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Long-term bisphosphonate therapy can change bones at the microscopic level to make them more susceptible to the rare catastrophic transverse breaks known as atypical femoral fractures (AFFs), scientists said.

Femoral bone tissue from women with AFFs treated with bisphosphonates for 6-8 years was harder and more mineralized than bone from bisphosphonate-treated women with typical osteoporotic fractures, reported Eve Donnelly, PhD, of Cornell University in Ithaca, N.Y., and colleagues

Yet fracture mechanics measurements showed that this tissue was also more susceptible to microscopic fractures, with lower crack-initiation toughness and less crack deflection at osteonal boundaries than that of bisphosphonate-naïve women. The latter difference reduces the bone's ability to stop a microscopic crack from propagating, Donnelly's group said online in the

"Together, these results suggest a loss of intrinsic and extrinsic toughening mechanisms, which contribute to atypical femoral fractures in patients treated with long-term bisphosphonates," the investigators wrote. "Our work resolves the apparent paradox of AFFs as a side effect of the most common osteoporosis treatment by clarifying the differing effects of bisphosphonates on bone tissue structure and mechanical properties across multiple length-scales."

A patient's risk for AFF depends upon more than just the loss of bone toughness, the investigators said. It requires a "perfect storm" of disadvantageous events, including an increased curvature of the femoral shaft that increases the mechanical load on the lateral femoral cortex and the propagation of a microscopic crack that outstrips the bone healing process, they explained.

The study does not suggest bisphosphonates, which inhibit bone resorption and are used to treat osteoporosis in postmenopausal women, should be avoided because of AFF risk, which is very small, Donnelly and colleagues stressed.

"That's one of the cautions I'd like to impart," Donnelly said in a statement. "What we have observed is really the result of long-term treatment, well beyond what the FDA is recommending for these drugs now. Our work explains some of the underlying mechanisms of AFFs and can inform the refinement of dosing schedules for patients at risk of fragility fractures."

Unfortunately, reports of AFFs with bisphosphonate treatment "have contributed to a crisis in osteoporosis treatment," with use declining by half from 2008 to 2012, the researchers wrote. They worried that fear of AFFs has outstripped the actual risk and that rates of ordinary osteoporotic fractures may rebound.

JoAnn Pinkerton, MD, executive director of the in Pepper Pike, Ohio, agreed that bisphosphonates are beneficial overall. "Bisphosphonates provide clear anti-fracture efficacy by suppressing bone turnover," Pinkerton said in an email to MedPage Today. However, the optimal duration of bisphosphonate therapy for postmenopausal women has not been determined, she added.

"For postmenopausal women who are not at high risk of fractures, a bisphosphonate treatment course of 3-5 years is generally recommended," Pinkerton explained. "Continuing the use of bisphosphonates more than 5 years may be associated with an increased rare risk of subtrochanteric femoral fractures, osteonecrosis of the jaw, or esophageal cancer. The need for continued therapy should be re-evaluated for each woman on a periodic basis with no specific limits on the duration of treatment. Drug holidays may be recommended every 3-5 years, depending on bone density response and degree of fracture risk, making determinations on an individual basis."

Donnelly and colleagues examined biopsies of cortical bone from the femurs of 50 women in their 70s and 80s. The patients were categorized into five groups: those on long-term bisphosphonate therapy with AFFs (n=12), typical fractures (n=10), or no fracture (n=5); and bisphosphonate-naïve women with typical fractures (n=11) and no fractures (n=12). The study participants had been treated with bisphosphonates for 6-8 years, longer than the U.S. FDA's of 3-5 years, followed by reassessment of fracture risk, the investigators noted.

Donnelly's group performed a variety of tests on the bone samples, including radiographic analysis, Raman imaging, and three-dimensional morphometric assessment via micro-computed tomography.

"At the whole-bone scale, bisphosphonate treatment has long been known to reduce fracture risk by preventing postmenopausal bone loss and micro-architectural deterioration, reducing structural weakness at trabecular sites. At the millimeter to microscales examined here, reductions in turnover with long-term bisphosphonate treatment contributed to decreased cortical resistance to crack propagation," Donnelly's group wrote.

"Despite this, the risk to benefit ratio of bisphosphonate treatment remains highly favorable for patients with osteoporosis. Thus, our work contributes to an evolving understanding of the complex effects of long-term bisphosphonate treatment on bone tissue properties and can inform guidelines for timing and duration of treatment for patients at risk of fracture," they concluded.

The investigators noted several study limitations, including the small sample size that limited statistical power. In addition, although AFFs do occur in bisphosphonate-naïve patients, none were observed during the five-year study period and so the study lacked this group for comparison, they said.

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