Ethical challenges in osteoporosis research a source of debate

The approval process for new osteoporosis drugs and the ethics surrounding placebo-controlled, randomized clinical trials used to test investigational drugs is often accompanied by controversy.

“Osteoporosis is a problem that endocrinologists ought to be concerned about, interested in and knowledgeable about,”

Michael McClung, MD, director of the Oregon Osteoporosis Center in Portland, told Endocrine Today. “If we are going to advance and have new treatments for osteoporosis — even more effective than the ones we currently have available — clinical trials are necessary.”

The controversy about clinical trials in osteoporosis is primarily focused on two points: the inclusion of participants who are highly susceptible to fractures, thus at risk from random assignment to placebo, and fracture used as a primary endpoint. Some experts argue in support of the need to adapt what they view as outdated guidelines for clinical trial standards that are more reflective of the current state of the field. Others maintain that the efficacy endpoints and study design required by the FDA are sound and necessary for robust research.

This debate received attention in September when The New England Journal of Medicine published two editorials with differing viewpoints on the ethics of placebo-controlled trials in osteoporosis. Clifford J. Rosen, MD, of the Maine Medical Center Research Institute, and Sundeep Khosla, MD, of the college of medicine at the Mayo Clinic in Rochester, Minn., said placebo-controlled trials of investigational osteoporosis agents are safe if researchers “proceed with caution.” But for C. Michael Stein, MB, ChB, and Wayne A. Ray, PhD, both of the Vanderbilt University School of Medicine, “placebo-controlled studies with fracture endpoints in patients with osteoporosis will nearly always be unethical.”

Endocrine Today interviewed osteoporosis experts about their take on clinical trials of drugs used to treat osteoporosis and standards for research in the future.

Ethical standard for research

Clinical studies intended to support new drug applications, also called registration or pivotal trials, must meet requirements set by the FDA. Although accepted efficacy endpoints depend on the therapeutic area and indication, inclusion of a placebo-controlled arm is fairly consistent across all fields. Placebo-controlled groups allow a clear assessment of the safety and efficacy of an active drug while limiting confounding factors.

The difficulty arises in studies of serious or potentially life-threatening conditions for which effective treatments exist.

The World Medical Association’s Declaration of Helsinki, regarded as the ethical standard for studies in humans, strongly advises against the use of placebo in situations in which effective treatments are available. Section 32 of the declaration states: “The benefits, risks, burdens and effectiveness of a new intervention must be tested against those of the best current proven intervention, except in the following circumstances: The use of placebo, or no treatment, is acceptable in studies where no current proven intervention exists; or where for compelling and scientifically sound methodological reasons the use of placebo is necessary to determine the efficacy or safety of an intervention and the patients who receive placebo or no treatment will not be subject to any risk of serious or irreversible harm. Extreme care must be taken to avoid abuse of this option.”

Steven M. Petak

The question then becomes how narrowly the statement should be interpreted.

“The direct application of the Declaration of Helsinki dramatically limits placebo-controlled studies,” Steven M. Petak, MD, director of the osteoporosis center and bone densitometry unit at the Texas Institute for Reproductive Medicine and Endocrinology in Houston, told Endocrine Today.

For Michael Kleerekoper, MD, an Endocrine Today Editorial Board member, the placebo-controlled trial design and interpretation of the Declaration of Helsinki creates another issue because “effective therapies for osteoporosis do exist,” he said.

Ethics of withholding treatment

A good example of a recent, large, placebo-controlled, randomized clinical trial in the field of osteoporosis research is the FREEDOM study, which evaluated the safety of denosumab (Prolia, Amgen) and found beneficial effects on vertebral and nonvertebral fracture protection. Researchers for the study randomly assigned more than 7,000 women to denosumab or placebo, given subcutaneously every 6 months for 36 months.

In their NEJM editorial, Stein and Ray said: “There is general agreement that placebo-controlled trials are unethical when a therapy that decreases the risk of serious complications or death is available. Many believe that it is ethical to withhold an effective treatment when adverse consequences are minor or rare. However, osteoporotic hip and vertebral fractures have serious consequences, including increased risk of death, surgical procedures and long-term impairment of physical function.”

Nelson Watts, MD, of the Bone Health and Osteoporosis Center at University of Cincinnati College of Medicine, said the inclusion of a true placebo-controlled arm in clinical trials of osteoporosis drugs is difficult, but not impossible.

