Prolonged use of oral bisphosphonates is associated with an increased risk of subtrochanteric or femoral shaft fractures in older women. However, the absolute risk for these fractures is low, according to a large population-based study.

"This study adds another piece to the puzzle," lead author Laura Y. Park-Wyllie, Pharm.D., said in an interview. "There wasn’t good research about what the absolute risk of the fractures was. This study adds that piece."

During the 7-year study period, researchers found that women aged 68 years or older who used bisphosphonates for 5 years or longer were 2.74 times more likely to have subtrochanteric or femoral shaft fractures after minimal trauma, compared with women who took the medications transiently. (JAMA 2011;305:783-9).

The study also showed that the absolute risk of such atypical fractures was at 1 in 1,000 women.

"If you combine all the information that we have about osteoporosis and the information we have about the risk versus benefits [of bisphosphonates] they would favor the continuation of treatment," Dr. Park-Wyllie said.

Bisphosphonate therapy reduces the risk of osteoporotic fractures, judging from findings from a number of studies. But bisphosphonate-related suppression of bone remodeling could have an adverse effect on bone strength, resulting in atypical fractures, the study authors noted.

The growing number of reports on the issue and conflicting studies prompted the group to launch the study, said Dr. Park-Wyllie, a research fellow at Li Ka Shing Knowledge Institute of St. Michael’s Hospital in Toronto.

The American Society for Bone and Mineral Research recently released a task force report about the issue. The Food and Drug Administration is monitoring instances of such cases. There have also been several studies on the topic, but the authors of this report say that the studies were too small to establish or negate an association.

The population-based, nested case-control study examined 205,466 women 68 years or older who were treated with bisphosphonates between April 1, 2002, and March 31, 2008. The women were followed until the first fracture, death, or end of the study. Women with a history of conditions that could affect bone integrity were excluded.

In the group, 716 women (0.35%) had subtrochanteric (411) or femoral shaft fractures (305). Each case was matched with up to five controls – 3,580 total – from the cohort not hospitalized for either type of fracture, according to the study.

When compared with women who had used bisphosphonates transiently during the study period (less than 100 days in total), women who used the medication for 5 years or longer had an increased risk of subtrochanteric or femoral shaft fracture, the authors concluded.

To validate their findings, the investigators also conducted a secondary analysis, examining the risk of typical osteoporotic fractures among women who used bisphosphonates for 5 years or more, compared with women who used the medication transiently. Of the cohort, 9,723 women sustained femoral neck or intertrochanteric region fractures. "As expected, we found that extended bisphosphonate use was associated with a reduced risk of fracture compared with transient use," the authors wrote.

The absolute risk was estimated from 52,595 women in the cohort with at least 5 years of bisphosphonate therapy. Seventy-one, or 0.13%, sustained subtrochanteric or femoral shaft fractures during the following year and 117 (0.22%) within 2 years.

The study had some limitations, according to the authors. They did not have access to lifestyle behaviors. They relied on prescription data and some degree of exposure misclassification may have occurred, they said. Also, they did not study women aged younger than 68 years, "so the generalizability of our findings to younger women is unknown," they reported.

The authors also noted that during their study period (2002-2008) only a small proportion of the cohort received 5 or more years of bisphosphonate therapy. "It is likely that the prevalence of long-term bisphosphonate exposure will increase over time as more women achieve 5 cumulative years of therapy because these drugs are still relatively new and because sustained adherence to bisphosphonates is actively promoted in the community setting," they wrote.

The study should not deter physicians and patients from the use of bisphosphonates, they said, noting that typical hip fractures were far more common than were subtrochanteric or femoral shaft fractures during the study period (9,723 vs. 716).

Dr. Park-Wyllie and coauthors said their findings showed the need for assessment of individual risk of fractures when extended bisphosphonate therapy is considered, especially in patients at relatively low risk of fractures. They added that additional research is needed to find out whether interruptions in therapy could reduce the risk of such atypical fractures over the long term.

One of the coauthors – Muhammad M. Mamdani, Pharm.D., – reported financial relationships with Boehringer Ingelheim, Janssen-Ortho, Novartis, and Pfizer. The study was funded by the Ontario Ministry of Health and Long-Term Care.

Absolute Risk of Atypical Fractures is Low in Bisphosphonate Users