Synthesis, characterization of strontium –bile acid salts and their bioactivity vs. the anti-osteoporosis drug strontium ranelate.

Evidence is growing that strontium (Sr) influences bone cells and bone metabolism in vitro and in vivo. Many studies have shown that Sr2+ can stimulate bone formation and inhibit bone resorption both in vitro and in vivo. Recently strontium ranelate (SrR), a compound containing two ions of stable bivalent strontium combined with ranelic acid, which acts as a carrier, is registered as drug in the treatment of post-menopausal osteoporosis. SrR is hypothesized to be a dual-acting agent with both anti-resorptive and anabolic skeletal benefits. The precise molecular mechanism responsible for SrR effects is not clear and needs to be investigated. Functional analyses that have been performed suggest that different signaling pathways may be involved in the osteoblastic and osteoclastic responses to SrR. Although, SrR is approved in several countries for the treatment of post-menopausal osteoporosis, it is a relatively new drug and its long-term safety still needs to be documented for the ideal management of osteopenic diseases. Although, SrR is now being administered to women for osteoporosis, it could have potentially therapeutic value in different osteopenic disorders, including Paget’s disease and cancer with bone metastases. To avoid possible adverse reactions in the greater population, it may be important to design analogous compounds that are better tolerated. Since it is evident that the therapeutic action of SrR is due exclusively to Sr2+, we reasoned that the performance of strontium-based drugs could be improved by modification of the carrier anion. Ranelate bears four carboxylic groups and allows the transport of a large amount of Sr2+ metal (two cations per tetra-charged anion, 34.1% in mass), but it showed a few drawbacks. First, it is known that a large proportion of Sr2+ administrated as ranelate is eliminated via gastrointestinal secretion; therefore SrR needs to be administrated as a daily dose of 2 g, resulting in a low patient compliance. Second, synthesis of ranelic acid requires a long, multistep chemical process which contributes to the high price of SrR. Therefore, it would be of first interest to couple the active Sr2+ cation to a readily available natural non-toxic anion that can increase the intestinal absorption of the metal. Analysis of the characteristics of bile acids indicates that their anions may be promising alternative carriers for Sr2+. Bile acids comprise a large group of natural or semi-synthetic molecules that are readily available at low cost; they have been used for pharmaceutical purposes for a long time, because of their known value as drug carriers. Bile acid transport in the gastrointestinal tract is recognized as being an efficient high capacity system because of its involvement in reabsorption of bile salts following fat digestion. Bile acid anions are of therapeutic value because they are known to form complexes that increase the absorption of metal ions, like calcium and iron. On this basis, we hypothesized that Sr2+ absorption also could be enhanced by the use of bile acids. To verify this hypothesis, and to ascertain if these observations can be exploited for the development of new strontium-based anti-osteoporosis drugs, it was essential to document that strontium bile salts are at least as active as SrR and are not cytotoxic. This was the aim of the present preliminary study.