In reality, “there is no true placebo group,” Watts said. “All patients at risk for osteoporosis in these trials are given calcium and vitamin D. They all receive advice on physical activity.”

Calcium and vitamin D supplementation are the customary first steps for treating osteoporosis. In most large-scale studies, the two supplements are given to both the placebo and drug treatment groups.

Michael Kleerekoper

In addition, because osteoporosis is generally asymptomatic, most people are not tested for osteoporosis, according to Watts.

“Some people would be tested for osteoporosis because they are considering participating in a trial who would not be tested or treated otherwise,” he said.

However, Kleerekoper said withholding active treatment can indeed cause harm to at-risk patients. As an example, he cited a 1-year mortality rate of 30% after a hip fracture.

“Patients in these trials often have existing fractures,” said Kleerekoper, who is an endocrinologist at St. John River District Hospital in East China Township, Mich.

Inclusion of high-risk participants

Another issue is the inclusion of patients with severe disease — and the greatest risk for fracture.

“This debate is often framed by the simple question of whether people who are highly susceptible to an osteoporotic fracture should be involved in a clinical trial,” Rosen and Khosla wrote in NEJM. “Simply excluding the highest-risk patients from placebo-controlled trials does not resolve concerns. The risk for fracture in women with untreated osteoporosis is substantial, even when those at highest risk are excluded.”

Michael McClung

McClung said during the past 15 years, clinical trialists have modified clinical trial entry criteria so that patients at high risk for fracture are no longer eligible to participate. He cited data from trials of alendronate (Fosamax, Merck) and risedronate (Actonel, Warner Chilcott) conducted in the 1990s in which the incidence of fracture at the spine was between 15% and 30% during 3 years in the placebo group compared with more recent studies, such as FREEDOM, in which the placebo group’s incidence of fracture was about 7%.

However, by changing entry criteria to enroll patients at lower risk for fracture, still “there are people who think that goes beyond appropriate ethical consideration,” McClung said.

“Including patients with severe osteoporosis in a placebo-controlled trial puts them at unnecessarily high risk for fracture,” Kleerekoper said. Rather, including those who have less severe disease would lower the potential risk for harm because they are less likely to experience a fracture, he said.

People who design these studies in osteoporosis are “not insensitive” to the ethical question of participants’ risk, McClung said.

“The choice is to either accept a modest amount of risk or a very modest amount of risk for each individual patient in a placebo-controlled trial in the more recent studies, with the advantage of being able to develop new treatments,” he said. “If we don’t take that risk, we will not have the chance to advance the field of osteoporosis treatment research. And, in the long run, the whole population benefits from the investment that the participants in the clinical trial make.”

So, who is suitable for enrollment in placebo-controlled, randomized clinical trials? According to Rosen and Khosla: “We would follow the recommendations of an expert panel that considered it appropriate to enroll patients with low [bone mineral density] in placebo-controlled trials if they had no history of fragility fractures or if radiologic imaging showed only asymptomatic morphometric vertebral fractures … [and] patients who had side effects from previous therapies or who did not have a response to conventional therapy.

“With use of appropriate guidelines to exclude high-risk patients, placebo-controlled trials of osteoporosis treatments can benefit some patients and can inform investigators and the health care profession in a safe, transparent and scientific manner,” Rosen and Khosla wrote.

Fracture as a primary endpoint

Guidance from the FDA allows placebo- or active-controlled trials, but the agency does not waver on the primary efficacy endpoint in pivotal phase 3 trials: “Studies of treatment in osteoporosis in patients with fractures should be double blind, with either placebo or active drug in the control group. … Demonstration that an agent preserves or enhances bone mass provides only suggestive evidence that it reduces fracture risk; fracture studies must be done to document reduction of fracture incidence.” In addition, the FDA specifies that the duration of the trials must be at least 3 years. Guidelines issued by WHO and the European Committee for Proprietary Medicinal Products also specify reduction in fracture incidence as the required primary endpoint.

For some, advances in measures of BMD and bone turnover markers have improved the reliability of these techniques to the point that they accurately reflect the effect of osteoporosis therapies on bone remodeling. Using fracture rate as the efficacy standard is no longer necessary when surrogate endpoints show bone restoration, Kleerekoper said.

