Study Seeks to Resolve Bisphosphonate Fracture Paradox

Researchers offer clearer understanding of the changes that occur in bone structure following treatment with bisphosphonates that may be behind the rare, atypical fractures.

With Eve Donnelly, PhD

In what might be viewed as a contradiction in osteoporosis treatment, a small percentage of women who take bisphosphonates to prevent fracture may experience atypical femur fractures (AFF) despite a 50% reduction in fracture risk in most women treated for osteoporosis.1,2

Cornell University researchers believe they have uncovered the cause of the rare yet worrisome, and until now, unexplained, bone breaks following prolonged bisphosphonate treatment for osteoporosis. Their findings, published in the Proceedings of the National Academy of Sciences,3 shed light on the bone changes that occur in some postmenopausal women with AFF, demonstrating that the fracture-resistance toughening mechanisms inherent in healthy bone were disrupted.

Catastrophic fractures of the femur are a rare complication of prolonged use of bisphosphonates, with the risk increasing among women who take the drugs for more than five years. Previous studies have shown that the bones in atypical breaks, which occur without trauma to the leg or hip, are more brittle than usual, although the reasons remained unclear.1,4

“Our work resolves the apparent paradox of AFFs as a side effect of bisphosphonate osteoporosis treatment by clarifying the differing effects of bisphosphonates on bone tissue structure and mechanical properties across multiple length scales,” the authors concluded.

Cornell researchers offer insight into cause of atypical fractures following osteoporosis treatment with bisphosphonates.

Seeking Answers to Unpredictable Fractures

The study was designed to compare bone composition and mechanical properties from biopsies taken from women who experienced AFFs following long-term bisphosphonate therapy with patients who had typical osteoporotic fractures with and without bisphosphonate treatment. Long-term users of the drugs had taken them for a mean of eight years.

Patients who were scheduled for surgery for femoral fractures (typical or atypical, n = 33) or hip replacement (n = 17) were grouped based on fracture morphology and history of bisphosphonate use. Imaging studies were conducted and biopsies were collected for radiographic analysis as well as fracture toughness testing.3

Using a variety of techniques to assess the integrity of bone, including spectroscopy and tests of hardness on the nanoscale level, the investigators found that the femurs of women who had experienced atypical fractures were significantly harder and denser than those of other women in the study. However, those bones also were more likely to crack under conditions of mechanical stress.

Patients with atypical fractures had a higher mean mineral-to-matrix ratio of trabecular bone based on Fourier transform infrared spectroscopy (FTIR) imaging compared with that of typical fracture patients and patients with no fractures (atypical +15% vs. typical, P = 0.01; +11% vs. no fracture, P = 0.05.)3 No differences in composition of trabecular tissue was noted with Ramen imaging.

Cortical bone from patients with atypical fractures showed greater narrowing distributions of hardness compared with those of patients without fractures or patients with typical fractures (atypical −30% vs. no fracture, P = 0.04; −4% vs. typical, P = 0.07).1

A Closer Look at Bone Biopsies and Imaging

Lead author, Eve Donnelly, PhD, a mechanical engineer at Cornell University in Ithaca, New York, said “we were excited to see the fracture mechanics results that showed that the resistance to crack propagation differed in bone from long-term bisphosphonate-treated and untreated patients because that had not been observed in animal models. We are the first to observe these differences.

“A growing body of evidence indicates that [atypical femoral fractures] are likely stress fractures caused by fatigue loading, in which modest loads--less than needed to cause outright fracture--from repetitive activities of daily living like walking and stair climbing propagate cracks in the bone incrementally, in contrast to typical fragility fractures, which usually arise from a single overload like a fall,” Dr. Donnelly told EndocrineWeb.

“We observed greater mineralization and decreased toughness of bone tissue of patients treated with long-term bisphosphonates, which are also consistent with bone tissue that has greater susceptibility to fatigue fracture,” she said, and we found that prolonged use of bisphosphonates appears to make bones more susceptible to straight-line cracks, perhaps because the mineralization is relatively homogenous.3

“Bone tissue in bisphosphonate-naïve patients is heterogeneous; cracks split and twist as they move from areas of lower mineral content to highly mineralized boundaries between osteons, and this impedes their propagation,” said Dr. Donnelly, “In contrast, bone tissue from long-term bisphosphonate-treated patients is more homogeneously mineralized, and because cracks are able to propagate with less splitting and twisting, the bone is less resistant to fracture.”

Ultimately, however, the new findings do not offer much guidance as to which long-term users of bisphosphonates might experience an atypical fracture, and which women need not worry.

“Atypical fractures likely require the convergence of several adverse conditions, representing a ‘perfect storm’ of risk, that include highly curved femurs, slow bone healing, and reduced cortical bone toughness,” Dr. Donnelly said.

Getting Closer to the Bone-Building Process

An unrelated bone study published this month in the Journal of Clinical Investigation  sheds light on how another treatment for osteoporosis, a form of parathyroid hormone—teriparitide (Forteo) works to increase bone strength.5

A team of researchers at Harvard Medical School in Boston looked at the effects of teriparatide on mice that received regular injections of the anabolic agent. (A second form of PTH, abaloparatide (TYMLOS), was approved in April 2017.)

Using transgenic mice, the researchers found that PTH works on three fronts to increase the number and activity of bone-forming osteoblast cells: they increase the production of osteoblasts from primitive stem cells; they spur dormant cells that line bone into becoming functioning osteoblasts, and they decrease the death rate of active osteoblasts.5

That last effect is potentially significant,5 the authors explained, because pre-market studies of teriparatide suggested that the drug could be linked to an increased risk of bone cancer in rats—a risk the FDA determined concerning enough to require a black-box warning for the medication.

“Our findings of suppression in the rate of apoptosis in the early progenitor cells, if sustained over the long term, might contribute to the vulnerability of such cells to undergoing malignant transformation,” according to the researchers. As yet, that risk has yet to be confirmed in people. 

EDITOR'S NOTE:  Commentary from a bone health specialist will be added next week; please return for further insights.

Dr. Lane consults for Bone Therapeutics, SA, CollPlant Ltd, Grafty’s Inc, Kuros Biosurgery AG, RadiusHealth Inc, Terumo BCT Inc, and Wright Medical Technology. All other authors declare no conflict of interest.  

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