Long-term use of osteoporosis medication associated with increased risk of atypical fractures

February 22, 2011

Older women who used bisphosphonates (medications that prevent loss of bone mass) for five years or more were more likely to experience "atypical" fractures involving the femoral shaft (bone in the leg that extends from the hip to the knee) or subtrochanteric (fractures in the bone just below the hip joint), compared to women with less usage. However, the absolute risk of these "atypical" fractures was low and bisphosphonate use was associated with a reduced risk of typical osteoporotic fractures, according to a study in the February 23 issue of JAMA.

"Approximately 50 percent of women older than 50 years will sustain an osteoporosis-related fracture during their lifetime, and 1 of 5 patients with an osteoporosis-related fracture will die within 12 months. Although randomized trials have shown that treatment with bisphosphonates reduces the risk of osteoporotic fractures, concerns have recently emerged that bisphosphonate-related suppression of bone remodeling may adversely influence bone strength," according to background information in the article. An increasing number of case reports describe women with long-term bisphosphonate therapy who develop fractures involving the subtrochanteric or shaft region of the femur, considered atypical because of their location and characteristic appearance on x-rays. The U.S. Food and Drug Administration recently announced its intent to actively monitor instances of bisphosphonate-induced atypical fractures.

Laura Y. Park-Wyllie, Pharm.D., M.Sc., of the Li Ka Shing Knowledge Institute of St. Michael's Hospital, Toronto, Canada, and colleagues examined the association between long-term bisphosphonate use and subtrochanteric or femoral shaft fractures in a large population of postmenopausal women. The study included women ages 68 years or older from Ontario who initiated therapy with an oral bisphosphonate between April 2002 and March 2008. Cases were those hospitalized with a subtrochanteric or femoral shaft fracture and were matched to up to 5 controls with no such fracture. Study participants were followed up until March 31, 2009.

Over the study period, the researchers identified 205,466 women treated with a bisphosphonate who met inclusion criteria for the study, and within this group, 716 women were identified who sustained a subtrochanteric or femoral shaft fracture following initiation of bisphosphonate therapy, including 411 women with a subtrochanteric fracture and 305 women with a femoral shaft fracture. These cases were matched to 3,580 controls.

In the primary analysis, the researchers found that use of bisphosphonates for 5 years or longer was associated with a 2.7 times higher odds of hospitalization for subtrochanteric or femoral shaft fracture compared with transient use (less than 100 days in total) of bisphosphonates.

The secondary analysis examining the risk of typical osteoporotic fractures included 9,723 women with fractures of the femoral neck or intertrochanteric region (a section of the femur) during bisphosphonate therapy. Extended bisphosphonate use (greater than 5 years) was associated with a 24 percent reduced risk of fracture compared with transient use. Women with intermediate bisphosphonate use (3-5 years) demonstrated a similarly low risk, while a shorter duration of bisphosphonate use (100 days to 3 years) was associated with a nonsignificant reduction in the risk of such fractures.

Further analysis suggested that more than half of subtrochanteric or femoral shaft fractures among women taking bisphosphonates for greater than 5 years were attributable to extended bisphosphonate use; and that approximately 1 of every 10 subtrochanteric or femoral shaft fractures cases in the population might be prevented if no patient received more than 5 years of exposure. Among 52,595 women with at least 5 years of bisphosphonate therapy, a subtrochanteric or femoral shaft fracture occurred in 71 (0.13 percent) during the subsequent year and 117 (0.22 percent) within 2 years.

"In summary, our findings provide strong evidence that prolonged bisphosphonate therapy is associated with an increased risk of subtrochanteric or femoral shaft fracture, although the absolute risk of these fractures is low. These findings also highlight the need for a thoughtful assessment of individual risk of fracture when considering extended bisphosphonate therapy and that long-term use of these drugs may warrant reconsideration, especially in patients at relatively low risk of fracture. It may be appropriate to consider a drug holiday for selected patients, particularly as the cumulative duration of bisphosphonate therapy surpasses 5 years. Additional research is needed to better understand the prognosis of subtrochanteric or femoral shaft fractures among frail older adults, identify the specific subgroups of long-term users at the highest risk for these adverse effects, and explore whether interruptions in therapy reduce the risk of subtrochanteric or femoral shaft fractures over the long term," the authors write.

They add that the results of their study should not deter clinicians and patients from using bisphosphonates in appropriate patients. "Our study confirms the known benefits of bisphosphonate treatment for typical osteoporotic fracture, and evidence suggests that bisphosphonate therapies are underused in individuals at high risk of fracture despite their established efficacy."
(JAMA. 2011;305[8]783-789. Available pre-embargo to the media at www.jamamedia.org)

Editor's Note: Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, funding and support, etc.

To contact Laura Y. Park-Wyllie, Pharm.D., M.Sc., call Leslie Shepherd at 416-864-6094 or email shepherdl@smh.ca.

For More Information: Contact the JAMA/Archives Media Relations Department at 312-464-JAMA or email: mediarelations@jama-archives.org.

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