Optimizing bone metabolism in osteoporosis: insight into the pharmacologic profile of strontium ranelate.
Strontium ranelate (SR) is currently being developed for the treatment of osteoporosis. Pharmacologic studies in animal models have shown that its efficacy on bone mass is based on its original mode of action on bone formation and bone resorption. In normal mice, SR increased bone formation and vertebral bone mass. In normal rats, SR increased bone mass and the mechanical properties of vertebral, humeral and femoral bones, associated with increased femoral shaft diameter. Vertebral bone mineral density and bone strength were also increased by SR, whereas stiffness was not altered, underlining that the improvement in bone strength occurs without inducing defective bone mineralization. In normal adult monkey alveolar bone, SR decreased bone resorption and increased bone. In ovariectomized (OVX) rats, SR limited the reduction in bone mineral content and the decrease in trabecular bone volume induced by estrogen deficiency, by inhibiting bone resorption while maintaining bone formation. Curative treatment with SR also partially restored bone mass in OVX rats. In the model of hind limb immobilization in rats, SR reduced bone resorption and partially limited long bone loss, as assessed by bone mineral content, bone volume, and histomorphometric and biochemical indices of bone resorption. The unique mode of action of SR on bone formation and resorption is also supported by in vitro studies. In calvaria culture systems and osteoblastic cell cultures, SR enhanced the replication of preosteoblastic cells and consequently increased collagen synthesis. Moreover, SR inhibited the bone-resorbing activity of isolated mouse osteoclasts and devreased osteoclast differentiation markers in chicken bone marrow cultures. Altogether, these pharmacologic results suggest that SR optimizes bone metabolism by decreasing bone resorption and promoting bone formation, which may be of potential value in the treatment of osteoporosis.
INSERM U349 affiliated CNRS, Lariboisière Hospital, 2 rue Ambroise Pare, 75475, Paris cedex 10, France. pierre.marie@larib.inserm.fr
P J
PJ
Marie
D000818:Animals; D015519:Bone Density / Q000502:physiology; D001846:Bone Development / Q000187:drug effects* / Q000502:physiology; D001862:Bone Resorption / Q000188:drug therapy* / Q000503:physiopathology; D000882:Haplorhini; D006801:Humans; D051379:Mice; D023421:Models, Animal; D009942:Organometallic Compounds / Q000494:pharmacology*; D010024:Osteoporosis / Q000188:drug therapy*; D051381:Rats; D013876:Thiophenes / Q000494:pharmacology*
D009942:Organometallic Compounds; D013876:Thiophenes; C081587:strontium ranelate