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Raloxifene Acts as an Estrogen Agonist on the Rabbit Growth Plate

Pediatric Endocrinology Unit (O.N., J.F., E.M.R., L.S.), Department of Women and Child Health, Karolinska Institutet, SE-17176 Stockholm, Sweden; and Developmental Endocrinology Branch (O.N., J.B.), National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892

Address all correspondence and requests for reprints to: Ola Nilsson, National Institutes of Health, National Institute of Child Health and Human Development, Building 10, Room 10N262, 10 Center Drive, MSC 1862, Bethesda, Maryland 20892-1862. E-mail: ola.nilsson{at}kbh.ki.se.

Estrogen treatment has been used to induce growth plate fusion, thereby reducing the final height in girls expected to achieve extreme tall stature. The treatment is effective, in terms of limiting final height, but concerns have been raised that it might also increase the risk for malignancies later in life. Raloxifene, a selective estrogen receptor modulator, has been shown to act as an estrogen agonist on bone density but as an estrogen antagonist on breast and uterine tissue. The effect of raloxifene treatment on growth plate fusion and final height is unknown. The aim of this study was to determine whether raloxifene would act as an estrogen agonist or antagonist on growth plate cartilage. Ovariectomized immature rabbits were treated for 4 wk with vehicle (controls), estradiol cypionate (E2), or raloxifene. Tibial growth velocity was decreased in both E2- (P < 0.001) and raloxifene-treated animals (P < 0.001), compared with controls. E2 and raloxifene treatment also decreased chondrocyte proliferation and the height of the proximal tibial growth plate. In addition, E2 and raloxifene hastened fusion of the distal tibial growth plate (P < 0.05) and decreased the number of proliferative and hypertrophic chondrocytes per column in the proximal tibial growth plate. As expected, the uterus was enlarged by estrogen, but not raloxifene, treatment. We conclude that raloxifene acts as an estrogen agonist on the growth plate, accelerating growth plate senescence and thus hastening epiphyseal fusion.

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