A (H1) viruses, which have been circulating in pigs for about a decade, and a Eurasian swine influenza virus.¹

Through the years, only a few influenza viruses have been successfully transmitted from birds to humans and then to swine.² It is interesting that exposure to pigs is not a risk factor for infection with the current S-OIV, unlike in prior cases of swine influenza reported in the literature.^3,4 Total reported cases of swine influenza in humans numbered only 50 from 1958 to 2005 and 11 from December 2005 through February 2009, but more cases must have occurred that were not readily identified.

The Veterinary Services of Canada announced on May 2, 2009, that a pig farm in Alberta had been infected with the current type of S-OIV. The infection was introduced to the farm by a carpenter who developed symptoms of influenza after a short stay in Mexico. It is reassuring to learn that, so far, the S-OIV causing illness in these pigs has not been transmitted to people living on that farm. The failure of the S-OIV to transmit back to people suggests that it did not come into the human population directly from swine.

AN EPIDEMIC IN MOTION

As of this writing, 2,532 cases of S-OIV have been confirmed in the United States by the CDC in 44 states, and 3 people have died, for a case-fatality rate of 0.11%. Simultaneously, the WHO reported 4,694 confirmed cases in 30 countries, with 53 deaths (a case-fatality rate of 1.1%), and with 48 of the deaths outside the United States occurring in Mexico.

It is unclear which direction this epidemic will take over the next several months. What happens in the annual influenza season in the Southern Hemisphere, which is just starting, and the early features of influenza activity in the Northern Hemisphere starting in September 2009 will indicate how this epidemic will materialize and the prospects of it’s progressing to an influenza pandemic.

While most adults today have some immunity against previously circulating H1 variants, it is not known if cross-reacting antibodies would provide any protection against the current S-OIV. An animal model showed that mice immunized against the neuraminidase of a human influenza A (H1N1) virus were partially protected from lethal challenge with H5N1 virus.⁵ In that same study, some humans also had serum antibodies that can inhibit sialidase activity of avian H5N1 viruses.

A remnant of the 1918 pandemic?

The two mechanisms by which pandemic influenza occurred in the 20th century were direct transmission of a novel virus and reassortment of avian and human viruses. In the 1918 pandemic, an influenza A (H1N1) virus closely related to avian viruses adapted to replicate efficiently in humans. Reassortment of an avian influenza A (H2N2) virus and a human influenza A (H1N1) virus resulted in the 1957 pandemic, and reassortment of an avian influenza A H3 virus and a human influenza A (H2N2) virus resulted in the 1968 pandemic.⁶ One could thus consider the current S-OIV epidemic as genetically a remnant or continuation of the 1918 pandemic, but so far it is less deadly.¹

What should we be looking for?

Several characteristic features were seen in prior pandemics that we should be looking for in the next few months to better understand the pandemic potential of the current S-OIV epidemic.⁷

While the severity of prior pandemics varied significantly, they were all heralded by an antigenic shift in viral subtype. Young adults and previously healthy people were disproportionately affected and had a higher-than-expected death rate. This may be explained by partial protection in older people due to antigen recycling. Secondary bacterial pneumonia is believed to have been a significant cause of death in the 1918 pandemic,⁸ and bacterial pharyngeal carriage rates are higher in younger people.

Pandemic waves smoldered, lasting 2 to 5 years, but the pattern of deaths varied significantly in different parts of the world. For example, in 1968, most deaths in North America occurred during the first pandemic season, whereas most deaths in Europe and Asia occurred during the second pandemic season.⁹ This may be explained by geographic variation in preexisting immunity, intrapandemic antigenic drift, viral adaptation, demographic differences, or seasonality.

Of importance, influenza viruses that caused prior pandemics were highly transmissible between humans.

CLINICAL FEATURES OF THE CURRENT OUTBREAK

The current S-OIV epidemic in the United States is affecting mainly younger people: 60% of people affected have been 18 years of age or younger.^10,11 It is unclear if this is due to transmission patterns or to possible immunity in older patients. Efficient human-to-human transmission within the United States is occurring, since only 18% of patients had recently traveled to Mexico. School outbreaks accounted for 16% of cases so far.

Patients have symptoms similar to those of seasonal influenza, with few exceptions. The most frequently reported symptoms are cough, fever, fatigue, headache, sore throat, runny nose, chills, and muscle aches, all occurring in 80% or more of patients. Almost all patients fit the CDC definition for influenza-like illness, consisting of subjective fever plus cough or sore throat.

Nausea, abdominal pain, and diarrhea, which are not common symptoms of seasonal influenza, have been reported in approximately 50% of patients with S-OIV. The spectrum of illness ranges from self-limited to severe, with 2% of patients developing pneumonia and 9% requiring hospitalization.

Continued analysis of the case-fatality rate highlights that people ages 20 to 29 are disproportionately represented among the fatalities.

A PCR test has been developed

Since clinical findings identify patients with influenza-like illness but cannot confirm or exclude the diagnosis of influenza,¹² a specific diagnostic real-time reverse-transcriptase polymerase chain reaction (RT-PCR) test has been developed, and the CDC is currently distributing it to state health departments.

An interim case definition

An interim case definition for the purpose of epidemiologic investigation of cases of S-OIV infection includes acute fever (temperature ≥ 100°F, 37.8°C) and acute respiratory illness (rhinorrhea, sore throat, or cough), plus:

• For a confirmed case, S-OIV infection confirmed by RT-PCR or viral culture
• For a probable case, laboratory-confirmed influenza A, but negative for H1 and H3 by RT-PCR
• For a suspected case, onset of above illness within 7 days of close contact with a confirmed case of S-OIV infection; or travel within 7 days to a community within the United States or internationally where there are one or more confirmed cases of S-OIV infection; or residing in such a community.

In practice, is it seasonal flu or swine flu?

In clinical practice in United States, in the springtime, a person with influenza-like illness and microbiologically confirmed seasonal influenza B obviously would not raise any concern about the ongoing S-OIV epidemic. Sporadic cases of seasonal influenza A are still occurring, but these are the ones that create a diagnostic dilemma, since very few laboratories currently have the ability to differentiate between influenza A H1 and H3. Since S-OIV has been reported in almost all states in the United States, one can argue that most cases of influenza A currently being identified should be considered suspected S-OIV.

PREVENTIVE MEASURES

In response to this ongoing outbreak, the WHO raised its epidemic alert level from 4 to 5, one level shy of declaring a pandemic. Several measures have been implemented in an attempt to halt this outbreak, the most important of which is the rapid dissemination of information to health professionals,¹³ with the Internet playing a central role.¹⁴

The world is better prepared for a pandemic now than at any time in history. Seed virus for vaccine development has been provided to various governments and pharmaceutical manufacturers. Stockpiles of antiviral agents are being mobilized and distributed to various locations, and dispensing plans are being reviewed for potential execution. The US Food and Drug Administration (FDA) issued emergency-use authorizations for mass deployment of the strategic stockpile of oseltamivir (Tamiflu), including for children younger than 1 year, and of zanamivir (Relenza) for the treatment and prophylaxis of S-OIV infection. It also authorized the use of disposable N95 respiratory masks by the general public, as well as the RT-PCR diagnostic test.

General advice for healthy people in the community

• Maintain a distance of at least 1 meter from a person with influenza-like illness.
• Wear a mask while providing care for a person with influenza-like illness.
• Avoid touching your eyes, nose, or mouth, since these are potential portals of entry for the virus. This may be a difficult recommendation to follow, since it requires constant vigilance of a common human behavior.
• Wash your hands often with either soap and water or an alcohol-based hand rub for 20 to 30 seconds, particularly after touching your eyes, nose, or mouth or after contact with respiratory secretions from a person, including your child, with influenza-like illness.
• If possible, reduce the time spent in close contact with people with influenza-like illness and in crowded settings.
• If possible, open windows in your living space to improve airflow.

While the CDC has recommended avoiding nonessential travel to Mexico at the current time, the WHO is not recommending any travel restrictions, since the outbreak has already spread to many parts of the world and all continents.

There is no limitation on handling or consuming pork meat or other well-processed swine products.

Recommendations for school dismissal and social-distancing interventions are evolving. During the 1918 pandemic, nonpharmaceutical interventions were associated with a significant reduction in deaths,¹⁵ but it is unclear how much additional benefit these measures would add to effective immunization, antiviral treatment for patients, and chemoprophylaxis for their contacts.

General advice for people with influenza-like illness

• Stay home for 7 days after the onset of symptoms or 48 hours after symptoms resolve, whichever is longer.
• Maintain a distance of at least 1 meter from all people.
• Cover your mouth and nose with tissues when coughing or sneezing, and dispose of the tissues immediately after use.
• Avoid touching your eyes, nose, and mouth.
• Wash your hands often with either soap and water or an alcohol-based hand rub for 20 to 30 seconds, particularly after touching your eyes, nose, or mouth or after contact with your respiratory secretions during coughing or sneezing. Adding virucidal agents or antiseptics to hand-washing is not likely to have an incremental effect.¹⁶
• If possible, open windows in your living space to improve airflow.
• If possible, when you are in close contact with other people, wear a mask to help contain your respiratory secretions.

Masks

The designs and standards of masks vary from country to country. Masks have been shown to reduce the transmission of influenza in health care settings,¹⁶ but the benefit in the community has not been established. Advice on proper use of a mask:

• Cover your mouth and nose with the mask and tie it securely to minimize gaps.
• Avoid touching the mask while it is on your face.
• Wash your hands with soap and water or an alcohol-based hand rub for 20 to 30 seconds after removing the mask.
• If the mask becomes damp, replace it with a new one.
• Avoid reusing single-use masks, and dispose of them immediately after removing.

VACCINE DEVELOPMENT

The most difficult question about vaccine development for S-OIV at this time is whether to prepare it as a separate product or try to incorporate it in the seasonal influenza vaccine.