Petak said although fracture is a “necessary endpoint” for pivotal trials, surrogate markers are useful as primary or secondary endpoints in trials supporting supplementary indications for already approved treatments.

Providing a different point of view, Watts said he believes that there is no sufficient surrogate for fracture reduction, adding that “BMD and other markers do not give the information that we need.”

With the high standard of fracture incidence, Kleerekoper said he believes that new classes of osteoporosis drugs will not reach the market.

“New classes in the pipeline will not come through the clinical wall because the bar is set so high,” he said.

Alternative trials in osteoporosis

An alternative to placebo-controlled trials is active comparator studies, for which two or more active agents are compared head to head. Such trials have been considered for placebo-controlled trials, such as investigation of patients with osteopenia, for whom osteoporosis agents are not currently indicated; add-on study designs that add placebo or a new agent to best available therapies; and trials with informed refusal from patients who refuse, cannot tolerate or do not benefit from currently available therapies.

However, although useful for comparing competing therapies, active comparator studies have several drawbacks.

These trials require a larger patient population than placebo-controlled trials to achieve statistical significance and eliminate the possibility that any observed differences in efficacy are due to chance. In therapeutic areas in which several treatments are available, demonstrating efficacy against placebo provides little practical information: Physicians want to know how the available drugs compare with each other.

“The significantly increased number of patients required for such active comparator trials with the associated cost would likely discourage the development of drugs for serious diseases and those disorders that impact small numbers of people,” Petak said. “On the other hand, therapies with a low risk for harm would have the added incentive of a less expensive approval pathway. This would tend to favor therapies for non-serious disorders applying to large numbers of people, such as cosmetic treatments.”

The value of comparator trials depends heavily on the design.

“The problem with comparator trials is they can be poorly designed,” Watts said. “They show non-inferiority, that the new drug is equally as good as the comparator. We want to see superiority.”

Ethical concerns in other research

According to Kleerekoper, the standard is much higher for osteoporosis trials than in other areas of research.

“Patients with increased cholesterol are at increased risk for heart attack, but the endpoint of those trials is reduction in cholesterol not heart attack. The same holds true for blood pressure drugs, which have to demonstrate a greater reduction in BP in the active treatment arm vs. placebo, not a reduction in stroke events. In diabetes, the drug has to simply show a greater reduction in HbA1c, not a reduction in complications from diabetes,” he said.

Alan J. Garber

Alan J. Garber, MD, PhD, Chief Medical Editor of Endocrine Today, said the issue of placebo-controlled trials in diabetes was confronted years ago by both investigators and the FDA. He said it was decided that brief placebo exposures of 3 to 6 months were tolerable with regard to the increased risk for diabetic complications. Additional safety was to be ensured by the institution of rescue therapies if evidence of improving glycemia was not found during the conduct of the trial. For longer-duration studies in patients with diabetes, active comparator trials were recommended and placebo-controlled studies were discouraged.

“The ethical concerns for osteoporosis research are similar, if not more difficult, as those for diabetes, for several reasons,” Garber said.

“First, the rate of complication development is higher per year with osteoporosis than diabetes. This consideration necessarily shortens the allowable duration of placebo exposure. Second, there are varying degrees of risk for fracture within the osteoporotic patient spectrum. To select low-risk patients minimizes risk for harm per patient, but necessarily requires more patients to be randomized in order to have an adequate number of fracture events for statistically valid conclusions to be drawn. Thus, a lesser risk is spread over a larger population, yielding a similar absolute number of adverse events; in essence, the same number of patients must be harmed. Thus, this approach is at best a sophistry.

“Third, by excluding so-called high-risk patients, a different patient population is being studied and the conclusions drawn from such a study may not generalize to the higher-risk groups, particularly if little therapeutic benefit is seen in low-risk populations. Fourth, fracture prevention has become relatively standardized therapy once osteoporosis is diagnosed. Failure to implement routine standards of care amounts to withholding treatment for experimental reasons and, therefore, violates the Helsinki Declaration among other canons of human research practice,” Garber said.

He believes that these concerns “can be cured by performing active comparator research with rescue therapy privisions included.” Although such a design may increase the costs and size of trials for osteoporosis, Garber said he feels it is essential for patient protection.

