Strontium ranelate: a new paradigm in the treatment of osteoporosis

Abstract

Not one of the currently available medications has, so far, unequivocally demonstrated its ability to fully prevent the occurrence of new vertebral or peripheral osteoporotic fractures once osteoporosis is established. Therefore, several new therapies are currently under development to optimize the risk/benefit ratio of osteoporosis treatment. Strontium ranelate is composed of an organic moiety (ranelic acid) and of two atoms of stable nonradioactive strontium. In vitro, strontium ranelate increases collagen and noncollagenic proteins synthesis by mature osteoblast enriched cells. The effects of strontium ranelate on bone formation were confirmed as strontium ranelate enhanced pre-osteoblastic cell replication. The stimulation by strontium ranelate of the replication of osteoprogenitor cell and collagen, as well as noncollagenic protein synthesis in osteoblasts, provides substantial evidence to categorize strontium ranelate as a bone-forming agent. In the isolated rat osteoclast assay, a pre-incubation of bone slices with strontium ranelate induced a dose- dependent inhibition of the bone resorbing activity of treated rat osteoclast. Strontium ranelate also dose-dependently inhibited, in a chicken bone marrow culture, the expression of both carbonic anhydrase II and the alpha-subunit of the vitronectin receptor. These effects showing that strontium ranelate significantly affects bone resorption due to a direct and/or matrix-mediated inhibition of osteoclast activity and also inhibits osteoclasts differentiation, are compatible with the profile of an anti-resorptive drug. In normal rats, administration of strontium ranelate induces an improvement in the mechanical properties of the humerus and/or the lumbar vertebra associated with a commensurate increase in bone dimension, shaft and volume. Strontium ranelate was administered in 160 early postmenopausal women, in a 24-month, double-blind, placebo-controlled, prospective randomized study. Daily oral dose of 125 mg, 500 mg and 1 g of strontium ranelate were compared with a placebo. At the conclusion of the study, the percent variation of lumbar-adjusted bone mineral density from baseline was significantly different in the group receiving 1 g/day of strontium ranelate compared with placebo (+1.41% vs. -0.98%, respectively). Increase in total hip and neck bone mineral density averages, respectively, 3.2% and 2.5%. Strontium ranelate does not induce any significant adverse reaction compared with those observed in women receiving a placebo for the same duration. In a phase II study, the effect of strontium ranelate in postmenopausal women with vertebral osteoporotic fractures was assessed during a double-blind, placebo-controlled trial. Doses of 500 mg, 1 g and 2 g daily of strontium ranelate or placebo were given to 353 Caucasian women with prevalent osteoporosis. At the conclusion of this 2-year study, the annual increase in lumbar-adjusted bone mineral density of the group receiving 2 g of strontium ranelate was + 2.97%. This result was significantly different compared with placebo. A significant increase in bone alkaline phosphatase and, over a 6-month period, a significant decrease in urinary-pyridium crosslinks (NTX) were evidenced. During the second year of treatment, the dose of 2 g was associated with a 44% reduction in the number of patients experiencing a new vertebral deformity. Bone histomorphometry showed no mineralization defects. The same percentage of withdrawals following an adverse effect was observed for patients receiving placebo and for those receiving 2 g of strontium ranelate. The compound was further investigated in a large phase III program that included two extensive trials for the treatment of severe osteoporosis, one assessing the effects of strontium ranelate on the risk of vertebral fractures (SOTI) and one evaluating its effects on peripheral (nonspinal) fractures (TROPOS). The primary analysis of the SOTI study, evaluating the effect of 2 g of strontium ranelate on vertebral fracture rates, revealed a 41% reduction in the relative risk of expein the relative risk of experiencing a first new vertebral fracture with strontium ranelate, throughout the 3-year study, compared with placebo. The TROPOS study, showed a significant (p = 0.05) reduction in the relative risk of experiencing a first non-vertebral fracture in the group treated with strontium ranelate throughout the 3-year study compared with placebo in the intention-to-treat population. A 41% reduction in the relative risk of experiencing a hip fracture was demonstrated in the per protocol population. All these results imply that strontium ranelate is a new, effective and safe treatment for vertebral and nonvertebral osteoporosis, with a unique mode of action.