FDA: Possible increased risk of thigh bone fracture with bisphosphonates

The U.S. Food and Drug Administration today warned patients and health care providers about the possible risk of atypical thigh bone (femoral) fracture in patients who take bisphosphonates, a class of drugs used to prevent and treat osteoporosis. A labeling change and Medication Guide will reflect this risk.

Bisphosphonates inhibit the loss of bone mass in people with osteoporosis. Bisphosphonates have been shown to reduce the rate of osteoporotic fractures -- fractures that can result in pain, hospitalization, and surgery-- in people with osteoporosis. While it is not clear whether bisphosphonates are the cause, atypical femur fractures, a rare but serious type of thigh bone fracture, have been predominantly reported in patients taking bisphosphonates. The optimal duration of bisphosphonate use for osteoporosis is unknown, and the FDA is highlighting this uncertainty because these fractures may be related to use of bisphosphonates for longer than five years.

The labeling changes and Medication Guide will affect only those bisphosphonates approved for osteoporosis, including oral bisphosphonates such as Fosamax, Fosamax Plus D, Actonel, Actonel with Calcium, Boniva, Atelvia, and their generic products, as well as injectable bisphosphonates such as Reclast and Boniva.

Labeling changes and the Medication Guide will not apply to bisphosphonates used for Paget’s disease or cancer/hypercalcemia such as Didronel, Zometa, Skelid, and their generic products.

“The FDA is continuing to evaluate data about the safety and effectiveness of bisphosphonates when used long-term for osteoporosis treatment,” said RADM Sandra Kweder, M.D., deputy director, Office of New Drugs in the FDA’s Center for Drug Evaluation and Research. "In the interim, it’s important for patients and health care professionals to have all the safety information available when determining the best course of treatment for osteoporosis.”

Today’s warning follows a March 10, 2010, Drug Safety Communication announcing the FDA’s ongoing safety review of bisphosphonate use and the occurrence of atypical femur fractures. The FDA has since reviewed all available data on bisphosphonate use, including data summarized in the American Society for Bone 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.

Based on the FDA’s review, the Warnings and Precautions section of all bisphosphonate products for osteoporosis will be revised, and the FDA will require the inclusion of a Medication Guide to better inform patients of the possible increased fracture risk.

The FDA recommends that health care professionals be aware of the possible risk in patients taking bisphosphonates and consider periodic reevaluation of the need for continued bisphosphonate therapy for patients who have been on bisphosphonates for longer than five years.

Patients taking bisphosphonates for osteoporosis should not stop using their medication unless told to do so by their health care professional. Those taking bisphosphonates also should report any new thigh or groin pain to their health care provider and be evaluated for a possible femur fracture. Patients and health care professionals should report side effects with the use of bisphosphonates to the FDA’s MedWatch Adverse Event Reporting program at www.fda.gov/MedWatch or by calling (800) 332-1088.

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HIV Components Drive Bone Breakdown, Even without Active Infection

Although individuals who are HIV positive can now expect to live longer because of the availability of anti-retroviral drugs, this advance brings on new health challenges. It is estimated that the majority of the HIV-infected population of the United States will be older than 50 by 2015.

The intersection of aging and HIV infection appears to have a destructive impact on bone health. Researchers at Emory University School of Medicine have shown in an animal model that the presence of HIV proteins, even without a replicating virus, leads to alterations in cells that break down bone.

The team's results were published this week online in the Early Edition of the Proceedings of the National Academy of Sciences.

"We found that HIV proteins, by themselves, can alter the output of hormones that affect the balance between bone formation and bone breakdown leading to bone loss," says senior author M. Neale Weitzmann, MD, assistant professor of endocrinology at Emory University School of Medicine. "This information could help doctors decide the best way to stave off osteoporosis and bone fractures, which are becoming increasingly common in individuals living with HIV infection."

Collaborating authors are David Guidot, MD, director of the Division of Pulmonary, Allergy and Critical Care Medicine at Emory and director of the Emory Alcohol and Lung Biology Center; and Igho Ofotokun, MD, assistant professor of medicine (infectious diseases).

The Emory team studied rats that have an HIV virus that cannot replicate incorporated into their DNA. The virus does not kill white blood cells directly as it does in human patients, but parts of the virus appear in the rats' blood, and appear to distort the function of immune cells.

Compared to normal rats, the HIV-transgenic rats' bone mineral density (determined by X-rays) in the femur was reduced by 36 percent, while the proportion of bone in the trabecular (spongy) areas of their femurs was reduced by 32 percent.

Some of the reduction in bone mass may be because the HIV-transgenic rats weigh 21 percent less, but they also have more osteoclasts-- cells that originate in the bone marrow that break down bone. The authors found that in the HIV-transgenic rats, B cells (a variety of immune cells) produce more of certain hormones that promote osteoclast differentiation. For instance, their B cells produce more RANKL, a key osteoclast promoting factor and the target of an anti-osteoporosis drug called denosumab, and less osteoprotegerin, an osteoclast inhibitor, Weitzmann says.

Previous studies have shown that viral infection drives changes in the balance of the types of B cells present in HIV-infected people. Weitzmann says the next step in the team's research will be to examine B cell subpopulations in HIV-infected people, and to measure their output of hormones involved in bone growth and breakdown.

The research was supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases, the National Institute of Allergy and Infectious Diseases and the Department of Veterans Affairs.

Reference:
T. Vikulina et al. Alterations in the immuno-skeletal interface drive bone destruction in HIV-1 transgenic rats. PNAS Early Edition (2010).

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