The problem is that the seasonal influenza vaccine for the Southern Hemisphere has already been made and distributed, and vaccination programs are already well under way. Although flu season in the Northern Hemisphere is not expected before September or October 2009, vaccine production and distribution take several months, leaving little time to observe which direction the S-OIV epidemic will take before making this decision.

Vaccine distribution also raises difficult questions, since a limited amount will be available initially and rationing to the most vulnerable people will be necessary. While health care workers are more likely to be exposed to people infected with S-OIV compared with the general population, mandating their immunization may pose other moral dilemmas.¹⁷

The current global capacity for production of seasonal influenza vaccine is approximately 400 million doses.¹⁸ Since the process of vaccine production takes at least 4 to 6 months, measures have been proposed to speed up the production of pandemic vaccine or immunogenicity; these include recombinant technology, reverse genetics, and the use of adjuvants. In April 2007, the FDA approved the first H5 subviron vaccine for people ages 19 to 64.

This topic brings back memories of the 1976 swine influenza immunization program, in which the rate of Guillain-Barré syndrome was 5 to 10 times the background rate, resulting in a halt in vaccine production.

Why this syndrome occurred is not known, but it is suspected to be due to cross-reacting antibodies against peripheral-nerve antigen that developed after the vaccine was given. Data since then have shown no association between vaccination and Guillain-Barré syndrome. ¹⁹ On the other hand, influenza viruses were found to trigger Guillain-Barré syndrome only infrequently, except during major outbreaks, in which they may play a significant role.²⁰

TREATMENT

Antiviral drugs

Tests of current S-OIV isolates showed them to be susceptible to the neuraminidase inhibitors, ie, oseltamivir and zanamivir, but resistant to the adamantanes, ie, amantadine (Symmetrel) and rimantadine (Flumadine).²¹ All isolates contained the S31N mutation in the M2 protein, which confers resistance against the adamantanes and which has been detected in most influenza A (H3N2) isolates in the United States since 2006. Fortunately, the H274Y mutation in N1—which confers resistance to oseltamivir but not to zanamivir and which has been detected in almost all seasonal influenza A (H1N1) isolates since the early weeks of the current influenza season— has not been detected in any of the current S-OIV isolates.

Patients who are otherwise healthy who present with an uncomplicated febrile illness due to S-OIV do not require antiviral treatment. Either oseltamivir or zanamivir is recommended for treatment of patients hospitalized for management of confirmed, probable, or suspected infection with S-OIV, or for those at high risk of influenza-related complications, defined similarly to seasonal influenza (Table 1).

The duration of shedding of S-OIV is unknown, but starting an antiviral agent early in the course of illness is expected to reduce contagiousness. Extrapolating from data in seasonal influenza, infected persons are assumed to be shedding virus from 1 day prior to illness onset until resolution of symptoms, usually 7 days, and up to 10 days in younger children.

Oseltamivir accounts for the lion’s share of the stockpile of antiviral drugs against pandemic influenza. However, with mass utilization, antiviral resistance to a single agent may develop. A mathematical model showed that adding a smaller stockpile of a second agent, such as zanamivir, to be used either in combination with or sequential to oseltamivir, can effectively prevent or at least delay the development of resistance.22

Other potential measures for management

Since secondary bacterial pneumonia is expected to play a significant role in influenza-related death during the next pandemic, stockpiling antibacterial agents may also be prudent.⁸ The death rate in methicillin-resistant Staphylococcus aureus pneumonia secondary to seasonal influenza is 50%, further complicating the choice of stockpiling for antibacterial agents.

A meta-analysis of 11 studies involving 1,703 patients during the 1918 pandemic showed that those who received influenza-convalescent human blood products were less likely to die than those who did not.²³ Anti-influenza drugs and advanced techniques to care for critically ill patients were not available at that time, so extrapolating these data to the current era may not be appropriate.

The cost of vaccine and antiviral drugs is an expected limitation to mass implementation during a pandemic, particularly in developing countries. Certain inexpensive generic drugs that have been shown to have some activity against influenza, such statins, fibrates, and chloroquine, deserve further attention.²⁴

PUTING THE CURRENT EPIDEMIC IN PERSPECTIVE

In summary, the world is now better prepared, vaccine is in development, and antiviral treatment is available. For more information, readers are directed to go to www.cdc.gov/h1n1flu/ or www.who.int/csr/don/2009_05_11/en/index.html.

Editor's note: This paper was posted online prior to publication in print. To expedite publication, the paper was peer-reviewed by a CCJM physician editor.

The unexpected and well-publicized appearance of swine-origin influenza A (H1N1) virus (S-OIV, informally known as swine flu) has both physicians and the general public on edge. The health care system is mobilizing while the world watches to see if S-OIV will become a pandemic or will just fade away, like the swine flu outbreak of 1976.

In this update, written in mid-May 2009, I try to provide an overview of our current understanding of S-OIV, its diagnosis, treatment, and prevention, knowing that the information about the outbreak is being updated almost daily. To stay abreast of the latest developments, physicians should also consult Web sites of the US Centers for Disease Control and Prevention (CDC) and the World Health Organization (WHO).

IS IT REALLY ‘SWINE’?

An unexpected surge in influenza A cases toward the end of the 2008–2009 influenza season occurring in and around Mexico City alerted health authorities to a type of influenza virus infection that does not commonly affect humans.

In most years, the annual influenza epidemics in the Northern Hemisphere wane by the end of April. S-OIV infection first appeared in Mexico in April 2009 and shortly after in California and Texas.

In the first few days, the specific viral genetic origin of the epidemic was unclear. But genetic analysis of the virus isolated from a patient in California found that this virus was a recent reassortant of previous triple-reassortants of viruses from pigs, humans, and birds, called triple-reassortant swine influenza A (H1) viruses, which have been circulating in pigs for about a decade, and a Eurasian swine influenza virus.¹

Through the years, only a few influenza viruses have been successfully transmitted from birds to humans and then to swine.² It is interesting that exposure to pigs is not a risk factor for infection with the current S-OIV, unlike in prior cases of swine influenza reported in the literature.^3,4 Total reported cases of swine influenza in humans numbered only 50 from 1958 to 2005 and 11 from December 2005 through February 2009, but more cases must have occurred that were not readily identified.

The Veterinary Services of Canada announced on May 2, 2009, that a pig farm in Alberta had been infected with the current type of S-OIV. The infection was introduced to the farm by a carpenter who developed symptoms of influenza after a short stay in Mexico. It is reassuring to learn that, so far, the S-OIV causing illness in these pigs has not been transmitted to people living on that farm. The failure of the S-OIV to transmit back to people suggests that it did not come into the human population directly from swine.

AN EPIDEMIC IN MOTION

As of this writing, 2,532 cases of S-OIV have been confirmed in the United States by the CDC in 44 states, and 3 people have died, for a case-fatality rate of 0.11%. Simultaneously, the WHO reported 4,694 confirmed cases in 30 countries, with 53 deaths (a case-fatality rate of 1.1%), and with 48 of the deaths outside the United States occurring in Mexico.

It is unclear which direction this epidemic will take over the next several months. What happens in the annual influenza season in the Southern Hemisphere, which is just starting, and the early features of influenza activity in the Northern Hemisphere starting in September 2009 will indicate how this epidemic will materialize and the prospects of it’s progressing to an influenza pandemic.

While most adults today have some immunity against previously circulating H1 variants, it is not known if cross-reacting antibodies would provide any protection against the current S-OIV. An animal model showed that mice immunized against the neuraminidase of a human influenza A (H1N1) virus were partially protected from lethal challenge with H5N1 virus.⁵ In that same study, some humans also had serum antibodies that can inhibit sialidase activity of avian H5N1 viruses.

A remnant of the 1918 pandemic?

The two mechanisms by which pandemic influenza occurred in the 20th century were direct transmission of a novel virus and reassortment of avian and human viruses. In the 1918 pandemic, an influenza A (H1N1) virus closely related to avian viruses adapted to replicate efficiently in humans. Reassortment of an avian influenza A (H2N2) virus and a human influenza A (H1N1) virus resulted in the 1957 pandemic, and reassortment of an avian influenza A H3 virus and a human influenza A (H2N2) virus resulted in the 1968 pandemic.⁶ One could thus consider the current S-OIV epidemic as genetically a remnant or continuation of the 1918 pandemic, but so far it is less deadly.¹

What should we be looking for?

Several characteristic features were seen in prior pandemics that we should be looking for in the next few months to better understand the pandemic potential of the current S-OIV epidemic.⁷

While the severity of prior pandemics varied significantly, they were all heralded by an antigenic shift in viral subtype. Young adults and previously healthy people were disproportionately affected and had a higher-than-expected death rate. This may be explained by partial protection in older people due to antigen recycling. Secondary bacterial pneumonia is believed to have been a significant cause of death in the 1918 pandemic,⁸ and bacterial pharyngeal carriage rates are higher in younger people.

Pandemic waves smoldered, lasting 2 to 5 years, but the pattern of deaths varied significantly in different parts of the world. For example, in 1968, most deaths in North America occurred during the first pandemic season, whereas most deaths in Europe and Asia occurred during the second pandemic season.⁹ This may be explained by geographic variation in preexisting immunity, intrapandemic antigenic drift, viral adaptation, demographic differences, or seasonality.

Of importance, influenza viruses that caused prior pandemics were highly transmissible between humans.

CLINICAL FEATURES OF THE CURRENT OUTBREAK

The current S-OIV epidemic in the United States is affecting mainly younger people: 60% of people affected have been 18 years of age or younger.^10,11 It is unclear if this is due to transmission patterns or to possible immunity in older patients. Efficient human-to-human transmission within the United States is occurring, since only 18% of patients had recently traveled to Mexico. School outbreaks accounted for 16% of cases so far.

Patients have symptoms similar to those of seasonal influenza, with few exceptions. The most frequently reported symptoms are cough, fever, fatigue, headache, sore throat, runny nose, chills, and muscle aches, all occurring in 80% or more of patients. Almost all patients fit the CDC definition for influenza-like illness, consisting of subjective fever plus cough or sore throat.

