Strontium ranelate: a novel mode of action optimizing bone formation and resorption.
Strontium ranelate has been shown to decrease the risk of fractures in postmenopausal women. Its efficacy in clinical studies results from its unique mode of action, on both bone resorption and bone formation. Pharmacological studies in animals have shown that strontium ranelate decreases bone resorption and increases bone formation, resulting in increased bone mass. In ovariectomized rats, strontium ranelate prevented the reduction in bone mineral content and the decrease in trabecular bone volume induced by estrogen deficiency. In this model, strontium ranelate decreased bone resorption, whereas bone formation was maintained at a high level as documented by plasma biochemical markers and histomorphometric indices of bone formation. In the model of osteopenia induced by hind-limb immobilization in rats, strontium ranelate reduced histomorphometric parameters of bone resorption and partially prevented long-bone loss, as assessed by bone mineral content, bone volume, and biochemical indices of bone resorption. In intact mice, strontium ranelate increased bone formation and vertebral bone mass. In intact growing rats, strontium ranelate increased the bone trabecular volume without alteration of mineralization. The unique mode of action of strontium ranelate on bone formation and resorption was supported by in vitro studies. In rat calvaria culture systems and rat osteoblastic cell cultures, strontium ranelate enhanced preosteoblastic cell replication and increased collagen synthesis by osteoblasts. Moreover, strontium ranelate decreased bone resorption in organ cultures and decreased the resorbing activity of isolated mouse osteoclasts. The assessment of bone markers in a clinical trial [Spinal Osteoporosis Therapeutic Intervention (SOTI)] supports the mode of action of strontium ranelate: bone alkaline phosphatase levels increased and C-telopeptide of type I collagen levels decreased in treated patients compared with the placebo group at all time points. Thus, pharmacological and clinical studies suggest that strontium ranelate optimizes bone resorption and bone formation, resulting in increased bone mass, which may be of great value in the treatment of osteoporosis.
Marie
P J
PJ
INSERM U606, Lariboisière Hospital, 2 rue Ambroise Paré, 75475 Paris, France. pierre.marie@larib.inserm.fr
D000469:Alkaline Phosphatase / Q000097:blood; D000818:Animals; D015415:Biomarkers / Q000097:blood; D001846:Bone Development / Q000187:drug effects*; D001862:Bone Resorption / Q000188:drug therapy*; D017326:Clinical Trials, Phase III as Topic; D003094:Collagen / Q000097:blood; D024042:Collagen Type I; D005260:Female; D000882:Haplorhini; D006801:Humans; D051379:Mice; D023421:Models, Animal; D009924:Organ Culture Techniques; D009942:Organometallic Compounds / Q000627:therapeutic use*; D010024:Osteoporosis / Q000097:blood / Q000188:drug therapy* / Q000503:physiopathology; D010052:Ovariectomy; D010455:Peptides / Q000097:blood; D051381:Rats; D013876:Thiophenes / Q000627:therapeutic use*; D014475:Uncoupling Agents / Q000627:therapeutic use*
D015415:Biomarkers; D024042:Collagen Type I; D009942:Organometallic Compounds; D010455:Peptides; D013876:Thiophenes; D014475:Uncoupling Agents; C052929:collagen type I trimeric cross-linked peptide; C081587:strontium ranelate; D003094:Collagen; D000469:Alkaline Phosphatase