Bone Abstracts

Introduction: Standard clinical treatments for postmenopausal osteoporosis utilize resorption-inhibiting drugs such as bisphosphonates, which selectively bind to bone mineral but also suppress bone formation over time. Prostaglandin E₂ (PGE₂) has bone-anabolic effects in vivo, but its clinical utility is hindered by side effects upon systemic administration. Since PGE₂ acts on bone via the EP4 receptor, our approach utilizes a specific EP4 receptor agonist (EP4a) to promote bone formation. The EP4a is reversibly linked with the bisphosphonate alendronate (ALN) to create an ALN-EP4a conjugate drug. When administered systemically, the bone-targeting property of ALN directly delivers EP4a to bone sites, where hydrolytic enzymes in the bone environment slowly cleave the chemical link. This liberates EP4a to promote bone formation while leaving ALN bound to bone.

Methods: We used the ovariectomized (OVX) rat model to investigate the in vivo effects of ALN-EP4a in a curative experiment. Three-month-old female Sprague–Dawley rats were OVX, allowed to lose bone for 6 weeks, then treated for 6 weeks before sacrifice (n=9–12/group). Treatments consisted of conjugate in low (5 mg/kg i.v. weekly) and high (25 mg/kg i.v. week 1, 15 mg/kg weeks 2, 4, 6) doses, vehicle for OVX (i.v. weekly) and sham-operated (s.c. daily) rats, co-dosed unconjugated EP4a and ALN (2.5 mg/kg each i.v. weekly), and PGE₂ (4 mg/kg s.c. daily).

Results: Undecalcified histomorphometry of the proximal tibial metaphysis shows that conjugate low dose significantly increases MAR by 69% and BFR/BS by 131% compared to OVX. Micro-computed tomography indicates that, compared to OVX, conjugate treatment results in dose-dependent increase in femoral mid-diaphyseal woven bone volume (1.3× and 8.2×, respectively) as well as femoral cortical porosity (1.2× and 31.6×, respectively). In the high dose group, the mechanical properties are compromised in the femurs and vertebrae.

Conclusions: The ALN-EP4a conjugate drug increases bone formation rate and has local anabolic effects in osteoporotic rats.