Guideline review

In 2008, a panel of osteoporosis opinion leaders, advocates and researchers representing the American Society for Bone and Mineral Research, the International Society for Clinical Densitometry and the National Osteoporosis Foundation convened at the request of the FDA to assess whether the osteoporosis research guidance should be revised. The consensus was published in the Journal of Bone and Mineral Research.

“The FDA asked the panel the feasibility of changing the fracture endpoint,” Watts said. He participated in the panel and co-authored the consensus statement. “They asked if the data were sufficiently robust to support the use of surrogate endpoints. The answer was no.”

The panel concluded that the existing guidelines were consistent with current practice and required no revision as far as primary endpoints or inclusion of a placebo control. The panel recommended shortening the duration of efficacy trials from 36 months to between 18 and 24 months, with long-term safety trials extending at least 5 years.

“In response to issues raised by the FDA, the panel of experts representing the major US osteoporosis societies recommends that placebo-controlled trials with vertebral or nonvertebral fracture endpoints are appropriate and, with thorough consent, are ethical for registration of new treatments,” the panel concluded. “After showing a particular treatment reduced fracture risk, other indications and dosing regimens could be established using bone turnover markers along with BMD, except for corticosteroid osteoporosis.”

Future directions

Although the FDA osteoporosis guidance currently remains unchanged, it could be revised in time. FDA officials noted in a position statement published in Annals of Internal Medicine in 2000 that after evidence demonstrated rheumatoid arthritis treatments prevented irreversible disease progression, study designs were altered to allow concomitant use of disease-modifying therapies and for shortened durations of studies in which placebo-control groups remained appropriate.

“Osteoporosis will become increasingly important as the population ages and the need for more effective therapies in new drug classes grows,” Kleerekoper said. “Ideally, I’d like to see trials with large groups of patients with moderate disease, with an active comparator and with BMD as the outcome.”

Looking at the bigger picture, McClung said, “The whole question of the ethics of placebo-controlled trials doesn’t pertain only to osteoporosis — it pertains to every kind of clinical study.” – by Cheryl Pokalo Jones, with additional reporting by Melissa Foster and Emily Shafer

For more information:

• Ellenberg SS. Ann Intern Med. 2000;133:464-470.
• Food and Drug Administration, Division of Metabolic and Endocrine Drug Products. Guidelines for preclinical and clinical evaluation of agents used in the prevention or treatment of postmenopausal osteoporosis. Find the PDF file by clicking here. Published April 1994. Accessed Jan. 2, 2011.
• Rosen CJ. N Engl J Med. 2010;363:1365-1367.
• Silverman SL. J Bone Miner Res. 2008;23:159-165.
• Stein CM. N Engl J Med. 2010;363:1367-1370.
• Temple R. Ann Intern Med. 2000;133:455-463.
• Watts NB. Curr Rheumatol Rep. 2004;6:79-84.

Disclosures: Dr. Kleerekoper is a consultant to Roche Diagnostics and Ortho Diagnostics, and is a member of the speakers bureau for Eli Lilly. Dr. McClung receives research grants and/or consulting fees from Amgen, Lilly, Merck, Novartis and Warner-Chilcott. Dr. Petak is a speaker for Amgen. Dr. Watts is co-founder, stockholder and director of OsteoDynamics; has received honoraria from Amgen, Novartis and Warner Chilcott for lectures in the past year; has received consulting fees from Amgen, Arena, Baxter, InteKrin, Johnson & Johnson, Lilly, Medpace, Merck, NPS, Orexigen, Pfizer/Wyeth, Sanofi-Aventis, Takeda, Vivus and Warner Chilcott in the past year; and has received research support from Amgen, Merck and NPS through his university. Dr. Garber reports no relevant financial disclosures.

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Does evidence suggest benefits of widespread screening for osteoporosis in men?

Not warranted unless risk factors are present

Current evidence suggests benefits of widespread osteoporosis screening in women, but not in men. The National Osteoporosis Foundation (NOF) suggests screening for osteoporosis starting at age 70 years in men and 65 years in women.

Mone Zaidi

There is good evidence that risk factors for osteoporosis increase after age 70 years in all men. However, I believe there is no point in screening men for osteoporosis earlier than age 70 years unless there is a specific risk. Osteoporosis screening in younger men may be warranted in those with specific risk factors such as a personal history of longstanding smoking, excessive alcohol intake, corticosteroid use and prostate cancer therapy, for example. Other medical conditions may additionally predispose men to greater osteoporotic risk.

