The mineralization of bone tissue: a forgotten dimension in osteoporosis research

Osteoporosis treatment should not only prevent the loss of bone tissue, not interfere with apatite and avoid bone mineral changes at the crystal level, but should also increase the mechanical resistance of bone and thus protect the skeleton against new fractures. Mineral substance is crystallized as nonstoichiometric carbonated apatite ionic crystals of small size and extended specific surface. Consequently, they have a very large interface with extracellular fluids, and numerous interactions between ions from the extracellular fluid and ions constituting apatite crystals are thus possible. It is generally agreed that bone strength depends on the bone matrix volume and the microarchitectural distribution of this volume, while the degree of mineralization of bone tissue is almost never mentioned as a determinant of bone strength. We now have evidence that the degree of mineralization of bone tissue strongly influences not only the mechanical resistance of bones but also the bone mineral density. In adult bone, our model is based on the impact of changes in the bone remodeling rate on the degree of mineralization of bone tissue. The purpose of this paper is to report the main results concerning the interactions of strontium (Sr) with bone mineral in animals and in osteoporotic women treated with strontium ranelate (SR). These studies aimed to evaluate using X-ray microanalysis, X-ray diffraction and computerized quantitative contact microradiography: (1) the relative calcium and Sr bone content, (2) the distribution of Sr in compact and cancellous bone, (3) the dose dependence of the deposition of Sr in bone, (4) the interactions between Sr and mineral at the crystal level (in monkeys), (5) the influence of Sr on the mean degree of mineralization of bone tissue and on the distribution of the degree of mineralization of bone tissue, and (6) the bone clearance of Sr over short periods of time (6 and 10 weeks) after cessation of SR administration (monkeys treated for 13 and 52 weeks, respectively). In monkeys killed at the end of exposure (13 or 52 weeks), Sr was taken up in a dose-dependent manner into compact and cancellous bone, with a higher content in new bone than in old bone. The Sr content greatly decreased (about 2-fold) in animals killed 6 or 10 weeks after the end of treatment but this affected new bone almost exclusively. After SR treatment, there were no significant changes in crystal characteristics. Easily exchangeable in bone mineral, Sr was slightly linked to crystals by ionic substitution (generally 1 calcium ion substituted by 1 Sr ion in each unit cell). The degree of bone mineralization was not significantly different in the various groups of monkeys. Thus, at the end of long-term SR treatment and after a period of withdrawal, Sr was taken up in a dose-dependent manner into new bone without alteration of the degree of bone mineralization and with no major modification of bone mineral at the crystal level. In postmenopausal osteoporotic women treated with SR (0.5, 1 and 2 g/day) for 2 years, Sr was dose-dependently deposited into new bone without changes in the degree of mineralization of bone tissue. These findings could reflect dose-dependent stimulation of bone formation and are of potential value for the use of SR in the treatment of osteoporosis. In conclusion, the different studies performed on bone samples from monkeys and humans treated with various doses of SR showed that Sr was heterogeneously distributed between new and old bone but in a dose-dependent manner without alteration of the crystal characteristics and the degree of mineralization of bone tissue, even after long-term administration of often high doses of SR (the highest therapeutic dose used in humans is 4-fold lower than the lowest experimental dose administered to monkeys). This emphasizes the value, as antiosteoporotic treatment, of SR, which is safe at the bone mineral level.