Bisphosphonate Use Increases Atypical Femur Fracture Risk

Troy Brown

May 25, 2012

May 25, 2012 — The incidence of atypical femur fractures has increased during the past decade, and this increased risk is associated with bisphosphonate use, according to a recent study published online May 21 in the Archives of Internal Medicine. Nevertheless, the actual number of atypical fractures remains much lower than the number of classic fractures.

Raphael P.H. Meier, MD, from the Department of Surgery at University Hospitals of Geneva and Faculty of Medicine in Geneva, Switzerland, and colleagues conducted a case-control study of 477 patients aged 50 years or older who were admitted to University Hospitals of Geneva with subtrochanteric or femoral shaft fractures from January 1999 through December 2010. The researchers wanted to determine the association between fracture pattern and bisphosphonate use.

For the study, they defined atypical fracture pattern as a "transverse or short oblique fracture line originating at the lateral femoral cortex between the lesser trochanter and the distal metaphysis." Fractures were categorized as classic if they occurred in the same location but had a different appearance (spiral, wedge, segmental, or complex irregular).

Fractures in both groups were examined radiographically for the occurrence of a contralateral fracture.

Dr. Meier and colleagues also studied a randomly chosen control group of 200 patients aged 50 years or older without femur fractures.

Significantly Elevated Risk Among Bisphosphonate Users

Of 477 femoral factures, 39 were atypical fractures and 438 were classic fractures. Of the patients with atypical fractures, 32 (82.1%) had received bisphosphonates compared with 28 (6.4%) of the classic fracture group (crude odds ratio [OR], 66.9; 95% confidence interval [CI], 27.1 - 165.1; P < .001), and 23 (11.5%) in the group without fracture (OR, 35.5; 95% CI, 13.9 - 88.8; P < .001).

After adjusting for potential risk factors for fracture (vitamin D, corticosteroids, proton pump inhibitor, sex, and age), bisphosphonate use (any vs none) was associated with an OR of 69.1 (95% CI, 22.8 - 209.5; P < .001) for experiencing an atypical fracture compared with patients who experienced classical fractures.

The only potential confounders that were statistically significant in the multivariate model were age groups 50 through 69 years and 70 through 79 years.

Increased Risk With Longer Duration of Use

Of the patients who took bisphosphonates, patients with atypical fractures had a longer treatment duration than patients with classic fractures (mean [SD], 5.1 [3.1] years vs 3.3 [2.6] years; P = .02).

After categorization by duration of treatment, the ORs (95% CIs) for atypical fracture vs classic fracture were 35.1 (10.0 - 123.6) for less than 2 years, 46.9 (14.2 - 154.4) for 2 to 5 years, 117.1 (34.2 - 401.7) for 5 to 9 years, and 175.7 (30.0 - 1027.6) for 9 years or more compared with no bisphosphonate use.

The ORs for atypical fracture were 1.7 (95% CI, 0.9 - 3.4; P = .12) for vitamin D use, 7.1 (95% CI, 2.2 - 22.4; P = .001) for corticosteroid use, and 3.3 (95% CI, 1.0 - 11.2; P = .06) for female sex. After adjustment for these factors, bisphosphonate use was associated with an OR of 49.7 (95% CI, 15.9 - 155.1; P < .001) for an atypical fracture.

The adjusted ORs were 0.3 (95% CI, 0.1 - 1.0; P = .05) for vitamin D use, 5.9 (95% CI, 1.1 - 30.4; P = .03) for corticosteroid use, and 1.7 (95% CI, 0.3 - 10.6; P = .59) for female sex. The OR was 0.5 (95% CI, 0.3 - 0.9; P = .03) for bisphosphonate use when the classic fracture group was compared with the nonfracture group. Thus, bisphosphonate use was associated with a 47% reduction in fracture risk.

In a telephone interview with Medscape Medical News, Joseph M. Lane, MD, professor of orthopedic surgery and chief of the Metabolic Bone Disease service at the Hospital for Special Surgery at Weill Medical College of Cornell University in New York City explained, "The bottom line is, the longer you take bisphosphonates, the greater the risk of getting into trouble with what we call 'frozen bone.' " Dr. Lane was not involved in the current study.

