On May 9, 2012 the U.S Food and Drug Administration (FDA) published (in the online version of The New England Journal of Medicine) an analysis it has completed on the long-term use of bisphosphonates in post-menopausal women.
According to the FDA, while bisphosphonate therapy has demonstrated “efficacy in preventing fractures in registration trials lasting 3 to 4 years … data on safety have raised concern regarding the optimal duration of use for achieving and maintaining protection against fractures”.
These safety concerns include increased risk of femoral shaft fractures, esophageal cancer and osteonecrosis of the jaw.
The Findings and Recommendation
The findings of this analysis were presented to a joint meeting of two FDA committees (the Advisory Committee for Reproductive Health Drugs and the Drug Safety and Risk Management Committee). The committees jointly decided that the data from the analysis “did not support a regulatory restriction on the duration of drug use”.
However, the joint committees did recommend that the labeling on bisphosphonate drugs be updated. Bisphophonate drugs now contain an “Important Limitation of Use” definition that states:
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.
What is the FDA Saying?
While this recommendation can appear to fall short in terms of specifics what you, as a patient of bisphosphonates, should be doing, it probably reflects the fact that the study data reviewed by the FDA was, at times, inconsistent and incomplete.
In addition, the behaviour of bisphosphonate is quite complex and can vary from person to person and from brand to brand. Since bisphosphonates are absorbed into the bone during the treatment phase, they can persist there for years – even after cessation of treatment. Further, there have been no long terms studies of the effects of bisphosphonates after cessation.
Basically, the FDA researchers state that more work and study has to be done and that individuals should consult, on a regular basis, with their health provider on what is right for them.
This regular evaluation should include an individual assessment of the risks and benefits of bisphosphonate therapy and patient preference. A good source for your health provider to use in evaluating your fracture risk is the online FRAX tool developed by the World Health Organization and the International Osteoporosis Foundation.
Clearly, the FDA and researchers are grappling with this complex issue. As someone with low bone density or osteoporosis, you want clear and easy to follow guidance on one question: Should I take a bisphosphonate?
Clearer Guidance, Please
The New England Journal of Medicine published another article to accompany the FDA review. This article was written by a group of physicians at a number of medical institutes across the United States.
In the article, the physicians review the data and shed more light on the results. They state the following:
- Vertebral Fractures (i.e., fractures of the spine): Although evidence is limited regarding the risk of fracture with the continuation of bisphosphonate therapy beyond 3 to 5 years, data from randomized controlled trials generally suggest that the risk of vertebral fracture is reduced.
- Nonvertebral Fractures (i.e., fractures of the wrist, ribs, hip, etc): The consistent evidence of a statistically significant reduction in nonvertebral fractures with the continuation of bisphosphonates is lacking.
Further, this team provides the following guidance regarding continued use of bisphosphonates – with the caveat that these recommendations could change as more research is published.
- Patients with low bone mineral density at the femoral neck (T score below −2.5) after 3 to 5 years of treatment are at the highest risk for vertebral fractures and therefore appear to benefit most from continuation of bisphosphonates.
- Patients with an existing vertebral fracture who have a somewhat higher (although not higher than −2.0) T score for bone mineral density may also benefit from continued therapy.
- Patients with a femoral neck T score above −2.0 have a low risk of vertebral fracture and are unlikely to benefit from continued treatment.
As you can see, these physicians recommend that patients with osteoporosis and a high fracture risk should continue bisphosphonate therapy. Those with low or moderate risk of fracture will probably not see material benefit from continued use of this therapy.
What I Recommend
Since each individual’s medical profile is unique, I strongly encourage you to discuss this issue with your physician. Hopefully, articles like this one make you a more informed patient.
As a general rule, if you are at a high risk of fracture, continued use of bisphosphonates is probably the prudent path.
If you are at low or moderate risk of fracture, you need to weigh the risks associated with long term use of this drug (as defined earlier in this article) and the research that is showing that there is no evidence that bisphoshonates cause a significant reduction in nonvertebral fractures.
And, of course, a well designed osteoporosis exercise program is something that everyone should be following.
Conclusion
Expect to hear more about this debate in the coming years as researchers spend more resources examining the long term effects of this drug. Clearly, people within the FDA and researchers in the field have concerns with the continued long term use of this drug and its effectiveness when it comes to reducing fracture risk. The problem today is that there is not enough data to provide definitive guidance or change the FDA’s regulatory position with regard to this drug.
FDA Review in More Detail
The FDA article goes into a lot of detail as to what the study involved. For those of you not interested in reviewing the article but still interested in the mechanics of the study, here is a brief summary.
The FDA examined the long term effects of three bisphosphonates: Fosamax, Reclast and Actonel. One study group took the bisphosphonate and the other took a placebo. The FDA studied the effect of the various bisphosphonates on changes in the bone density in the femoral neck and the lumbar spine. They also looked the effect on vertebral fractures.
The FDA found that continued use of bisphosphonate therapy beyond five years lead to “maintenance of bone mineral density in the femoral neck and further increases in bone mineral density at the lumbar spine”.
However, the FDA review found that the “data raise[s] the question of whether continued bisphosphonate therapy imparts additional fracture-prevention benefit, relative to cessation of therapy after 5 years.” It was this finding that caused the FDA to issue the label change mentioned above.
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