Nausea, abdominal pain, and diarrhea, which are not common symptoms of seasonal influenza, have been reported in approximately 50% of patients with S-OIV. The spectrum of illness ranges from self-limited to severe, with 2% of patients developing pneumonia and 9% requiring hospitalization.

Continued analysis of the case-fatality rate highlights that people ages 20 to 29 are disproportionately represented among the fatalities.

A PCR test has been developed

Since clinical findings identify patients with influenza-like illness but cannot confirm or exclude the diagnosis of influenza,¹² a specific diagnostic real-time reverse-transcriptase polymerase chain reaction (RT-PCR) test has been developed, and the CDC is currently distributing it to state health departments.

An interim case definition

An interim case definition for the purpose of epidemiologic investigation of cases of S-OIV infection includes acute fever (temperature ≥ 100°F, 37.8°C) and acute respiratory illness (rhinorrhea, sore throat, or cough), plus:

• For a confirmed case, S-OIV infection confirmed by RT-PCR or viral culture
• For a probable case, laboratory-confirmed influenza A, but negative for H1 and H3 by RT-PCR
• For a suspected case, onset of above illness within 7 days of close contact with a confirmed case of S-OIV infection; or travel within 7 days to a community within the United States or internationally where there are one or more confirmed cases of S-OIV infection; or residing in such a community.

In practice, is it seasonal flu or swine flu?

In clinical practice in United States, in the springtime, a person with influenza-like illness and microbiologically confirmed seasonal influenza B obviously would not raise any concern about the ongoing S-OIV epidemic. Sporadic cases of seasonal influenza A are still occurring, but these are the ones that create a diagnostic dilemma, since very few laboratories currently have the ability to differentiate between influenza A H1 and H3. Since S-OIV has been reported in almost all states in the United States, one can argue that most cases of influenza A currently being identified should be considered suspected S-OIV.

PREVENTIVE MEASURES

In response to this ongoing outbreak, the WHO raised its epidemic alert level from 4 to 5, one level shy of declaring a pandemic. Several measures have been implemented in an attempt to halt this outbreak, the most important of which is the rapid dissemination of information to health professionals,¹³ with the Internet playing a central role.¹⁴

The world is better prepared for a pandemic now than at any time in history. Seed virus for vaccine development has been provided to various governments and pharmaceutical manufacturers. Stockpiles of antiviral agents are being mobilized and distributed to various locations, and dispensing plans are being reviewed for potential execution. The US Food and Drug Administration (FDA) issued emergency-use authorizations for mass deployment of the strategic stockpile of oseltamivir (Tamiflu), including for children younger than 1 year, and of zanamivir (Relenza) for the treatment and prophylaxis of S-OIV infection. It also authorized the use of disposable N95 respiratory masks by the general public, as well as the RT-PCR diagnostic test.

General advice for healthy people in the community

• Maintain a distance of at least 1 meter from a person with influenza-like illness.
• Wear a mask while providing care for a person with influenza-like illness.
• Avoid touching your eyes, nose, or mouth, since these are potential portals of entry for the virus. This may be a difficult recommendation to follow, since it requires constant vigilance of a common human behavior.
• Wash your hands often with either soap and water or an alcohol-based hand rub for 20 to 30 seconds, particularly after touching your eyes, nose, or mouth or after contact with respiratory secretions from a person, including your child, with influenza-like illness.
• If possible, reduce the time spent in close contact with people with influenza-like illness and in crowded settings.
• If possible, open windows in your living space to improve airflow.

While the CDC has recommended avoiding nonessential travel to Mexico at the current time, the WHO is not recommending any travel restrictions, since the outbreak has already spread to many parts of the world and all continents.

There is no limitation on handling or consuming pork meat or other well-processed swine products.

Recommendations for school dismissal and social-distancing interventions are evolving. During the 1918 pandemic, nonpharmaceutical interventions were associated with a significant reduction in deaths,¹⁵ but it is unclear how much additional benefit these measures would add to effective immunization, antiviral treatment for patients, and chemoprophylaxis for their contacts.

General advice for people with influenza-like illness

• Stay home for 7 days after the onset of symptoms or 48 hours after symptoms resolve, whichever is longer.
• Maintain a distance of at least 1 meter from all people.
• Cover your mouth and nose with tissues when coughing or sneezing, and dispose of the tissues immediately after use.
• Avoid touching your eyes, nose, and mouth.
• Wash your hands often with either soap and water or an alcohol-based hand rub for 20 to 30 seconds, particularly after touching your eyes, nose, or mouth or after contact with your respiratory secretions during coughing or sneezing. Adding virucidal agents or antiseptics to hand-washing is not likely to have an incremental effect.¹⁶
• If possible, open windows in your living space to improve airflow.
• If possible, when you are in close contact with other people, wear a mask to help contain your respiratory secretions.

Masks

The designs and standards of masks vary from country to country. Masks have been shown to reduce the transmission of influenza in health care settings,¹⁶ but the benefit in the community has not been established. Advice on proper use of a mask:

• Cover your mouth and nose with the mask and tie it securely to minimize gaps.
• Avoid touching the mask while it is on your face.
• Wash your hands with soap and water or an alcohol-based hand rub for 20 to 30 seconds after removing the mask.
• If the mask becomes damp, replace it with a new one.
• Avoid reusing single-use masks, and dispose of them immediately after removing.

VACCINE DEVELOPMENT

The most difficult question about vaccine development for S-OIV at this time is whether to prepare it as a separate product or try to incorporate it in the seasonal influenza vaccine.

The problem is that the seasonal influenza vaccine for the Southern Hemisphere has already been made and distributed, and vaccination programs are already well under way. Although flu season in the Northern Hemisphere is not expected before September or October 2009, vaccine production and distribution take several months, leaving little time to observe which direction the S-OIV epidemic will take before making this decision.

Vaccine distribution also raises difficult questions, since a limited amount will be available initially and rationing to the most vulnerable people will be necessary. While health care workers are more likely to be exposed to people infected with S-OIV compared with the general population, mandating their immunization may pose other moral dilemmas.¹⁷

The current global capacity for production of seasonal influenza vaccine is approximately 400 million doses.¹⁸ Since the process of vaccine production takes at least 4 to 6 months, measures have been proposed to speed up the production of pandemic vaccine or immunogenicity; these include recombinant technology, reverse genetics, and the use of adjuvants. In April 2007, the FDA approved the first H5 subviron vaccine for people ages 19 to 64.

This topic brings back memories of the 1976 swine influenza immunization program, in which the rate of Guillain-Barré syndrome was 5 to 10 times the background rate, resulting in a halt in vaccine production.

Why this syndrome occurred is not known, but it is suspected to be due to cross-reacting antibodies against peripheral-nerve antigen that developed after the vaccine was given. Data since then have shown no association between vaccination and Guillain-Barré syndrome. ¹⁹ On the other hand, influenza viruses were found to trigger Guillain-Barré syndrome only infrequently, except during major outbreaks, in which they may play a significant role.²⁰

TREATMENT

Antiviral drugs

Tests of current S-OIV isolates showed them to be susceptible to the neuraminidase inhibitors, ie, oseltamivir and zanamivir, but resistant to the adamantanes, ie, amantadine (Symmetrel) and rimantadine (Flumadine).²¹ All isolates contained the S31N mutation in the M2 protein, which confers resistance against the adamantanes and which has been detected in most influenza A (H3N2) isolates in the United States since 2006. Fortunately, the H274Y mutation in N1—which confers resistance to oseltamivir but not to zanamivir and which has been detected in almost all seasonal influenza A (H1N1) isolates since the early weeks of the current influenza season— has not been detected in any of the current S-OIV isolates.

Patients who are otherwise healthy who present with an uncomplicated febrile illness due to S-OIV do not require antiviral treatment. Either oseltamivir or zanamivir is recommended for treatment of patients hospitalized for management of confirmed, probable, or suspected infection with S-OIV, or for those at high risk of influenza-related complications, defined similarly to seasonal influenza (Table 1).

The duration of shedding of S-OIV is unknown, but starting an antiviral agent early in the course of illness is expected to reduce contagiousness. Extrapolating from data in seasonal influenza, infected persons are assumed to be shedding virus from 1 day prior to illness onset until resolution of symptoms, usually 7 days, and up to 10 days in younger children.

Oseltamivir accounts for the lion’s share of the stockpile of antiviral drugs against pandemic influenza. However, with mass utilization, antiviral resistance to a single agent may develop. A mathematical model showed that adding a smaller stockpile of a second agent, such as zanamivir, to be used either in combination with or sequential to oseltamivir, can effectively prevent or at least delay the development of resistance.22

Other potential measures for management

Since secondary bacterial pneumonia is expected to play a significant role in influenza-related death during the next pandemic, stockpiling antibacterial agents may also be prudent.⁸ The death rate in methicillin-resistant Staphylococcus aureus pneumonia secondary to seasonal influenza is 50%, further complicating the choice of stockpiling for antibacterial agents.

A meta-analysis of 11 studies involving 1,703 patients during the 1918 pandemic showed that those who received influenza-convalescent human blood products were less likely to die than those who did not.²³ Anti-influenza drugs and advanced techniques to care for critically ill patients were not available at that time, so extrapolating these data to the current era may not be appropriate.

The cost of vaccine and antiviral drugs is an expected limitation to mass implementation during a pandemic, particularly in developing countries. Certain inexpensive generic drugs that have been shown to have some activity against influenza, such statins, fibrates, and chloroquine, deserve further attention.²⁴

PUTING THE CURRENT EPIDEMIC IN PERSPECTIVE

In summary, the world is now better prepared, vaccine is in development, and antiviral treatment is available. For more information, readers are directed to go to www.cdc.gov/h1n1flu/ or www.who.int/csr/don/2009_05_11/en/index.html.

Editor's note: This paper was posted online prior to publication in print. To expedite publication, the paper was peer-reviewed by a CCJM physician editor.