Increasing Incidence During Last Decade

When averaged during the 12-year observation period, the incidence rates for classic fractures were 357 cases per million person-years and 32 cases per million person-years for atypical fractures. During that time, the overall incidence rate remained stable for classic fractures, but increased for atypical fractures.

Using Poisson regression models, the mean annual change in incidence was +0.4% (95% CI, −2.3% to 3.1%; P = .78) for classic fractures and +10.7% (95% CI, 1.2% to 20.3%; P = .03) for atypical femoral fractures.

There was a statistically significant difference between the temporal trend of atypical fractures and the temporal trend of classic fractures (difference, +10.3% per year; 95% CI, 0.4% - 20.3%; P = .04). During the course of the observation period, the prevalence of bisphosphonate users (mean [SD], 19.8% [7.5%]) in the study population remained stable, and the mean annual change was −1.5% (95% CI, −5.2% to 2.2%; P = .43).

Favorable Absolute Benefit to Risk Ratio

The authors note that there were 11 times more classic fractures than atypical fractures during the observation period. "[I]f we consider a 50% reduction of proximal femur and classic fractures (supported by our results and by literature) and a prescription rate of approximately 10% in the population at risk, the absolute benefit to risk ratio of bisphosphonate treatment would remain clearly favorable, notably keeping in mind that the use of bisphosphonates would also reduce vertebral fractures by 40% to 70% and wrist fractures by 50%," they write.

Contralateral Fractures

Contralateral fractures occurred in 28.2% of atypical cases and in 0.9% of classic cases (OR, 42.6; 95% CI, 12.8 - 142.4).

"It is interesting to note that bilateral fractures were frequent in patients with atypical fractures. This finding strongly supports the need for radiographic examination of the contralateral femur in all patients presenting with an atypical fracture, whether or not symptomatic, to decide about treatment, including perhaps possible prophylactic internal fixation if a stress fracture pattern is detected," the authors note.

Fractures Tend to Occur With Prolonged Use

In an accompanying editorial, Douglas C. Bauer, MD, writes, "atypical femur fractures are uncommon but do appear to be more frequent among individuals who are being treated with oral and intravenous bisphosphonates, and longer duration of use further increases the risk."

Dr. Bauer is a professor in residence, director of the University of California, San Francisco (UCSF), Division of General Internal Medicine Research Program and of the UCSF Clinical and Translational Resident Research Training Program, and codirector of the UCSF Clinical and Translational Science Pathways to Discovery.

More research is needed, but for now, "clinicians should continue the current practice of using bisphosphonates as first-line therapy for individuals who are at high risk of fracture and should be sure to discuss with their patients the rare but apparently causal relationship between bisphosphonate use and atypical fractures. Finally, discontinuation of treatment with selected bisphosphonates after 3 to 5 years should be considered in lower-risk individuals, but the optimal duration without therapy and the utility of follow-up [bone mineral density] assessment or other tests after discontinuation of treatment remain uncertain," Dr. Bauer writes.

Dr. Lane explained that bisphosphonates are extremely safe for 3 to 5 years, but after 5 years, the physician should reevaluate whether the patient still needs the drug. If the patient's bone density has been unchanged, and their bone markers are within the therapeutic window, the patient can be put on a holiday, he noted. "If the markers go up, or they start losing bone, restart a drug that's appropriate for the patient at that period of time," said Dr. Lane.

"This drug is not for the lifetime of the patient...5 years is a reasonable period of time, and then rethink," Dr. Lane explained. If the patient is gaining bone, and the markers are at the upper limit of normal, the patient can keep taking the drug as long as they are making bone, said Dr. Lane. If they have plateaued, they should stop taking it, he said.

"These fractures occur with prolonged use in people who don't need the drug any longer," said Dr. Lane.

One coauthor has served on paid advisory boards and has received fees for consulting and lecturing from Servier, Novartis, Eli Lilly, Amgen, Roche, Nycomed, Merck, Sharp and Dohme, Alken, and Danone. Dr. Bauer has received research support from Amgen and Novartis for the adjudication of clinical trial end points. Dr. Lane has worked as an advisor or speaker for most, if not all, metabolic bone disease companies, including Merck, Eli Lilly, P&G, Novartis, and Amgen.

Arch Internal Med. Published online May 21, 2012. Article full text, Editorial full text