Although I believe that the current recommendations for osteoporosis screening in men at age 70 years are appropriate, the guidelines for women are far too delayed. There is evolving evidence that bone loss starts early in menopause, so women should be screened earlier than the NOF guidelines recommend. Depending on new scientific evidence in future years, these paradigms may undergo change.

Mone Zaidi, MD, PhD, FRCP, Hon MD, is professor of medicine and director of the Mount Sinai Bone Program at Mount Sinai School of Medicine, N.Y.

Disclosure: Dr. Zaidi reports no relevant financial disclosures.

Personal, societal burden for fractures justifies action

There are several kinds of evidence that support widespread screening for fracture risk in men. Of course the personal and societal burden for fractures in men is sufficiently large to justify action. Risk factors important in men are easily ascertained in primary care; some are remediable and others can direct the degree of clinical concern and intervention.

Eric Orwoll

Many men have inadequate calcium and vitamin D intake, and assessing nutritional status is not difficult. Insuring calcium/vitamin D nutrition is safe, fairly inexpensive and likely to provide benefit in reducing risk. Bone density measures are highly predictive of fracture risk in men, and even when anti-osteoporosis drug costs are assumed to be relatively high BMD measures have been shown to be cost-effective in identifying older men who would benefit from pharmacological intervention. Several anti-osteoporotic drugs are approved by regulatory agencies for use in men because well-designed clinical trials show they are safe and effective in improving bone density. Also, the data available overwhelmingly indicate the absence of sex differences in response to available agents. This is important since, to date, the available clinical trials in men have been too small to unequivocally demonstrate fracture risk reduction from drug treatments, while in postmenopausal women their anti-fracture efficacy is incontrovertible.

All of this information supports the judgment that it is appropriate to discover, or screen, osteoporotic men at risk for fracture and to reduce the risk with appropriate intervention. Recently, however, a critical argument against screening in men has been that the final step (demonstrating that intervention results in fracture risk reduction) has not been achieved with large, adequately-powered studies. In that light, the argument goes on to conclude that interventions cannot be recommended in men and that screening is thus inappropriate. However, this conclusion seems to fly in the face of a large body of evidence that indicates the likelihood of great benefit at low risk and reasonable cost. Certainly, anti-fracture efficacy trials in men are critically needed, but now we shouldn’t let the perfect interfere with the good.

Eric Orwoll, MD, is professor of medicine at Oregon Health and Science University.

Disclosure: Dr. Orwoll has received research support from Amgen, Eli Lilly and Merck and has been a consultant for Eli Lilly, Merck and Wright Medical Technology.

Sundeep Khosla

At present, most people would not advocate widespread screening in men because current evidence does not indicate that it is cost-effective. Because DXA can be costly, targeting the population in which the yield is going to be highest is probably the best option. Therefore, most organizations, including the National Osteoporosis Foundation, recommend screening in men aged older than 70 years because this is when osteoporosis becomes a significant issue. For younger men, the decision to test for osteoporosis requires clinical judgment. Men with fractures resulting from mild to moderate trauma, for example, or those with strong family histories of osteoporosis may warrant testing before age 70 years.

Several groups of researchers are also attempting to identify men who may be at higher risk for osteoporosis. In the future, as we develop better genetic and serum-based biomarkers, we may be able to use them as part of initial testing before progressing to DXA.

Additionally, we should consider that a lot of people aged older than 50 years are starting to have CT scan-based procedures for other health issues, such as colon cancer screening or to evaluate calcification of coronary arteries, that yield images of the lumbar or thoracic spine. These CT-based imaging techniques can perhaps identify people who have disproportionate bone loss relative to age-matched controls without added cost. This would apply to both women and men. Yet, at this point, we cannot use CT imaging to predict future risk or define osteoporosis because that is still being done based on the DXA normal ranges. As our population ages, we need to think about osteoporosis in men and concentrate on measuring bone densities in those older than 70 years and on identifying risk factors in men younger than 70 years to target those in whom testing would be appropriate.

– Sundeep Khosla, MD

Professor of Medicine,

College of Medicine, Mayo Clinic

President, American Society for Bone and Mineral Research

Disclosure: Dr. Khosla reports no relevant financial disclosures.