The unexpected and well-publicized appearance of swine-origin influenza A (H1N1) virus (S-OIV, informally known as swine flu) has both physicians and the general public on edge. The health care system is mobilizing while the world watches to see if S-OIV will become a pandemic or will just fade away, like the swine flu outbreak of 1976.

In this update, written in mid-May 2009, I try to provide an overview of our current understanding of S-OIV, its diagnosis, treatment, and prevention, knowing that the information about the outbreak is being updated almost daily. To stay abreast of the latest developments, physicians should also consult Web sites of the US Centers for Disease Control and Prevention (CDC) and the World Health Organization (WHO).

IS IT REALLY ‘SWINE’?

An unexpected surge in influenza A cases toward the end of the 2008–2009 influenza season occurring in and around Mexico City alerted health authorities to a type of influenza virus infection that does not commonly affect humans.

In most years, the annual influenza epidemics in the Northern Hemisphere wane by the end of April. S-OIV infection first appeared in Mexico in April 2009 and shortly after in California and Texas.

In the first few days, the specific viral genetic origin of the epidemic was unclear. But genetic analysis of the virus isolated from a patient in California found that this virus was a recent reassortant of previous triple-reassortants of viruses from pigs, humans, and birds, called triple-reassortant swine influenza A (H1) viruses, which have been circulating in pigs for about a decade, and a Eurasian swine influenza virus.¹

Through the years, only a few influenza viruses have been successfully transmitted from birds to humans and then to swine.² It is interesting that exposure to pigs is not a risk factor for infection with the current S-OIV, unlike in prior cases of swine influenza reported in the literature.^3,4 Total reported cases of swine influenza in humans numbered only 50 from 1958 to 2005 and 11 from December 2005 through February 2009, but more cases must have occurred that were not readily identified.

The Veterinary Services of Canada announced on May 2, 2009, that a pig farm in Alberta had been infected with the current type of S-OIV. The infection was introduced to the farm by a carpenter who developed symptoms of influenza after a short stay in Mexico. It is reassuring to learn that, so far, the S-OIV causing illness in these pigs has not been transmitted to people living on that farm. The failure of the S-OIV to transmit back to people suggests that it did not come into the human population directly from swine.

AN EPIDEMIC IN MOTION

As of this writing, 2,532 cases of S-OIV have been confirmed in the United States by the CDC in 44 states, and 3 people have died, for a case-fatality rate of 0.11%. Simultaneously, the WHO reported 4,694 confirmed cases in 30 countries, with 53 deaths (a case-fatality rate of 1.1%), and with 48 of the deaths outside the United States occurring in Mexico.

It is unclear which direction this epidemic will take over the next several months. What happens in the annual influenza season in the Southern Hemisphere, which is just starting, and the early features of influenza activity in the Northern Hemisphere starting in September 2009 will indicate how this epidemic will materialize and the prospects of it’s progressing to an influenza pandemic.

While most adults today have some immunity against previously circulating H1 variants, it is not known if cross-reacting antibodies would provide any protection against the current S-OIV. An animal model showed that mice immunized against the neuraminidase of a human influenza A (H1N1) virus were partially protected from lethal challenge with H5N1 virus.⁵ In that same study, some humans also had serum antibodies that can inhibit sialidase activity of avian H5N1 viruses.

A remnant of the 1918 pandemic?

The two mechanisms by which pandemic influenza occurred in the 20th century were direct transmission of a novel virus and reassortment of avian and human viruses. In the 1918 pandemic, an influenza A (H1N1) virus closely related to avian viruses adapted to replicate efficiently in humans. Reassortment of an avian influenza A (H2N2) virus and a human influenza A (H1N1) virus resulted in the 1957 pandemic, and reassortment of an avian influenza A H3 virus and a human influenza A (H2N2) virus resulted in the 1968 pandemic.⁶ One could thus consider the current S-OIV epidemic as genetically a remnant or continuation of the 1918 pandemic, but so far it is less deadly.¹

What should we be looking for?

Several characteristic features were seen in prior pandemics that we should be looking for in the next few months to better understand the pandemic potential of the current S-OIV epidemic.⁷

While the severity of prior pandemics varied significantly, they were all heralded by an antigenic shift in viral subtype. Young adults and previously healthy people were disproportionately affected and had a higher-than-expected death rate. This may be explained by partial protection in older people due to antigen recycling. Secondary bacterial pneumonia is believed to have been a significant cause of death in the 1918 pandemic,⁸ and bacterial pharyngeal carriage rates are higher in younger people.

Pandemic waves smoldered, lasting 2 to 5 years, but the pattern of deaths varied significantly in different parts of the world. For example, in 1968, most deaths in North America occurred during the first pandemic season, whereas most deaths in Europe and Asia occurred during the second pandemic season.⁹ This may be explained by geographic variation in preexisting immunity, intrapandemic antigenic drift, viral adaptation, demographic differences, or seasonality.

Of importance, influenza viruses that caused prior pandemics were highly transmissible between humans.

CLINICAL FEATURES OF THE CURRENT OUTBREAK

The current S-OIV epidemic in the United States is affecting mainly younger people: 60% of people affected have been 18 years of age or younger.^10,11 It is unclear if this is due to transmission patterns or to possible immunity in older patients. Efficient human-to-human transmission within the United States is occurring, since only 18% of patients had recently traveled to Mexico. School outbreaks accounted for 16% of cases so far.

Patients have symptoms similar to those of seasonal influenza, with few exceptions. The most frequently reported symptoms are cough, fever, fatigue, headache, sore throat, runny nose, chills, and muscle aches, all occurring in 80% or more of patients. Almost all patients fit the CDC definition for influenza-like illness, consisting of subjective fever plus cough or sore throat.

Nausea, abdominal pain, and diarrhea, which are not common symptoms of seasonal influenza, have been reported in approximately 50% of patients with S-OIV. The spectrum of illness ranges from self-limited to severe, with 2% of patients developing pneumonia and 9% requiring hospitalization.

Continued analysis of the case-fatality rate highlights that people ages 20 to 29 are disproportionately represented among the fatalities.

A PCR test has been developed

Since clinical findings identify patients with influenza-like illness but cannot confirm or exclude the diagnosis of influenza,¹² a specific diagnostic real-time reverse-transcriptase polymerase chain reaction (RT-PCR) test has been developed, and the CDC is currently distributing it to state health departments.

An interim case definition

An interim case definition for the purpose of epidemiologic investigation of cases of S-OIV infection includes acute fever (temperature ≥ 100°F, 37.8°C) and acute respiratory illness (rhinorrhea, sore throat, or cough), plus:

• For a confirmed case, S-OIV infection confirmed by RT-PCR or viral culture
• For a probable case, laboratory-confirmed influenza A, but negative for H1 and H3 by RT-PCR
• For a suspected case, onset of above illness within 7 days of close contact with a confirmed case of S-OIV infection; or travel within 7 days to a community within the United States or internationally where there are one or more confirmed cases of S-OIV infection; or residing in such a community.

In practice, is it seasonal flu or swine flu?

In clinical practice in United States, in the springtime, a person with influenza-like illness and microbiologically confirmed seasonal influenza B obviously would not raise any concern about the ongoing S-OIV epidemic. Sporadic cases of seasonal influenza A are still occurring, but these are the ones that create a diagnostic dilemma, since very few laboratories currently have the ability to differentiate between influenza A H1 and H3. Since S-OIV has been reported in almost all states in the United States, one can argue that most cases of influenza A currently being identified should be considered suspected S-OIV.

PREVENTIVE MEASURES

In response to this ongoing outbreak, the WHO raised its epidemic alert level from 4 to 5, one level shy of declaring a pandemic. Several measures have been implemented in an attempt to halt this outbreak, the most important of which is the rapid dissemination of information to health professionals,¹³ with the Internet playing a central role.¹⁴

The world is better prepared for a pandemic now than at any time in history. Seed virus for vaccine development has been provided to various governments and pharmaceutical manufacturers. Stockpiles of antiviral agents are being mobilized and distributed to various locations, and dispensing plans are being reviewed for potential execution. The US Food and Drug Administration (FDA) issued emergency-use authorizations for mass deployment of the strategic stockpile of oseltamivir (Tamiflu), including for children younger than 1 year, and of zanamivir (Relenza) for the treatment and prophylaxis of S-OIV infection. It also authorized the use of disposable N95 respiratory masks by the general public, as well as the RT-PCR diagnostic test.

General advice for healthy people in the community

• Maintain a distance of at least 1 meter from a person with influenza-like illness.
• Wear a mask while providing care for a person with influenza-like illness.
• Avoid touching your eyes, nose, or mouth, since these are potential portals of entry for the virus. This may be a difficult recommendation to follow, since it requires constant vigilance of a common human behavior.
• Wash your hands often with either soap and water or an alcohol-based hand rub for 20 to 30 seconds, particularly after touching your eyes, nose, or mouth or after contact with respiratory secretions from a person, including your child, with influenza-like illness.
• If possible, reduce the time spent in close contact with people with influenza-like illness and in crowded settings.
• If possible, open windows in your living space to improve airflow.

While the CDC has recommended avoiding nonessential travel to Mexico at the current time, the WHO is not recommending any travel restrictions, since the outbreak has already spread to many parts of the world and all continents.

There is no limitation on handling or consuming pork meat or other well-processed swine products.

Recommendations for school dismissal and social-distancing interventions are evolving. During the 1918 pandemic, nonpharmaceutical interventions were associated with a significant reduction in deaths,¹⁵ but it is unclear how much additional benefit these measures would add to effective immunization, antiviral treatment for patients, and chemoprophylaxis for their contacts.

