FDA panels call for clarification on duration of bisphosphonate use

The FDA's Reproductive Health Drugs Advisory Committee and the Drug Safety and Risk Management Advisory Committee today voted 17-6 to add clarifications to bisphosphonate labeling regarding duration of use and timing of evaluation.

"We are mainly talking about the label as the vehicle through which we communicate the importance to both the clinical community and patient community," panel member and consumer representative Michele Orza, ScD, of George Washington University, said during the joint meeting.

Long-term efficacy issues

In January 2011, the agency revised the drug's labeling to note that optimal duration of use remains undetermined and recommend periodic re-evaluation of the need for therapy. The labeling also differs with each drug, explaining that safety and efficacy are based on data from trials that lasted a certain number of years involving the specific medication.

Studies analyzing the bisphosphonates' benefits suggest that bone mineral density continues to increase at the lumbar spine and maintains its level at the femoral neck after 10 years of exposure to the medication. Small increases in BMD at the lumbar spine and small decreases in BMD followed by a plateau at the femoral neck were noted in patients who discontinued bisphosphonate use after 3 to 5 years.

Fracture data also denote benefits, but the positive effects do not increase after 3 to 4 years of treatment with bisphosphonates, according to background documents.

When posed with the question about whether the labeling requires clarification, several committee members suggested that, although optimal duration of use has not been established, the parameters could be stricter based on the data implying safety out to approximately 5 years.

"I thought the statement was too general," Kenneth Burman, MD, chief of the endocrine section at Washington Hospital Center and professor of medicine at Georgetown University, said during the meeting. He suggested adding an indication that data are not clear on the safety and efficacy of taking the drug longer than 5 to 10 years.

Kenneth Burman

Others, however, pointed out that study results are insufficient to restrict use to a specific time period.

"We don't have enough data to restrict the limitation of use," William Duncan, MD, PhD, of the department of Veterans Affairs in Washington, D.C., said during the meeting.

Many panel members also highlighted the need to clarify when re-evaluation of the need for therapy should occur.

"My concern is that for patient labeling, the ambiguity of having 're-evaluated on a periodic basis' means that it's never going to happen," panel member and patient representative Elizabeth Tucker said. Instead, she and several panel members proposed including a set period, such as once per year.

The concept of a "drug holiday" was also up for debate. Elaine H. Morrato, DrPH, assistant professor in the department of pediatrics at the University of Colorado Denver, pointed out that the term implies that a patient will return to treatment despite the fact that evidence suggests efficacy may not last longer than 3 to 5 years. Moreover, other committee members expressed concern that the research does not indicate the benefits of a drug holiday and asked for further studies.

Safety concerns

After a March 2010 FDA Drug Safety Communication announcing the agency's ongoing safety review of bisphosphonate use and the occurrence of atypical femur fractures, the FDA reviewed all available data on the medication, including data summarized in the American Society for Bone and Mineral Research Task Force report. The report recommended additional product labeling, better identification and tracking of patients experiencing these breaks, and more research to determine whether and how these drugs cause the serious but uncommon fractures, according to the FDA statement.

At the meeting, the various sponsors and the FDA reviewed data regarding adverse events associated with bisphosphonates, particularly focusing on atypical subtrochanteric fractures, osteonecrosis of the jaw and esophageal cancer. Panel members expressed serious concern about these events and requested more information and further analyses to determine the prevalence and incidence of these problems associated with bisphosphonate use. This information is required, they said, if they are to determine an accurate risk-benefit profile.

The initial marketing application for bisphosphonates submitted to the FDA list the following adverse events in the warnings and precautions section of labeling: disorders of mineral metabolism, gastrointestinal disorders, musculoskeletal pain, osteonecrosis of the jaw, atypical subtrochanteric and femoral diaphyseal fractures, acute phase reactions, inflammatory eye disease and atrial fibrillation.

The various medications and generic equivalents under review included:

• Alendronate tablets and solution (Fosamax, Merck).
• Combination alendronate and cholecalciferol tablets (Fosamax Plus D, Merck).
• Risedronate tablets (Actonel, Warner Chilcott).
• Risedronate delayed-release tablets (Atelvia, Warner Chilcott).
• Co-packaged risedronate and calcium carbonate tablets (Actonel with Calcium, Warner Chilcott).
• Ibandronate tablets and injection (Boniva, Roche).
• Zoledronic acid (Reclast, Novartis).

"At the end of the day, we need to know how many deleterious events occur if treated and how many occur if not treated," panel member Maria Suarez-Almazor, MD, PhD, Barnts Family Distinguished Professor at the University of Texas MD Anderson Cancer Center, said at the meeting. "That's what is important to us."

Although the FDA is not required to follow the recommendations of the advisory committees, it usually does.

Nelson B. Watts

I was disappointed in the process and outcome of the FDA hearing. There are few if any situations where more data would not be of interest, and bisphosphonate treatment for osteoporosis is one where we would like to have more. However, I believe we have more long-term data with bisphosphonates than is available for statins or antihypertensives and for any anti-diabetes drug other than insulin. The committee wanted more long-term trials but did not deal with the ethical issue of placebo-controlled trials and how long such a trial might be continued. The safety concerns discussed by the committee at length are quite uncommon and can be managed. Data were presented suggesting that high-risk patients benefit from continuing treatment longer than 3 to 5 years. The committee seemed to want to limit the duration of treatment, but did not provide guidance on what to do with high-risk patients if bisphosphonate therapy is stopped. They seemed to want to insist on a schedule of periodic re-evaluation of the need for treatment but did not say what would be the indications for continuing or stopping. The committee voted for changes in labeling but individual members found it difficult to articulate what those changes should be - even if the changes should be the same for all bisphosphonate or different for each drug in the class.

"Clinical judgment is required" is sometimes a trite-sounding phrase but applies to the many decisions in clinical medicine where definitive data are lacking. I will continue to recommend long-term (up to 10 years) bisphosphonate treatment for patients at high risk for fracture but consider 5 years adequate for lower-risk patients. I'm happy with the concept of a "drug holiday," which I think implies that treatment will be re-started after some time off.

– Nelson B. Watts, MD
Bone and Health Osteoporosis Center
University of Cincinnati College of Medicine

Disclosure: 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.

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