Minodronic acid (ONO-5920/YM529) prevents decrease in bone mineral density and bone strength, and improves bone...

Area of Science:

• Pharmacology and Toxicology
• Bone Biology and Disease
• Preclinical Research

Background:

• Ovariectomized (OVX) cynomolgus monkeys serve as a relevant model for postmenopausal osteoporosis.
• Estrogen deficiency in OVX monkeys leads to decreased bone mineral density (BMD), altered bone turnover, and reduced bone strength.
• Nitrogen-containing bisphosphonates are a key therapeutic class for osteoporosis management.

Purpose of the Study:

• To evaluate the efficacy of minodronic acid, a potent bisphosphonate, in preventing OVX-induced bone loss and deterioration.
• To assess the effects of minodronic acid on bone mineral density, bone turnover, microarchitecture, and bone strength in a primate model.
• To determine the optimal dosage and long-term safety profile of minodronic acid in OVX monkeys.

Main Methods:

• Skeletally mature female cynomolgus monkeys underwent ovariectomy or sham surgery.
• Minodronic acid was administered orally at doses of 0, 0.015, and 0.15 mg/kg daily for 17 months.
• Bone turnover markers, lumbar vertebral BMD, bone microarchitecture (micro-CT), and mechanical bone strength were assessed.

Main Results:

• Minodronic acid dose-dependently inhibited OVX-induced increases in bone turnover and decreases in lumbar vertebral BMD.
• The 0.15 mg/kg dose of minodronic acid completely prevented these OVX-induced changes and suppressed bone resorption and formation markers.
• Minodronic acid treatment prevented reductions in the ultimate load of lumbar vertebral bodies and femoral necks, correlating with BMD increases.
• Micro-CT analysis revealed improved trabecular architecture with minodronic acid, shifting from rod to plate structures.

Conclusions:

• Minodronic acid effectively prevented bone loss, deterioration of microarchitecture, and reduced bone strength in OVX cynomolgus monkeys.
• The drug demonstrated a favorable safety profile with no adverse effects detected during long-term administration.
• These findings support the potential clinical utility of minodronic acid for treating postmenopausal osteoporosis.