Questions have been raised regarding the mechanical effects of suppressing bone turnover on bone strength. These discussions have influenced FDA decisions about guidelines for drugs for the treatment of osteoporosis. The goals of this work are to determine (a) whether a significant reduction in bone turnover will increase bone fragility; (b)how much bone remodeling can be suppressed before strength is compromised; and, (c) whether suppression of bone turnover will reduce bone strength by allowing microdamage to accumulate. Two different bisphosphonates (etidronate and risedronate) will be used to suppress bone turnover. Dogs (n= l2/group) will be treated daily for 7 or 12 months with placebo, low-dose etidronate, or high-dose etidronate. Separate groups will be treated for 12 months with low- or high-dose risedronate, which suppresses bone turnover without inhibiting mineralization. Dogs will be double labeled with fluorochromes prior to sacrifice, and radiographs will be taken between 7 and 12 months to detect spontaneous fractures. Biochemical markers of bone formation and resorption will be measured from serum taken at baseline, 3, 6, 9, and 12 months. The primary outcomes will be strength and elastic modulus of ribs, femoral diaphysis, vertebral bodies and vertebral spinous processes measured from mechanical tests, and stiffness measured by scanning acoustic microscopy. Microdamage accumulation, static and dynamic histomorphometric parameters, and biochemical markers will be secondary outcome measures. Analysis of variance will be the primary statistical method for between-group differences in means of primary and secondary outcome variables. This experiment will test the hypothesis that prolonged suppression of normal bone turnover reduces bone strength, and that the reduction in strength is caused by the accumulation of microdamage in bone matrix.
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