Mechanisms of action of antiresorptive therapies of postmenopausal osteoporosis.
In the treatment of osteoporosis, the aim of the antiresorptive therapy is to restore bone density by decreasing bone remodeling. The process of bone remodeling plays a role in plasma calcium homeostasis and serves to modify bone architecture in order to meet changing mechanical needs, to maintain osteocyte viability, and to repair microdamage in bone matrix. Estrogen deficiency results in a number of detrimental effects on bone, including suppression of osteocyte survival as well as impairment of osteoblast response to mechanical stimuli and repair of ageing bone. In this review, effects of available antiresorptive therapies on endocrine regulations of bone metabolism in postmenopausal osteoporosis are compared. The aim of antiresorptive treatment is to ensure adequate bone remodeling, reparation of microdamage of bone, and increased bone strength. Ideally, this effect should be maintained long-term. Several agents are approved for the treatment of osteoporosis. Calcitonin transiently inhibits osteoclast activity without decreasing osteoblast collagen synthesis. Aminobisphosphonates decrease bone remodeling by decreasing osteoclast activity and by inducing osteoclast apoptosis. This allows more time for secondary mineralization to proceed to completion in the existing bone tissue mass, so increasing the mechanical resistance of bone to loading. Estrogens and raloxifene (a selective estrogen receptor modulator that acts as an estrogen agonist in bone) suppress bone remodeling to the premenopausal range, maintaining the function of osteoblasts and osteocytes. In the placebo-controlled osteoporosis treatment trials, all the above treatments reduced the risk of fractures. Raloxifene therapy was also associated with a favorable or neutral effect in the cardiovascular system, and a reduced incidence of breast cancer. Selection of appropriate drug for treatment of postmenopausal osteoporosis should take into account the long-term effect of the antiresorptive agent on bone. Moreover, the effects on other tissues ++should also be considered, and this encompasses both safety concerns, as well as the potentially beneficial effects on other tissues. Further investigation is needed to evaluate the different modes of action of these agents, and their long-term effects on bone and other tissues.
Stepan
J J
JJ
3rd Clinic of International Medicine, Charles University School of Medicine, Prague, Czech Republic. jstepan@vol.cz
Alenfeld
F
F
Boivin
G
G
Feyen
J H M
JH
Lakatos
P
P
D019386:Alendronate / Q000494:pharmacology / Q000627:therapeutic use; D015519:Bone Density; D016723:Bone Remodeling / Q000187:drug effects; D001862:Bone Resorption / Q000188:drug therapy*; D002116:Calcitonin / Q000494:pharmacology / Q000627:therapeutic use; D004164:Diphosphonates / Q000494:pharmacology / Q000627:therapeutic use; D015914:Estrogen Replacement Therapy; D004967:Estrogens / Q000502:physiology; D005260:Female; D006801:Humans; D015663:Osteoporosis, Postmenopausal / Q000188:drug therapy*; D020849:Raloxifene Hydrochloride / Q000494:pharmacology / Q000627:therapeutic use; D020845:Selective Estrogen Receptor Modulators / Q000494:pharmacology / Q000627:therapeutic use
D004164:Diphosphonates; D004967:Estrogens; D020845:Selective Estrogen Receptor Modulators; D020849:Raloxifene Hydrochloride; D002116:Calcitonin; D019386:Alendronate