Bone quality in ovariectomized monkeys treated with two doses of teriparatide for either 18 months, or 12 months followed by withdrawal for 6 months

Abstract

Previous studies of ovariectomized monkeys, treated with recombinant human parathyroid hormone (PTH)(1-34) at 1 (clinically relevant) or 5 mg/kg/day for 18 months or for 12 months followed by 6 months withdrawal from treatment, displayed significant changes in the geometry, histomorphometry, and bone quality (albeit without strict tissue age criteria) of cortical bone of the midshaft humerus. Since bone quality significantly depends on tissue age amongst other factors, the aim of the present study was to establish the bone-turnover independent effects of two doses of PTH, as well as the effects of treatment withdrawal on bone quality, by measuring bone material composition at precisely known tissue ages ranging from osteoid, to mineralized tissue older than 373 days. We also investigated the relationship between osteoid composition and the mineral content of the youngest formed mineralized tissue. The variables considered in the present study were: i) the mineral / matrix ratio (correlates with bone bending stiffness); ii) the mineral content at the youngest tissue age; iii) tissue water content (correlates with bone toughness and strength); iv) glycosaminoglycan content (negative modulator of bone mineralization); v) mineral maturity/crystallinity (inversely correlates with bone strength); vi) pyridinoline content (determinant of bone strength even in cases where bone mineral content does not correlate with fracture occurrence). Raman microspectroscopic analysis of bone tissue from the mid-shaft humerus of ovariectomized monkeys demonstrated that effects of PTH administration for 18 months on bone quality are dependent on dose, while the clinically relevant one reverses the effects of ovariectomy. Additionally, both doses investigated in the present study restore the mineralization regulation mechanisms to SHAM levels. The experiments involving 12-month PTH treatment followed by 6 months of withdrawal showed that the beneficial effects induced by 12 months of clinically relevant PTH therapy were sustained after six months of therapy withdrawal.