General advice for people with influenza-like illness

• Stay home for 7 days after the onset of symptoms or 48 hours after symptoms resolve, whichever is longer.
• Maintain a distance of at least 1 meter from all people.
• Cover your mouth and nose with tissues when coughing or sneezing, and dispose of the tissues immediately after use.
• Avoid touching your eyes, nose, and mouth.
• Wash your hands often with either soap and water or an alcohol-based hand rub for 20 to 30 seconds, particularly after touching your eyes, nose, or mouth or after contact with your respiratory secretions during coughing or sneezing. Adding virucidal agents or antiseptics to hand-washing is not likely to have an incremental effect.¹⁶
• If possible, open windows in your living space to improve airflow.
• If possible, when you are in close contact with other people, wear a mask to help contain your respiratory secretions.

Masks

The designs and standards of masks vary from country to country. Masks have been shown to reduce the transmission of influenza in health care settings,¹⁶ but the benefit in the community has not been established. Advice on proper use of a mask:

• Cover your mouth and nose with the mask and tie it securely to minimize gaps.
• Avoid touching the mask while it is on your face.
• Wash your hands with soap and water or an alcohol-based hand rub for 20 to 30 seconds after removing the mask.
• If the mask becomes damp, replace it with a new one.
• Avoid reusing single-use masks, and dispose of them immediately after removing.

VACCINE DEVELOPMENT

The most difficult question about vaccine development for S-OIV at this time is whether to prepare it as a separate product or try to incorporate it in the seasonal influenza vaccine.

The problem is that the seasonal influenza vaccine for the Southern Hemisphere has already been made and distributed, and vaccination programs are already well under way. Although flu season in the Northern Hemisphere is not expected before September or October 2009, vaccine production and distribution take several months, leaving little time to observe which direction the S-OIV epidemic will take before making this decision.

Vaccine distribution also raises difficult questions, since a limited amount will be available initially and rationing to the most vulnerable people will be necessary. While health care workers are more likely to be exposed to people infected with S-OIV compared with the general population, mandating their immunization may pose other moral dilemmas.¹⁷

The current global capacity for production of seasonal influenza vaccine is approximately 400 million doses.¹⁸ Since the process of vaccine production takes at least 4 to 6 months, measures have been proposed to speed up the production of pandemic vaccine or immunogenicity; these include recombinant technology, reverse genetics, and the use of adjuvants. In April 2007, the FDA approved the first H5 subviron vaccine for people ages 19 to 64.

This topic brings back memories of the 1976 swine influenza immunization program, in which the rate of Guillain-Barré syndrome was 5 to 10 times the background rate, resulting in a halt in vaccine production.

Why this syndrome occurred is not known, but it is suspected to be due to cross-reacting antibodies against peripheral-nerve antigen that developed after the vaccine was given. Data since then have shown no association between vaccination and Guillain-Barré syndrome. ¹⁹ On the other hand, influenza viruses were found to trigger Guillain-Barré syndrome only infrequently, except during major outbreaks, in which they may play a significant role.²⁰

TREATMENT

Antiviral drugs

Tests of current S-OIV isolates showed them to be susceptible to the neuraminidase inhibitors, ie, oseltamivir and zanamivir, but resistant to the adamantanes, ie, amantadine (Symmetrel) and rimantadine (Flumadine).²¹ All isolates contained the S31N mutation in the M2 protein, which confers resistance against the adamantanes and which has been detected in most influenza A (H3N2) isolates in the United States since 2006. Fortunately, the H274Y mutation in N1—which confers resistance to oseltamivir but not to zanamivir and which has been detected in almost all seasonal influenza A (H1N1) isolates since the early weeks of the current influenza season— has not been detected in any of the current S-OIV isolates.

Patients who are otherwise healthy who present with an uncomplicated febrile illness due to S-OIV do not require antiviral treatment. Either oseltamivir or zanamivir is recommended for treatment of patients hospitalized for management of confirmed, probable, or suspected infection with S-OIV, or for those at high risk of influenza-related complications, defined similarly to seasonal influenza (Table 1).

The duration of shedding of S-OIV is unknown, but starting an antiviral agent early in the course of illness is expected to reduce contagiousness. Extrapolating from data in seasonal influenza, infected persons are assumed to be shedding virus from 1 day prior to illness onset until resolution of symptoms, usually 7 days, and up to 10 days in younger children.

Oseltamivir accounts for the lion’s share of the stockpile of antiviral drugs against pandemic influenza. However, with mass utilization, antiviral resistance to a single agent may develop. A mathematical model showed that adding a smaller stockpile of a second agent, such as zanamivir, to be used either in combination with or sequential to oseltamivir, can effectively prevent or at least delay the development of resistance.22

Other potential measures for management

Since secondary bacterial pneumonia is expected to play a significant role in influenza-related death during the next pandemic, stockpiling antibacterial agents may also be prudent.⁸ The death rate in methicillin-resistant Staphylococcus aureus pneumonia secondary to seasonal influenza is 50%, further complicating the choice of stockpiling for antibacterial agents.

A meta-analysis of 11 studies involving 1,703 patients during the 1918 pandemic showed that those who received influenza-convalescent human blood products were less likely to die than those who did not.²³ Anti-influenza drugs and advanced techniques to care for critically ill patients were not available at that time, so extrapolating these data to the current era may not be appropriate.

The cost of vaccine and antiviral drugs is an expected limitation to mass implementation during a pandemic, particularly in developing countries. Certain inexpensive generic drugs that have been shown to have some activity against influenza, such statins, fibrates, and chloroquine, deserve further attention.²⁴

PUTING THE CURRENT EPIDEMIC IN PERSPECTIVE

In summary, the world is now better prepared, vaccine is in development, and antiviral treatment is available. For more information, readers are directed to go to www.cdc.gov/h1n1flu/ or www.who.int/csr/don/2009_05_11/en/index.html.

In the case of the antiresorptive drugs for treating osteoporosis, the bisphosphonates have been shown not only to improve bone density but also to reduce the risk of fractures. The clinical trials used dual-energy x-ray absorptiometry (DXA) measurements as a surrogate marker for fragility fractures, and the two correlated reasonably well. Thus, clinicians for the past 10-plus years have used DXA results to justify prescribing these drugs for patients (primarily women) with low T scores to prevent future fractures. There is no doubt that osteoporosis had previously been undertreated, and the projected number of patients with hip and spine fractures would overflow chronic-care beds. Yet there has been a sense that bisphosphonates are prescribed so often they may as well be “put in the water,” and that we are prophylactically treating many thousands of patients who are never going to suffer a fracture.

How can we better predict who will, with a given low T score, have a fracture of the hip or spine and who will not? Why do patients exposed to excess corticosteroids suffer strikingly more fractures than patients with identical T scores who were not exposed to steroids? Why do smoking and family history of fracture contribute to fracture risk in a way not accounted for by density measures alone?

Thus enters the intellectually pleasing concept of bone quality. However, bone quality is pragmatically as tough to measure as emotional stress. Yet we have learned to not minimize either of these when looking at hard outcomes. In this issue of the Journal, Dr. Angelo Licata discusses how clinicians can use the concept of bone quality in daily practice.

In the case of the antiresorptive drugs for treating osteoporosis, the bisphosphonates have been shown not only to improve bone density but also to reduce the risk of fractures. The clinical trials used dual-energy x-ray absorptiometry (DXA) measurements as a surrogate marker for fragility fractures, and the two correlated reasonably well. Thus, clinicians for the past 10-plus years have used DXA results to justify prescribing these drugs for patients (primarily women) with low T scores to prevent future fractures. There is no doubt that osteoporosis had previously been undertreated, and the projected number of patients with hip and spine fractures would overflow chronic-care beds. Yet there has been a sense that bisphosphonates are prescribed so often they may as well be “put in the water,” and that we are prophylactically treating many thousands of patients who are never going to suffer a fracture.

How can we better predict who will, with a given low T score, have a fracture of the hip or spine and who will not? Why do patients exposed to excess corticosteroids suffer strikingly more fractures than patients with identical T scores who were not exposed to steroids? Why do smoking and family history of fracture contribute to fracture risk in a way not accounted for by density measures alone?

Thus enters the intellectually pleasing concept of bone quality. However, bone quality is pragmatically as tough to measure as emotional stress. Yet we have learned to not minimize either of these when looking at hard outcomes. In this issue of the Journal, Dr. Angelo Licata discusses how clinicians can use the concept of bone quality in daily practice.

In the case of the antiresorptive drugs for treating osteoporosis, the bisphosphonates have been shown not only to improve bone density but also to reduce the risk of fractures. The clinical trials used dual-energy x-ray absorptiometry (DXA) measurements as a surrogate marker for fragility fractures, and the two correlated reasonably well. Thus, clinicians for the past 10-plus years have used DXA results to justify prescribing these drugs for patients (primarily women) with low T scores to prevent future fractures. There is no doubt that osteoporosis had previously been undertreated, and the projected number of patients with hip and spine fractures would overflow chronic-care beds. Yet there has been a sense that bisphosphonates are prescribed so often they may as well be “put in the water,” and that we are prophylactically treating many thousands of patients who are never going to suffer a fracture.

How can we better predict who will, with a given low T score, have a fracture of the hip or spine and who will not? Why do patients exposed to excess corticosteroids suffer strikingly more fractures than patients with identical T scores who were not exposed to steroids? Why do smoking and family history of fracture contribute to fracture risk in a way not accounted for by density measures alone?

Thus enters the intellectually pleasing concept of bone quality. However, bone quality is pragmatically as tough to measure as emotional stress. Yet we have learned to not minimize either of these when looking at hard outcomes. In this issue of the Journal, Dr. Angelo Licata discusses how clinicians can use the concept of bone quality in daily practice.

Most clinicians were taught directly or indirectly that bone density is the gauge for assessing bone strength and the response to antiosteoporotic treatment. In recent years, however, the concept of bone strength has moved beyond density alone and has expanded to include a number of characteristics of bone that collectively are called quality.

This paper describes how the notion of quality has emerged and some of the clinical scenarios in which quality applies. It discusses several observations in the clinical literature that challenge our understanding of bone density and strength and provides the practitioner a better understanding of densitometry in clinical practice.

WHAT IS BONE QUALITY?

