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

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Abstract
This study was designed to evaluate the long‐term effects of incadronate disodium (YM175) after its withdrawal on cancellous bone mass in ovariectomized (OVX) rats. Thirteen‐week‐old female SD rats were randomized into four groups: sham‐operated, OVX, low‐YM, and high‐YM (0.01 mg/kg or 0.1 mg/kg subcutaneously [sc], three times a week after OVX) groups. After 4 weeks of treatment with vehicle or YM175, rats from each group were killed at time points 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‐energy 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 bone formation rate (BFR/BS) were measured as histomorphometric parameters of the fifth lumbar vertebra. BMD, BV/TV, Tb.N, and Tb.Sp in YM175‐treated 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 withdrawal in the low‐YM group. YM175 decreased both bone formative and resorptive parameters in histomorphometry. Serum bone‐specific alkaline phosphatase (ALP) and urinary deoxypyridinoline at both doses of YM175 also showed a suppressive effect of this agent on bone turnover. These results indicate that YM175, after withdrawal, still maintains bone volume dose dependently by depressing bone resorption and formation in OVX rats. Intermittent YM175 treatment with a long interval may be sufficient to maintain the bone volume and structure in OVX rats.

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