We examined the effects of a nonantimicrobial
tetracycline analogue,
CMT-8, on bone loss and osteoclasts in ovariectomized (OVX) rats. Three-month-old female rats were OVX, and, one week later, distributed into three groups:
sham-operated non-OVX controls, untreated OVX controls, and CMT-8-treated OVX rats. After 145 days of daily
drug administration (p.o.), the femurs were dissected and examined histologically.
Ovariectomy markedly decreased trabecular and cortical bone volume in the metaphyses compared to
sham-operated controls. Treating the OVX rats with
CMT-8 produced a significant inhibition of trabecular and cortical bone loss and induced new bone formation, in which connectivity of the trabecular struts was increased by bridging the adjacent longitudinal bone trabeculae. Ultrastructurally,
CMT-8 reduced ruffled border formation in osteoclasts, while it caused no structural impairment in osteoblasts. To further evaluate the effects of
CMT-8 on the resorbing activity of osteoclasts, osteoclasts were cultured on dentine slices pretreated with
CMT-8 at concentrations of 2, 10, or 50 micrograms/ml, and resorption lacuna formation on the dentine surface was found to be reduced, dose-dependently, by the bound
CMT-8. Our results suggest that
CMT-8 therapy effectively inhibits post-
ovariectomy bone loss not only by inducing new bone formation, but also by inhibiting osteoclastic
bone resorption, and that
CMT-8 binding to bone may provide a prolonged release delivery of this anti-resorptive
therapy.