Bisphosphonates

Over the past decade, bisphosphonates have been widely used to treat a variety of bone diseases. The marked inhibitory action of bisphosphonates on osteoclast-mediated bone resorption has led to success in the treatment of pathologic processes with increased bone turnover such as Paget's disease, bone tumors, and osteoporosis. More recently, investigators have speculated on whether bisphosphonates can play an important role in fracture repair by enhancing the healing process and limiting disuse osteoporosis.

Two separate studies [2,3] have evaluated the effect of bisphosphonate therapy on fracture healing in osteoporotic women with distal radius fractures. Each study assessed bone mineral density at the fracture site as the primary outcome measure. Post-fracture bisphosphonate treatment increased bone mineral den* Corresponding author. E-mail address: [email protected] (M.C. Koester).

sity at the site of fracture, compared with placebo. However, the clinical significance of these findings was not established. Adolphson and colleagues [2] have reported no differences in pain and elapsed time until return to function between treatment groups, whereas van der Poest Clement and colleagues [3] have not attempted to assess patient-oriented outcomes.

The clinical relevance of increased bone mineral density within a fracture callous is uncertain because neither morphologic appearance nor mineral content correlate with mechanical bone strength [4]. Calcium may be present in either cartilage or bone, thus the mechanical properties of the callus may vary greatly. In an animal model, Li and colleagues [5] have reported that bisphos-phonate treatment resulted in a larger fracture callus, but the maturation of the fracture was delayed. These changes may be secondary to the inhibition of bone resorption, because bone formation and resorption are intimately linked.

Given their inhibitory action on osteoclast activity, a potential role exists for the prophylactic use of bisphosphonates in stress fracture prevention. When placed under cyclic stress, microtrauma is inflicted on bone. The bone must then remodel while attempting to repair areas of microfracture. The first stage of bone remodeling involves bone resorption, further weakening the already compromised bone. In theory, if the initial turnover of bone is suppressed, it may not be transiently weakened as the normal healing process ensues [6].

Milgrom and colleagues [7] randomized a group of male Israeli military recruits to receive risedronate or placebo during the first 12 weeks of basic training. The primary outcome measure was the occurrence of a stress fracture during the study period. Over one third of the entire study group discontinued treatment because of concerns regarding potential adverse side effects, although only two soldiers actually reported symptoms. No patients were lost to follow-up. Intention-to-treat analysis and per-protocol analysis showed no difference in stress fracture incidence between the groups. Because of the large early dropout rate, the study was no longer adequately powered to detect a difference between the treatment groups, introducing the possibility of a type II statistical error. Further research is warranted regarding stress fracture prevention in both military and athletic populations.

A case series [8] has recently detailed the successful use of intravenous pamidronate in five intercollegiate female athletes with tibia stress fractures. The five subjects showed bone scan results consistent with stress fracture, with four of the five athletes having symptoms more than 5 months before treatment. According to the report, only one athlete missed any time from activity, and the symptoms resolved in all five athletes within a few weeks of treatment. No decision regarding the efficacy of bisphosphonates in stress fracture treatment can be made from this uncontrolled study. The proper role of bisphosphonates in stress fracture treatment can be determined only by a well-designed clinical trial with fractures graded by MRI and groups randomized according to gender, fracture site, MRI findings, and activity.

To date, bisphosphonates have been most widely used in post-menopausal women for the treatment of osteoporosis. However, the safety of bisphospho-

nates has yet to be clearly established in women who are pregnant or of child-bearing age. In rat studies, alendronate has been found to cross the placenta and accumulate in fetal bone [9]. Obviously, the presence of alendronate may interfere with fetal bone mineralization and development. Such changes have been reported in animal studies [9,10], but there have been no case reports of teratogenic effects in humans, to date.

The half-life of the bisphosphonates is proportional to bone turnover time, which may be as long as 433 days in rats [11]. Therefore, it may take several years for a young woman to completely clear the drug from her body. Any harmful effects on the fetus could potentially persist for years after the initial treatment. Current studies of the use of bisphosphonates in young athletes should be limited to men. If it is found to be efficacious in the prevention or treatment of stress fractures, further studies in women, along with post-treatment surveillance for the occurrence of birth defects, should then be initiated.

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