Bone quality is not precisely defined. It is described operationally as an amalgamation of all the factors that determine how well the skeleton can resist fracturing, such as microarchitecture, accumulated microscopic damage, the quality of collagen, the size of mineral crystals, and the rate of bone turnover. The term became popular in the early 1990s, when paradoxes in the treatment of osteoporosis challenged the generally accepted orthodoxy that bone density itself was the best way to assess strength of bone.

FROM BONE MASS TO T SCORES TO BONE QUALITY

Today’s practitioners appreciate the importance of the T score in diagnosing osteoporosis. It was not always this way, since the early attempts to use bone densitometry focused on a specific cutoff of bone mass as a risk for fracture and not the statistical T scores or Z scores that we know.^1–3

The T score concept was originally developed to assess the probability of fragility fractures in postmenopausal white women in their mid to late 60s and older.⁴ It has been useful because the disease prevalence is high in this age group. The T score as originally used was a surrogate marker for the histologic changes in aged bone that render it weak and susceptible to fractures from low loading forces: the lower the score, the worse the fracture risk. It followed intuitively that a low T score clinched the diagnosis of primary osteoporosis.

But the T score has its problems when used outside this intended population. Practitioners have assumed that all patients with abnormally low scores have primary osteoporosis. However, this number alone is insufficient to accurately make such a diagnosis in patients outside the demographic group in which it was developed, because the low disease prevalence in younger groups makes the score less accurate as a predictive tool. Moreover, reevaluation of data from pivotal clinical trials has brought into question our long-held idea that increases in bone density parallel increases in bone strength and reduction in fractures, and that therapeutic improvement in bone density is the mark of success. Bone strength or resistance to fracture is more complex than density alone. Into this arena enters the concept of bone quality, which attempts to explain the following observations.

DENSER BONE IS NOT ALWAYS STRONGER

NOT ALL LOW BONE MINERAL DENSITY IS OSTEOPOROSIS

The following case describes a clinical scenario in which a patient has low bone density but does not have osteoporosis.

A young healthy woman with low bone density

A 35-year-old healthy woman who has jogged recreationally for decades is evaluated for possible treatment of osteoporosis. She started to feel back pain after doing heavy work in her garden. Spinal radiographs did not show a reason for her pain, but her physician, concerned about osteopenia, sent her for dual-energy x-ray absorptiometry. Her spinal T scores and Z scores were 2.5 standard deviations below the mean.

Should she start pharmacologic therapy?

Young bone is stronger than older bone

This case shows the other end of the spectrum from the fluoride story. Here, a young healthy person inappropriately underwent a density scan, which led to confusion about how to interpret the results.

As stated above, T scores are not appropriate for young patients—the Z score is used instead. In this case, the low value implied deficiency of bone mass compared with age-matched norms. However, in this patient with no clinical risk factors for fracture, a low T score meant that her bone density was low, but not that she had osteoporosis.

Several factors could account for her low bone density. It could be genetic, if her family is small in stature, or she could be at the extreme end of the distribution curve for normal individuals. Runners tend to be slight in build, and so may have lighter bones. Furthermore, for women, excessive running could lead to lower estrogen activity and therefore lower bone mineral density.

Drug treatment is not warranted for this patient, but standard therapy with exercise, vitamin D, and adequate elemental calcium from the diet or supplements is reasonable.

Thus, the notion of quality entered the clinical arena. Young bone and older bone are qualitatively different in strength, even with similar bone density. This difference was later found to be related to significant qualitative changes within the microscopic architecture of the bone, the collagen, the mineral, and the physiologic activity of the skeletal cells—elements that the T score does not reflect.

Hence, young bone is stronger than older bone across all levels of bone mass or T scores. Its quality is better.

CHANGES IN DENSITY ACCOUNT FOR ONLY PART OF THE DECREASE IN RISK

BONES BECOME STRONGER BEFORE THEY BECOME DENSER

In a number of clinical trials, antiresorptive drugs of various classes started to reduce the risk of fractures before the increases in bone density reached their maximum. Raloxifene significantly reduces the incidence of fractures within 6 to 12 months of starting treatment, whereas the maximal increase in spinal bone density of 2% to 3% is seen at 3 years.¹⁵ This type of information further supported the discordance of density and bone strength and underscored the concept that drug therapy affects other factors in bone physiology.

One of these other factors is skeletal turnover, which is assessed by measuring the levels of enzymes or collagen fragments released by osteoblasts or osteoclasts in the blood or urine. These substances are markers of bone metabolism. They do not establish the diagnosis of specific diseases, but their concentrations are higher in high-bone-turnover states such as in some cases of primary osteoporosis. The topic has been reviewed in detail by Singer and Eyre.¹⁶

Antiresorptive therapy decreases the levels of these markers to normal within weeks of starting therapy. This prompt response is believed to be the reason that fracture risk reduction is seen so early. This effect of therapy represents a reduction in high osteoclastic activity and, secondarily, preservation of the microarchitecture. Meanwhile, osteoblastic activity adds bone to these less-active osteoclastic sites. If the amount is sufficient, bone densitometry may detect it.

LACK OF CHANGE IN DENSITY DOES NOT NECESSARILY MEAN LACK OF RESPONSE

The lack of change in bone density in patients taking bisphosphonates does not necessarily mean a lack of response. The following clinical scenario exemplifies this paradox.

A middle-aged woman on bisphosphonate therapy

A 68-year-old woman is seen because she seems to be having a poor response to oral bisphosphonate therapy, which was started 3 years ago after she had two vertebral fractures. Her bone density has not changed during this time, but the levels of her bone turnover markers have decreased and remain normal.

Should she start another type of therapy?

Bone turnover markers indicate a response

Studies show that patients with osteoporosis can be stratified into those at low or high risk of fractures on the basis of the activity of bone turnover markers. The risk of fractures is two times higher in people who have high levels of these markers than in those with normal levels, and can rise to four to five times as high in people who have both high marker levels and low bone density.¹⁷

All antiresorptive treatments lower the levels of these markers to the normal range and keep them low. In the patient described above, her normal levels of bone turnover markers after treatment indicate a good therapeutic response. The treatment should be continued.

WHAT’S A CLINICIAN TO DO?

These cases illustrate some important questions that often arise in the treatment of patients.

How should the risk of fractures be assessed? Bone densitometry is a better marker of fracture risk than of bone strength because it cannot detect the important qualitative elements of strength. The higher prevalence of osteoporosis in the older population gives the T score cutoff of 2.5 standard deviations below the mean a greater predictive power to diagnose osteoporosis than it does in a younger population with a lower disease prevalence. In younger patients, this cutoff at best represents low bone density and is not diagnostic of osteoporosis unless it is present with other risk factors for fracture.

Newer tools for assessing fracture risk are now entering clinical practice. Estimates of absolute fracture risk are being used,^18–20 and a fracture risk assessment tool is being implemented worldwide.^21–23 Developed by the World Health Organization and called FRAX, it is based on the bone mineral density of the femoral neck combined with other factors: the patient’s age, sex, weight, and height, whether the patient has a personal or family history of fracture, and whether the patient smokes, uses glucocorticoids, has rheumatoid arthritis, has secondary osteoporosis, or consumes alcohol in excess. It is available online (www.shef.ac.uk/FRAX/tool.jsp) and gives an estimate of the 10-year risk of fracture.

How should response to therapy be assessed? In clinical practice, patients who show no changes in bone density may still be responding to therapy, and the response can be detected by the levels of bone turnover markers. Patients using antiresorptive drugs have normal levels of these markers, decreased from a higher baseline value. Patients using anabolic agents show higher levels of these bone markers, indicating enhanced bone building. So therapeutic efficacy is seen as stable or increased bone density coupled with decreased and normal turnover markers with antiresorptive drug use and increased turnover markers with anabolic drug use.

When fractures occur in patients on therapy, however, it becomes difficult to assess good or poor drug response. Patients who have a fracture within the first year of therapy are best left on the treatment, since this may not generate the full response. Patients who start having fractures years into therapy, however, may be experiencing secondary forms of osteoporosis superimposed on the original primary disease.²⁴ Vitamin D deficiency, hyperparathyroidism, and celiac disease are common problems. Or, perhaps, patients may not be adherent to therapy.^25–27 Poor compliance, inappropriate use of medications (especially the bisphosphonate drugs), or even problems of malabsorption of oral medication may be a consideration. The intravenous forms of bisphosphonate drugs warrant consideration in this scenario.^28–30

In the future, we may have better tests of bone quality. One such test, called finite element analysis, uses computer modeling and three-dimensional imaging. It has been used for years by engineers designing and testing the strength of bridges, airplanes, and other structures and is now being evaluated as a way to estimate bone strength.

In summary, bone physiology and bone strength are very complex issues that have recently attained new and important nuances. The original use of bone densitometry was to assess the risk of fragility fractures and, secondarily, to diagnose primary osteoporosis in the population of patients for which it was originally developed. While the bone densitometry score does bear some relationship to bone strength, it is not a sufficient surrogate marker in many cases. Hence, clinicians need to judiciously use these testing procedures in combination with a number of clinical factors to diagnose osteoporosis and assess the response to therapy.

Most clinicians were taught directly or indirectly that bone density is the gauge for assessing bone strength and the response to antiosteoporotic treatment. In recent years, however, the concept of bone strength has moved beyond density alone and has expanded to include a number of characteristics of bone that collectively are called quality.

This paper describes how the notion of quality has emerged and some of the clinical scenarios in which quality applies. It discusses several observations in the clinical literature that challenge our understanding of bone density and strength and provides the practitioner a better understanding of densitometry in clinical practice.

WHAT IS BONE QUALITY?

Bone quality is not precisely defined. It is described operationally as an amalgamation of all the factors that determine how well the skeleton can resist fracturing, such as microarchitecture, accumulated microscopic damage, the quality of collagen, the size of mineral crystals, and the rate of bone turnover. The term became popular in the early 1990s, when paradoxes in the treatment of osteoporosis challenged the generally accepted orthodoxy that bone density itself was the best way to assess strength of bone.

