The effect of prophylactic treatment with risedronate on stress fracture incidence among infantry recruits
Introduction
Millions of people worldwide participate in regular exercise programs [1]. While enhancing cardiovascular and musculoskeletal fitness, exercise programs often result in acute or overuse injuries, many involving bone.
Like any other structural material when subjected to cyclic overloading, the bone can undergo fatigue failure [2]. In bone, this process is called a stress or fatigue fracture. Infantry recruits, runners, and usually sedentary people who suddenly increase their activity are at risk for stress fracture [3].
Unlike nonbiological materials, bone has the ability to adapt itself to unusual forces that can produce fatigue failure, thereby preventing or delaying the onset of fracture. This ability is greatest in the young and decreases with advancing age [4]. When bone is subjected to higher than usual strains and strain rates that create microdamage, it remodels to repair the damage [5]. The first stage of remodeling involves resorption of bone during which bone is transiently weakened. If the excessive loading continues during this stage before new and stronger bone is deposited and mineralized, then microdamage may accumulate and lead to stress fracture formation [6], [7], [8], [9], [10].
The etiology of stress fractures has been the focus of both ex vivo and in vivo bone strain studies [11], [12], [13], [14], [15], [16], [17]. During physical activity, forces placed on bone result in its deformation (strain). In ex vivo laboratory bench testing cortical bone fails in fatigue within 103 to 105 loading cycles when strains are between 5000 and 10,000 με [14]. Strains in the physiologic range of 1000–1500 με in ex vivo studies have been shown to cause fatigue and microdamage, but not to cause complete fracture of cortical bone even after 37 million loading cycles [2]. Human in vivo bone studies have focused on the tibia both because it is the most common site for stress fractures among runners and military recruits [18] and because it is surgically a convenient site for strain gauge application [11]. Even during the most vigorous of physical activities, human tibial strains of sufficient magnitude to cause stress fracture from cyclic loading alone have not been found in vivo [11], yet fracture occurs within a few thousand cycles [9]. In contrast, strain levels sufficiently high to cause fatigue failure of the second metatarsal within 10,000 cycles have been found in human ex vivo [19] and in vivo studies [17].
The strain magnitude and cycle number required to produce tibial stress fractures in vivo are apparently much lower than those required to produce fatigue fracture during ex vivo mechanical testing [9]. This apparent discrepancy may be an effect of stressed volumes, whereby larger volumes of material are expected to have worse fatigue properties than the small segments of cortical bone often used in ex vivo mechanical testing [20]. However, others have hypothesized that tibial stress fractures and probably femoral stress fractures occur through the mediation of the bone remodeling response [6], [7], [8], [9], [10]. If this is true, then short-term suppression of bone turnover using bisphosphonates could prevent the initial loss of bone during the remodeling response to high bone strains and potentially prevent stress fracture [21]. This pharmacological approach could offer a potential solution to the problem of stress fractures without compromising the high level of training that is essential for the development of an elite athlete or infantry soldier. To test this hypothesis, we performed a randomized, double-blind, placebo-controlled study evaluating the effect of prophylactic treatment with the bisphosphonate risedronate on the incidence of stress fractures among infantry recruits known to be at high risk for stress fracture.
Section snippets
Materials and methods
New male infantry recruits (473), training on the same base between December 2002 and March 2003, were approached to participate in the study. Three hundred twenty-four recruits, median age 18.8 (range 18–28), signed informed consent that was administered by civilian personnel. The study was approved by the Institutional Review Board of the Israel Defense Forces Medical Corps.
The recruits were surveyed for the presence of known risk factors for stress fracture. Preinduction participation in
Results
Of the 324 subjects in the study, 165 were randomized into the risedronate group and 159 into the placebo group (Fig 1). There was no statistically significant difference in the mean values of possible risk factors for stress fracture between subjects randomized into the two treatment groups, except for femoral length that was minimally higher in the placebo group (Table 1).
At the end of the third week of basic training, 283 out of 324 subjects in the study filled out a survey of the presence
Discussion
The results of the intention-to-treat analysis show that prophylactic treatment with risedronate did not lower the incidence, the time of onset, or the severity of stress fractures among infantry recruits. The 14% overall incidence of stress fractures found in the study was within the range of that expected for nonelite infantry recruits in the Israeli Army [18].
Compliance in this study was defined as subjects who took at least 80% of their weekly doses. When a per-protocol analysis was
Acknowledgements
Supported in part by P&G Pharmaceuticals and the Israeli Defense Forces. Both risedronate and placebo were provided at no charge directly from the manufacturer.
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