Long-Term Use of Bisphosphonates Increases Risk for Atypical Fractures

Laurie Barclay, MD

February 22, 2011

February 22, 2011 — Long-term use of bisphosphonates increases the risk for atypical (subtrochanteric or femoral shaft) fractures in older women, according to the results of a population-based, nested case-control study reported in the February 23 issue of the Journal of the American Medical Association.

Radiographs of atypical fractures

However, the investigators are not recommending stopping use of bisphosphonates in appropriate patients. They note that the absolute risk for atypical fractures is low and that the benefits of bisphosphonate therapy still appear to outweigh the risks, because bisphosphonate use was associated with a reduced risk for typical osteoporotic fractures.

"Osteoporosis is associated with significant morbidity and mortality," write Laura Y. Park-Wyllie, PharmD, MSc, from the Li Ka Shing Knowledge Institute of St. Michael's Hospital, Toronto, Canada, and colleagues. "Oral bisphosphonates have become a mainstay of treatment, but concerns have emerged that long-term use of these drugs may suppress bone remodeling, leading to unusual fractures."

Previous Concerns About Bisphosphonates

Previous concerns that bisphosphonate-related suppression of bone remodeling may adversely affect bone strength, and an increasing number of case reports of women receiving long-term bisphosphonate therapy who sustained subtrochanteric or femoral shaft fractures has led the US Food and Drug Administration (FDA) to announce its intent to actively monitor cases of atypical fractures related to bisphosphonate use.

As previously reported by Medscape Medical News, results of this monitoring led the FDA, in September 2010, to consider revision of bisphosphonate labels to reflect a possible increased risk for atypical fractures. The label was changed to include a warning regarding an increased risk for subtrochanteric or femoral shaft fractures in October 2010.

Recent Study Findings

The goal of the current study was to examine whether prolonged treatment with bisphosphonates is associated with an increased risk for subtrochanteric or femoral shaft fracture, using a cohort of women 68 years or older from Ontario, Canada, who began treatment with an oral bisphosphonate between April 1, 2002, and March 31, 2008. Case patients, defined as women hospitalized with a subtrochanteric or femoral shaft fracture, were matched to up to 5 control participants without such fractures. Follow-up of participants continued until March 31, 2009.

The main analysis evaluated the association between hospitalization for a subtrochanteric or femoral shaft fracture and duration of bisphosphonate therapy. The investigators also studied the association between bisphosphonate use and fractures of the femoral neck or intertrochanteric region. Because fractures in these sites are characteristic of osteoporotic fractures, this secondary analysis was designed to assess the specificity of findings from the primary analysis.

After starting bisphosphonate therapy, 716 women had a subtrochanteric or femoral shaft fracture, and 9723 women had a typical osteoporotic fracture of the intertrochanteric region or femoral neck.

The risk for a subtrochanteric or femoral shaft fracture was increased among women treated with bisphosphonates for at least 5 years vs those who had only transient use (< 100 days in total) of bisphosphonates (adjusted odds ratio [OR], 2.74; 95% confidence interval [CI], 1.25 - 6.02).

However, women treated with bisphosphonates for at least 5 years had a 24% reduced risk for typical osteoporotic fractures (adjusted OR, 0.76; 95% CI, 0.63 - 0.93). This risk was similarly low in women with intermediate duration of bisphosphonate use (3 - 5 years), whereas women using bisphosphonates for 100 days to less than 3 years had a nonsignificant reduction in the risk for typical osteoporotic fractures.

Of the 52,595 participants treated with bisphosphonates for 5 years or longer, 71 (0.13%) had a subtrochanteric or femoral shaft fracture during the subsequent year, and 117 (0.22%) had a subtrochanteric or femoral shaft fracture within 2 years. Medscape Medical News previously reported that femoral fractures occur infrequently with bisphosphonate use.

Among women taking bisphosphonates for longer than 5 years, more than half of subtrochanteric or femoral shaft fractures could be attributed to extended bisphosphonate use. Additional analysis suggested that if no patient received more than 5 years of bisphosphonate exposure, approximately 1 of every 10 cases of subtrochanteric or femoral shaft fractures in the population might be prevented.

"Among older women, treatment with a bisphosphonate for more than 5 years was associated with an increased risk of subtrochanteric or femoral shaft fractures; however, the absolute risk of these fractures is low," the study authors write.

Limitations of this study include possible residual confounding, reliance on prescription data possibly resulting in some degree of exposure misclassification, and inability to determine the frequency of bilateral femoral fractures.

"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," the study authors conclude.

"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."

Benefits Outweigh Certain Risks

Another study, as covered by Medscape Medical News, found that the reduction of typical hip fractures appears to outweigh the increased risk for atypical fractures associated with bisphosphonate therapy.

The current findings by Park-Wyllie and colleagues corroborate with previous research. Also, they recommend that their findings should not prevent clinicians and patients from using bisphosphonates when appropriate.

"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," Park-Wyllie and colleagues conclude.

This study was funded by the Ontario Ministry of Health and Long-Term Care. One of the study authors (Muhammad M. Mamdani, PharmD, MA, MPH) has participated in paid advisory board meetings and has received consulting fees from Novartis, Janssen-Ortho, Pfizer, and Boehringer-Ingelheim. Dr. Park-Wyllie was supported by a Fellowship Award from the Canadian Institutes of Health Research. A third study author (Peter C. Austin, PhD) was supported by a Career Investigator Award from the Heart and Stroke Foundation of Ontario. The remaining study authors have disclosed no relevant financial relationships.

JAMA. 2011;305:783-789. Full text

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