FROM BONE MASS TO T SCORES TO BONE QUALITY

Today’s practitioners appreciate the importance of the T score in diagnosing osteoporosis. It was not always this way, since the early attempts to use bone densitometry focused on a specific cutoff of bone mass as a risk for fracture and not the statistical T scores or Z scores that we know.^1–3

The T score concept was originally developed to assess the probability of fragility fractures in postmenopausal white women in their mid to late 60s and older.⁴ It has been useful because the disease prevalence is high in this age group. The T score as originally used was a surrogate marker for the histologic changes in aged bone that render it weak and susceptible to fractures from low loading forces: the lower the score, the worse the fracture risk. It followed intuitively that a low T score clinched the diagnosis of primary osteoporosis.

But the T score has its problems when used outside this intended population. Practitioners have assumed that all patients with abnormally low scores have primary osteoporosis. However, this number alone is insufficient to accurately make such a diagnosis in patients outside the demographic group in which it was developed, because the low disease prevalence in younger groups makes the score less accurate as a predictive tool. Moreover, reevaluation of data from pivotal clinical trials has brought into question our long-held idea that increases in bone density parallel increases in bone strength and reduction in fractures, and that therapeutic improvement in bone density is the mark of success. Bone strength or resistance to fracture is more complex than density alone. Into this arena enters the concept of bone quality, which attempts to explain the following observations.

DENSER BONE IS NOT ALWAYS STRONGER

NOT ALL LOW BONE MINERAL DENSITY IS OSTEOPOROSIS

The following case describes a clinical scenario in which a patient has low bone density but does not have osteoporosis.

A young healthy woman with low bone density

A 35-year-old healthy woman who has jogged recreationally for decades is evaluated for possible treatment of osteoporosis. She started to feel back pain after doing heavy work in her garden. Spinal radiographs did not show a reason for her pain, but her physician, concerned about osteopenia, sent her for dual-energy x-ray absorptiometry. Her spinal T scores and Z scores were 2.5 standard deviations below the mean.

Should she start pharmacologic therapy?

Young bone is stronger than older bone

This case shows the other end of the spectrum from the fluoride story. Here, a young healthy person inappropriately underwent a density scan, which led to confusion about how to interpret the results.

As stated above, T scores are not appropriate for young patients—the Z score is used instead. In this case, the low value implied deficiency of bone mass compared with age-matched norms. However, in this patient with no clinical risk factors for fracture, a low T score meant that her bone density was low, but not that she had osteoporosis.

Several factors could account for her low bone density. It could be genetic, if her family is small in stature, or she could be at the extreme end of the distribution curve for normal individuals. Runners tend to be slight in build, and so may have lighter bones. Furthermore, for women, excessive running could lead to lower estrogen activity and therefore lower bone mineral density.

Drug treatment is not warranted for this patient, but standard therapy with exercise, vitamin D, and adequate elemental calcium from the diet or supplements is reasonable.

Thus, the notion of quality entered the clinical arena. Young bone and older bone are qualitatively different in strength, even with similar bone density. This difference was later found to be related to significant qualitative changes within the microscopic architecture of the bone, the collagen, the mineral, and the physiologic activity of the skeletal cells—elements that the T score does not reflect.

Hence, young bone is stronger than older bone across all levels of bone mass or T scores. Its quality is better.

CHANGES IN DENSITY ACCOUNT FOR ONLY PART OF THE DECREASE IN RISK

BONES BECOME STRONGER BEFORE THEY BECOME DENSER

In a number of clinical trials, antiresorptive drugs of various classes started to reduce the risk of fractures before the increases in bone density reached their maximum. Raloxifene significantly reduces the incidence of fractures within 6 to 12 months of starting treatment, whereas the maximal increase in spinal bone density of 2% to 3% is seen at 3 years.¹⁵ This type of information further supported the discordance of density and bone strength and underscored the concept that drug therapy affects other factors in bone physiology.

One of these other factors is skeletal turnover, which is assessed by measuring the levels of enzymes or collagen fragments released by osteoblasts or osteoclasts in the blood or urine. These substances are markers of bone metabolism. They do not establish the diagnosis of specific diseases, but their concentrations are higher in high-bone-turnover states such as in some cases of primary osteoporosis. The topic has been reviewed in detail by Singer and Eyre.¹⁶

Antiresorptive therapy decreases the levels of these markers to normal within weeks of starting therapy. This prompt response is believed to be the reason that fracture risk reduction is seen so early. This effect of therapy represents a reduction in high osteoclastic activity and, secondarily, preservation of the microarchitecture. Meanwhile, osteoblastic activity adds bone to these less-active osteoclastic sites. If the amount is sufficient, bone densitometry may detect it.

LACK OF CHANGE IN DENSITY DOES NOT NECESSARILY MEAN LACK OF RESPONSE

The lack of change in bone density in patients taking bisphosphonates does not necessarily mean a lack of response. The following clinical scenario exemplifies this paradox.

A middle-aged woman on bisphosphonate therapy

A 68-year-old woman is seen because she seems to be having a poor response to oral bisphosphonate therapy, which was started 3 years ago after she had two vertebral fractures. Her bone density has not changed during this time, but the levels of her bone turnover markers have decreased and remain normal.

Should she start another type of therapy?

Bone turnover markers indicate a response

Studies show that patients with osteoporosis can be stratified into those at low or high risk of fractures on the basis of the activity of bone turnover markers. The risk of fractures is two times higher in people who have high levels of these markers than in those with normal levels, and can rise to four to five times as high in people who have both high marker levels and low bone density.¹⁷

All antiresorptive treatments lower the levels of these markers to the normal range and keep them low. In the patient described above, her normal levels of bone turnover markers after treatment indicate a good therapeutic response. The treatment should be continued.

WHAT’S A CLINICIAN TO DO?

These cases illustrate some important questions that often arise in the treatment of patients.

How should the risk of fractures be assessed? Bone densitometry is a better marker of fracture risk than of bone strength because it cannot detect the important qualitative elements of strength. The higher prevalence of osteoporosis in the older population gives the T score cutoff of 2.5 standard deviations below the mean a greater predictive power to diagnose osteoporosis than it does in a younger population with a lower disease prevalence. In younger patients, this cutoff at best represents low bone density and is not diagnostic of osteoporosis unless it is present with other risk factors for fracture.

Newer tools for assessing fracture risk are now entering clinical practice. Estimates of absolute fracture risk are being used,^18–20 and a fracture risk assessment tool is being implemented worldwide.^21–23 Developed by the World Health Organization and called FRAX, it is based on the bone mineral density of the femoral neck combined with other factors: the patient’s age, sex, weight, and height, whether the patient has a personal or family history of fracture, and whether the patient smokes, uses glucocorticoids, has rheumatoid arthritis, has secondary osteoporosis, or consumes alcohol in excess. It is available online (www.shef.ac.uk/FRAX/tool.jsp) and gives an estimate of the 10-year risk of fracture.

How should response to therapy be assessed? In clinical practice, patients who show no changes in bone density may still be responding to therapy, and the response can be detected by the levels of bone turnover markers. Patients using antiresorptive drugs have normal levels of these markers, decreased from a higher baseline value. Patients using anabolic agents show higher levels of these bone markers, indicating enhanced bone building. So therapeutic efficacy is seen as stable or increased bone density coupled with decreased and normal turnover markers with antiresorptive drug use and increased turnover markers with anabolic drug use.

When fractures occur in patients on therapy, however, it becomes difficult to assess good or poor drug response. Patients who have a fracture within the first year of therapy are best left on the treatment, since this may not generate the full response. Patients who start having fractures years into therapy, however, may be experiencing secondary forms of osteoporosis superimposed on the original primary disease.²⁴ Vitamin D deficiency, hyperparathyroidism, and celiac disease are common problems. Or, perhaps, patients may not be adherent to therapy.^25–27 Poor compliance, inappropriate use of medications (especially the bisphosphonate drugs), or even problems of malabsorption of oral medication may be a consideration. The intravenous forms of bisphosphonate drugs warrant consideration in this scenario.^28–30

In the future, we may have better tests of bone quality. One such test, called finite element analysis, uses computer modeling and three-dimensional imaging. It has been used for years by engineers designing and testing the strength of bridges, airplanes, and other structures and is now being evaluated as a way to estimate bone strength.

In summary, bone physiology and bone strength are very complex issues that have recently attained new and important nuances. The original use of bone densitometry was to assess the risk of fragility fractures and, secondarily, to diagnose primary osteoporosis in the population of patients for which it was originally developed. While the bone densitometry score does bear some relationship to bone strength, it is not a sufficient surrogate marker in many cases. Hence, clinicians need to judiciously use these testing procedures in combination with a number of clinical factors to diagnose osteoporosis and assess the response to therapy.

Most clinicians were taught directly or indirectly that bone density is the gauge for assessing bone strength and the response to antiosteoporotic treatment. In recent years, however, the concept of bone strength has moved beyond density alone and has expanded to include a number of characteristics of bone that collectively are called quality.

This paper describes how the notion of quality has emerged and some of the clinical scenarios in which quality applies. It discusses several observations in the clinical literature that challenge our understanding of bone density and strength and provides the practitioner a better understanding of densitometry in clinical practice.

WHAT IS BONE QUALITY?

Bone quality is not precisely defined. It is described operationally as an amalgamation of all the factors that determine how well the skeleton can resist fracturing, such as microarchitecture, accumulated microscopic damage, the quality of collagen, the size of mineral crystals, and the rate of bone turnover. The term became popular in the early 1990s, when paradoxes in the treatment of osteoporosis challenged the generally accepted orthodoxy that bone density itself was the best way to assess strength of bone.

