Effects of minodronic acid and alendronate on bone remodeling, microdamage accumulation, degree of mineralization and bone mechanical properties in ovariectomized cynomolgus monkeys

Suppression of bone remodeling by bisphosphonates leads to accumulation of microdamage in bone. If this microdamage develops due to suppressed repair of remodeling only, more potent bisphosphonates should cause more damage. In this study, we evaluated the effects of reduced bone turnover produced by a potent bisphosphonate, minodronic acid, on microdamage accumulation, the degree of mineralization and mechanical properties of bone in ovariectomized cynomolgus monkeys, and compared these effects with those of alendronate. Sixty female monkeys aged 9-17 years old were divided into five groups. The sham group and the ovariectomized group were treated daily for 17 months with lactose vehicle. The other three groups were treated daily with minodronic acid at a dose of 0.015 mg/kg or 0.15 mg/kg, or alendronate at 0.5 mg/kg orally. After sacrifice, lumbar vertebrae and left femurs were subjected to histomorphometry, microdamage, mineralization analyses, and mechanical testing. Minodronic acid suppressed bone remodeling of cancellous and cortical bone in a dose-dependent manner and the higher dose of minodronic acid suppressed bone remodeling more strongly than alendronate. The lower dose of minodronic acid did not increase microdamage accumulation and compressive strength, but the higher dose of minodronic acid and alendronate resulted in similar increases in cancellous microdamage accumulation and ultimate load in lumbar vertebra. There were no significant differences among the groups in microdamage, degree of mineralization and mechanical properties in cortical bone of the femoral shaft; however, only alendronate showed a tendency to increase highly mineralized osteons and microdamage. These findings suggest that microdamage caused by minodronic acid is less than that expected based on the extent of remodeling suppression, in comparison with alendronate although this was not reflected in any significant change of mechanical properties.

► Effects of minodronic acid and alendronate on bone turnover, microdamage, mineralization and mechanical properties were compared in ovariectomized cynomolgus monkeys ► Minodronic acid suppressed bone remodeling dose-dependently and more strongly than alendronate ► High-dose of minodronic acid and alendronate produced similar increases in microdamage and ultimate load in cancellous bone. ► Only alendronate showed a tendency to increase highly mineralized osteons and microdamage in cortical bone ► Minodronic acid causes less microdamage than expected based on the extent of suppression of remodeling, in comparison with alendronate