Minodronic acid ameliorates vertebral bone strength by increasing bone mineral density in 9-month treatment of ovariectomized cynomolgus monkeys

Abstract

The effect of treatment for 9months with minodronic acid, a nitrogen-containing bisphosphonate, on vertebral mechanical strength was examined in ovariectomized (OVX) cynomolgus monkeys. Forty skeletally mature female monkeys were randomized into four OVX groups and one sham group (n=8) based on lumbar bone mineral density (BMD). OVX animals were treated orally with 15 and 150μg/kg QD of minodronic acid or 500μg/kg QD alendronate as a reference drug. Measurements of bone turnover markers and lumbar BMD were conducted at 0, 4 and 8months. Measurements of bone mechanical strength and minodronic acid concentration in vertebral bodies were also performed. OVX resulted in a decrease in lumbar BMD and an increase in bone turnover markers at 4 and 8months, compared to the sham group, and the ultimate load on the lumbar vertebra was decreased in OVX animals. Minodronic acid and alendronate prevented the OVX-induced increase in bone turnover markers and decrease in lumbar BMD. Minodronic acid at 150μg/kg increased the ultimate load on lumbar vertebra compared to untreated OVX animals. Regression analysis revealed that the ultimate load was correlated with lumbar BMD and bone mineral content (BMC), and most strongly with the increase in lumbar BMD and BMC over 8months. In a separate analysis within the sham-OVX controls and minodronic acid and alendronate treatment groups, the ultimate loads were also correlated with BMD and BMC. The load-BMD (BMC) correlation in the minodronic acid group showed a trend for a shift to a higher load from the basal relationship in the sham-OVX controls. These results indicate that treatment with minodronic acid for 9months increases vertebral mechanical strength in OVX monkeys, mainly by increasing BMD and BMC.