Osteoporosis Drugs Linked to a Rare Form of Fracture
Bisphosphonate drugs, such as alendronate (Fosamax), ibandronate (Boniva) and zoledronic acid (Reclast), are proven to combat bone loss and fractures in people with the bone-thinning disease osteoporosis. However, prolonged use of the drugs can alter the composition of bone, making it more brittle—and vulnerable to a rare but serious form of fracture. Now a new study (Proceedings of the National Academy of Sciences, Aug. 15, 2017) points to two possible explanations for the phenomenon.
Double-Edged Sword. It has been known for some time that prolonged use of bisphosphonates can put people at risk for atypical femoral fracture (AFF), a break in the femur (thigh bone) that can occur with little or no trauma. Scientists from Cornell University, Weill Cornell Medicine, and the Hospital for Special Surgery in New York, among others, set out to understand the link by examining biopsies of cortical bone (the outer layer) from the femur, obtained from older women during fracture repair surgery.
The study participants were placed in five groups, based on fracture type and bisphosphonate use. The testing pointed to a couple of contributing factors. Firstly, bisphosphonate-treated women with AFF had bone that was harder and more mineralized than bisphosphonate-treated women with typical osteoporotic fractures. In a Cornell University press release, study leader Eve Donnelly, BS, MS, PhD, assistant professor of materials science and engineering at Cornell, noted that this is due to bisphosphonates’ main function: the drugs slow the resorption (shedding) of old bone, which is typically followed by remodeling (the growth of new bone). In healthy adults, cortical bone is constantly being resurfaced, with the entire adult skeleton overhauled every 10 years or so. But this process begins with resorption—and if resorption is slowed by bisphosphonates, the remodeling process is affected. The result is that the existing bone ages, and grows brittle over time. “It’s kind of a double-edged sword,” said Professor Donnelly. “It’s extremely good to prevent bone loss, but the drugs will also slow this natural process, which allows turnover.”
New Bone a “Firewall.” The other unforeseen side effect to long-term bisphosphonate use involves crack-deflection: new bone’s ability to stop a microscopic crack from progressing to become a fracture. New layers of bone can act as a “firewall” that stops a crack from spreading—but mineralized, older bone loses that function. “Bone usually has natural variability in mineralization within the tissue, which may help to deflect cracks,” Professor Donnelly said. “As you increase the mineralization, you may tend to lose that natural variation.”
Avoid Prolonged Use. The Food and Drug Administration (FDA) recommends that patients use bisphosphonates for three to five years, after which they should be reassessed by their clinician. In many cases, women will be advised to have a “drug holiday,” but those who are still at high risk of osteoporotic fractures may need to keep taking the drugs.
Professor Donnelly emphasized that the study is not proposing doing away with bisphosphonate treatment. Indeed, evidence from many trials supports the drugs’ effectiveness in decreasing the risk of vertebral fractures by 40 to 70 percent, hip fractures by 20 to 50 percent, and non-vertebral fractures by 15 to 39 percent. These fractures can be disabling, and many older adults never recover from them—hip fractures in particular can be devastating, with studies suggesting that one-fifth of hip fracture patients die within a year of sustaining their injury. Conversely, AFF risk is low, with an incidence of up to 50 in 100,000 during the first five years of bisphosphonate treatment. “That’s one of the cautions I’d like to impart,” Professor Donnelly said. “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.”
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