Changes in bone turnover following gonadotropin-releasing hormone (GnRH) agonist administration and estrogen treatment in cynomolgus monkeys: A short-term model for evaluation of antiresorptive therapy

In this study we determine the early time course of estrogen deficiency-induced bone loss in the cynomolgus monkey and examine the potential of this method for evaluating antiresorptive therapies. In two groups of animals, estrogen deficiency was induced by the administration of a gonadotropin-releasing hormone agonist (GnRHa) and bone turnover was measured using biochemical markers, Two weeks after receiving GnRHa, serum estradiol decreased to below the detection limit in most animals and remained there through 6 months or until estrogen replacement started (months 4-6), Relative to untreated animals, urinary deoxypyridinoline (dPyr), as well as C- and N-telopeptides of type I collagen, were significantly elevated 4 weeks after receiving GnRHa, Serum osteocalcin increased in GnRHa-treated animals as early as week 4 and the level was significantly higher than in untreated control animals from weeks 8-24, Estradiol treatment returned all measures of bone turnover to control levels within 2 weeks. The use of biochemical markers as surrogates of bone turnover and loss was validated by measurement of bone mineral density (BMD), which showed a significant reduction at 6 months in estrogen-deficient animals, However, lumbar BMD in animals that received GnRHa and estradiol was similar to that in animals that had not received GnRHa, In conclusion, a monthly depot injection of GnRHa resulted in increased bone turnover due to estrogen deficiency, as early as 4 weeks after treatment. Estrogen administration returned bone turnover to control levels in 2 weeks, This method represents a valid model for evaluating antiresorptive agents in the short term in a nonhuman primate, Furthermore, the data suggest that changes in biochemical markers in response to antiresorptive therapy in humans may be detectable at much earlier time-points than commonly used. (C) 2001 by Elsevier Science Inc. All rights reserved.