Long-term effects of withdrawal of bisphosphonate incadronate disodium (YM175) on bone mineral density, mass, structure, and turnover in the lumbar vertebrae of ovariectomized rats

This study was designed to evaluate the long-term effects of incadronate di sodium (YM175) after its withdrawal on cancellous bone mass in ovariectomiz ed (OVX) rats. Thirteen-week-old female SD rats were randomized into four g roups: sham-operated, OVX, low-YM, and high-YM (0.01 mg/kg or 0.1 mg/kg sub cutaneously [sc], three times a week after OVX) groups. After 4 weeks of tr eatment with vehicle or YM175, rats from each group were killed at time poi nts of 0 (baseline), 3, 6, 9, and 12 months after withdrawal of the agent. Bone mineral density (BMD) of the lumbar vertebrae was measured by dual-ene rgy X-ray absorptiometry (DXA). Bone volume (BV/TV), trabecular number and trabecular separation (Tb.N and Tb.Sp), eroded surface (ES/BS), osteoclast number and osteoclast surface (N.Oc/BS and Oc.S/BS), osteoid surface (OS/BS ), and hone formation rate (BFR/BS) were measured as histomorphometric para meters of the fifth lumbar vertebra. BMD, BV/TV, Tb.N, and Tb.Sp in YM175-t reated groups were maintained at the same level as in the sham group until 12 months after withdrawal in the high-YM group and until 3 months after wi thdrawal in the low-YM group. YM175 decreased both bone formative and resor ptive parameters in histomorphometry. Serum bone-specific alkaline phosphat ase (ALP) and urinary deoxypyridinoline at both doses of YM175 also shelved a suppressive effect of this agent on bone turnover. These results indicat e that YM175, after withdrawal, still maintains bone volume dose dependentl y by depressing bone resorption and formation in OVX rats. Intermittent YM1 75 treatment with a long interval may be sufficient to maintain the bone vo lume and structure in OVX rats.