FROM BONE MASS TO T SCORES TO BONE QUALITY

Today’s practitioners appreciate the importance of the T score in diagnosing osteoporosis. It was not always this way, since the early attempts to use bone densitometry focused on a specific cutoff of bone mass as a risk for fracture and not the statistical T scores or Z scores that we know.^1–3

The T score concept was originally developed to assess the probability of fragility fractures in postmenopausal white women in their mid to late 60s and older.⁴ It has been useful because the disease prevalence is high in this age group. The T score as originally used was a surrogate marker for the histologic changes in aged bone that render it weak and susceptible to fractures from low loading forces: the lower the score, the worse the fracture risk. It followed intuitively that a low T score clinched the diagnosis of primary osteoporosis.

But the T score has its problems when used outside this intended population. Practitioners have assumed that all patients with abnormally low scores have primary osteoporosis. However, this number alone is insufficient to accurately make such a diagnosis in patients outside the demographic group in which it was developed, because the low disease prevalence in younger groups makes the score less accurate as a predictive tool. Moreover, reevaluation of data from pivotal clinical trials has brought into question our long-held idea that increases in bone density parallel increases in bone strength and reduction in fractures, and that therapeutic improvement in bone density is the mark of success. Bone strength or resistance to fracture is more complex than density alone. Into this arena enters the concept of bone quality, which attempts to explain the following observations.

DENSER BONE IS NOT ALWAYS STRONGER

NOT ALL LOW BONE MINERAL DENSITY IS OSTEOPOROSIS

The following case describes a clinical scenario in which a patient has low bone density but does not have osteoporosis.

A young healthy woman with low bone density

A 35-year-old healthy woman who has jogged recreationally for decades is evaluated for possible treatment of osteoporosis. She started to feel back pain after doing heavy work in her garden. Spinal radiographs did not show a reason for her pain, but her physician, concerned about osteopenia, sent her for dual-energy x-ray absorptiometry. Her spinal T scores and Z scores were 2.5 standard deviations below the mean.

Should she start pharmacologic therapy?

Young bone is stronger than older bone

This case shows the other end of the spectrum from the fluoride story. Here, a young healthy person inappropriately underwent a density scan, which led to confusion about how to interpret the results.

As stated above, T scores are not appropriate for young patients—the Z score is used instead. In this case, the low value implied deficiency of bone mass compared with age-matched norms. However, in this patient with no clinical risk factors for fracture, a low T score meant that her bone density was low, but not that she had osteoporosis.

Several factors could account for her low bone density. It could be genetic, if her family is small in stature, or she could be at the extreme end of the distribution curve for normal individuals. Runners tend to be slight in build, and so may have lighter bones. Furthermore, for women, excessive running could lead to lower estrogen activity and therefore lower bone mineral density.

Drug treatment is not warranted for this patient, but standard therapy with exercise, vitamin D, and adequate elemental calcium from the diet or supplements is reasonable.

Thus, the notion of quality entered the clinical arena. Young bone and older bone are qualitatively different in strength, even with similar bone density. This difference was later found to be related to significant qualitative changes within the microscopic architecture of the bone, the collagen, the mineral, and the physiologic activity of the skeletal cells—elements that the T score does not reflect.

Hence, young bone is stronger than older bone across all levels of bone mass or T scores. Its quality is better.

CHANGES IN DENSITY ACCOUNT FOR ONLY PART OF THE DECREASE IN RISK

BONES BECOME STRONGER BEFORE THEY BECOME DENSER

In a number of clinical trials, antiresorptive drugs of various classes started to reduce the risk of fractures before the increases in bone density reached their maximum. Raloxifene significantly reduces the incidence of fractures within 6 to 12 months of starting treatment, whereas the maximal increase in spinal bone density of 2% to 3% is seen at 3 years.¹⁵ This type of information further supported the discordance of density and bone strength and underscored the concept that drug therapy affects other factors in bone physiology.

One of these other factors is skeletal turnover, which is assessed by measuring the levels of enzymes or collagen fragments released by osteoblasts or osteoclasts in the blood or urine. These substances are markers of bone metabolism. They do not establish the diagnosis of specific diseases, but their concentrations are higher in high-bone-turnover states such as in some cases of primary osteoporosis. The topic has been reviewed in detail by Singer and Eyre.¹⁶

Antiresorptive therapy decreases the levels of these markers to normal within weeks of starting therapy. This prompt response is believed to be the reason that fracture risk reduction is seen so early. This effect of therapy represents a reduction in high osteoclastic activity and, secondarily, preservation of the microarchitecture. Meanwhile, osteoblastic activity adds bone to these less-active osteoclastic sites. If the amount is sufficient, bone densitometry may detect it.

LACK OF CHANGE IN DENSITY DOES NOT NECESSARILY MEAN LACK OF RESPONSE

The lack of change in bone density in patients taking bisphosphonates does not necessarily mean a lack of response. The following clinical scenario exemplifies this paradox.

A middle-aged woman on bisphosphonate therapy

A 68-year-old woman is seen because she seems to be having a poor response to oral bisphosphonate therapy, which was started 3 years ago after she had two vertebral fractures. Her bone density has not changed during this time, but the levels of her bone turnover markers have decreased and remain normal.

Should she start another type of therapy?

Bone turnover markers indicate a response

Studies show that patients with osteoporosis can be stratified into those at low or high risk of fractures on the basis of the activity of bone turnover markers. The risk of fractures is two times higher in people who have high levels of these markers than in those with normal levels, and can rise to four to five times as high in people who have both high marker levels and low bone density.¹⁷

All antiresorptive treatments lower the levels of these markers to the normal range and keep them low. In the patient described above, her normal levels of bone turnover markers after treatment indicate a good therapeutic response. The treatment should be continued.

WHAT’S A CLINICIAN TO DO?

These cases illustrate some important questions that often arise in the treatment of patients.

How should the risk of fractures be assessed? Bone densitometry is a better marker of fracture risk than of bone strength because it cannot detect the important qualitative elements of strength. The higher prevalence of osteoporosis in the older population gives the T score cutoff of 2.5 standard deviations below the mean a greater predictive power to diagnose osteoporosis than it does in a younger population with a lower disease prevalence. In younger patients, this cutoff at best represents low bone density and is not diagnostic of osteoporosis unless it is present with other risk factors for fracture.

Newer tools for assessing fracture risk are now entering clinical practice. Estimates of absolute fracture risk are being used,^18–20 and a fracture risk assessment tool is being implemented worldwide.^21–23 Developed by the World Health Organization and called FRAX, it is based on the bone mineral density of the femoral neck combined with other factors: the patient’s age, sex, weight, and height, whether the patient has a personal or family history of fracture, and whether the patient smokes, uses glucocorticoids, has rheumatoid arthritis, has secondary osteoporosis, or consumes alcohol in excess. It is available online (www.shef.ac.uk/FRAX/tool.jsp) and gives an estimate of the 10-year risk of fracture.

How should response to therapy be assessed? In clinical practice, patients who show no changes in bone density may still be responding to therapy, and the response can be detected by the levels of bone turnover markers. Patients using antiresorptive drugs have normal levels of these markers, decreased from a higher baseline value. Patients using anabolic agents show higher levels of these bone markers, indicating enhanced bone building. So therapeutic efficacy is seen as stable or increased bone density coupled with decreased and normal turnover markers with antiresorptive drug use and increased turnover markers with anabolic drug use.

When fractures occur in patients on therapy, however, it becomes difficult to assess good or poor drug response. Patients who have a fracture within the first year of therapy are best left on the treatment, since this may not generate the full response. Patients who start having fractures years into therapy, however, may be experiencing secondary forms of osteoporosis superimposed on the original primary disease.²⁴ Vitamin D deficiency, hyperparathyroidism, and celiac disease are common problems. Or, perhaps, patients may not be adherent to therapy.^25–27 Poor compliance, inappropriate use of medications (especially the bisphosphonate drugs), or even problems of malabsorption of oral medication may be a consideration. The intravenous forms of bisphosphonate drugs warrant consideration in this scenario.^28–30

In the future, we may have better tests of bone quality. One such test, called finite element analysis, uses computer modeling and three-dimensional imaging. It has been used for years by engineers designing and testing the strength of bridges, airplanes, and other structures and is now being evaluated as a way to estimate bone strength.

In summary, bone physiology and bone strength are very complex issues that have recently attained new and important nuances. The original use of bone densitometry was to assess the risk of fragility fractures and, secondarily, to diagnose primary osteoporosis in the population of patients for which it was originally developed. While the bone densitometry score does bear some relationship to bone strength, it is not a sufficient surrogate marker in many cases. Hence, clinicians need to judiciously use these testing procedures in combination with a number of clinical factors to diagnose osteoporosis and assess the response to therapy.

In an article that appeared in the April issue of the Cleveland Clinic Journal of Medicine (Kim L, Lipton S, Deodhar A. Pregabalin for fibromyalgia: some relief but no cure. Cleve Clin J Med 2009; 76:255–261.), journal editors failed to list the participation of one of the authors in a clinical trial of pregabilin (Lyrica) that was funded by the drug’s manufacturer. Dr. Atul Deodhar had disclosed his participation in the trial to an editor, and the failure to list it with the article at the time of publication was an oversight on the part of CCJM.

In an article that appeared in the April issue of the Cleveland Clinic Journal of Medicine (Kim L, Lipton S, Deodhar A. Pregabalin for fibromyalgia: some relief but no cure. Cleve Clin J Med 2009; 76:255–261.), journal editors failed to list the participation of one of the authors in a clinical trial of pregabilin (Lyrica) that was funded by the drug’s manufacturer. Dr. Atul Deodhar had disclosed his participation in the trial to an editor, and the failure to list it with the article at the time of publication was an oversight on the part of CCJM.

In an article that appeared in the April issue of the Cleveland Clinic Journal of Medicine (Kim L, Lipton S, Deodhar A. Pregabalin for fibromyalgia: some relief but no cure. Cleve Clin J Med 2009; 76:255–261.), journal editors failed to list the participation of one of the authors in a clinical trial of pregabilin (Lyrica) that was funded by the drug’s manufacturer. Dr. Atul Deodhar had disclosed his participation in the trial to an editor, and the failure to list it with the article at the time of publication was an oversight on the part of CCJM.