FDA Cautions Against Long-Term Use of Bisphosphonates

Posted on May 21st, 2012 by

The U.S. Food and Drug Administration (FDA) has performed a systematic review of the long-term safety and efficacy of bisphosphonates and has recommended caution and updated labeling, but stopped short of imposing a regulatory restriction on the duration of drug use. The review was published in an online edition of the New England Journal of Medicine.[1]

Bisphosphonates are bone-building drugs used to treat osteoporosis, which is a condition characterized by low bone mass and deterioration of bone structure. Each year, roughly 1.5 million Americans experience an osteoporosis-related bone fracture. These fractures commonly involve the wrist, hip, or spine, but can affect any part of the body. Bisphosphonates are widely prescribed for osteoporosis and there are a number of them on the market, including Fosamax® [alendronate], Actonel® [risedronate], Boniva® [ibandronate], Reclast® [zoledronic acid]), Prolia® (denosumab), calcitonin, estrogen, Evista® (raloxifene), and Forteo® (teriparatide).

The FDA review of bisphosphonates was prompted by concerns over long-term use of the drugs. The drugs have been shown to be effective in clinical trials lasting 3 to 4 years; however, the pharmacologic effects of bisphosphonate activity continue long after patients stop taking the medication. There is a concern that after many years of use, the drugs may actually lead to weaker bones in some women. There have been some rare but serious adverse events, including unusual femur fractures, esophageal cancer, and osteonecrosis of the jaw, a painful and disfiguring crumbling of the jawbone. One study showed that use of a bisphosphonate for five years or longer was linked with a more than two-fold increase in risk of subtrochanteric or femoral shaft fracture.[2] These fractures occur lower down on the femur than hip fractures.

The FDA review focused on two long-term studies of bisphosphonates—a ten-year study of Fosamax and a six-year study of Reclast. Both studies showed significant reductions in fracture risks during the first three to four years of use, but little or no benefit with long-term use. The FDA’s opinion is that the meaningful endpoint of osteoporosis therapy is the rate of fracture. While bisphosphonates offer an advantage over placebo in the first several years of use, after five years, the advantage narrows—leading the FDA to conclude that long-term use may not provide benefit.

Bisphosphonates are currently labeled with an “Important Limitation of Use” statement that reads: “The optimal duration of use has not been determined. All patients on bisphosphonate therapy should have the need for continued therapy re-evaluated on a periodic basis.”

The report did not provide specific guidelines for use—instead leaving it up to physicians and patients to decide on an individualized basis. For low-risk patients, three to five years of bisphosphonate therapy may be sufficient, whereas older patients may benefit from longer use of the therapy. An accompanying article offers evidence that women who continue to have very low bone density after three to five years of treatment might benefit from long-term use of the drugs.[3] More specifically, they say that women with a T score lower than -2.5, a history of spinal fracture, or an existing fracture are most likely to benefit from long-term use of the drugs. However, women who have moderate to low bone density—meaning a diagnosis of osteopenia rather than osteoporosis—are not likely to benefit from long-term use of bisphosphonates.

The bottom line—caution is warranted with long-term use of bisphosphonates. The optimal duration of use depends on individual characteristics. Patients who take bisphosphonates should be closely monitored to assess the risks and benefits of continued therapy.

References:


[1] Whitaker M, Guo J, Kehoe T, Benson, G, et al. Bisphosphonates for Osteoporosis — Where Do We Go from Here? New England Journal of Medicine. Published online May 9, 2012.

Doi:10.1056/NEJMp1202619

[2] Park-Wyllie L, Mamdani MM, Juurlink DN et al. Bisphosphonate use and the risk of subtrochanteric or femoral shaft fractures in older women. JAMA. 2011;305:783-789.

[3] Black DM, Bauer DC, Schwartz AV, et al. Continuing Bisphosphonate Treatment for Osteoporosis — For Whom and for How Long? New England Journal of Medicine. Published online May 9, 2012. Doi: 10.1056/NEJMp1202623

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