Strontium is an alkaline earth metal that is chemically similar to calcium — it has the same +2 valence, it forms similar salts with the carbonate and the phosphate, and it is incorporated into the bone matrix in place of the calcium during the bone remodelling process. This bone-seeking property of strontium is the basis for its therapeutic use in the treatment of the osteoporosis — when strontium is administered as the strontium ranelate salt (the pharmaceutical form that has been most extensively studied in clinical trials), it is incorporated into the bone matrix and increases the bone density by approximately 1-2% per year (as measured by the DXA scan), and it reduces the fracture risk by approximately 30-40% in postmenopausal women with the established osteoporosis. The mechanism of the strontium effect on the bone involves both the stimulation of the bone formation (by the osteoblasts) and the inhibition of the bone resorption (by the osteoclasts) — making it one of the few therapeutic agents that has a dual effect on the bone turnover and that can therefore increase the bone mass rather than merely preventing the further bone loss. This dual mechanism of action is distinct from the bisphosphonate drugs (which primarily inhibit the bone resorption) and from the parathyroid hormone fragments (which primarily stimulate the bone formation), and it makes the strontium a unique and valuable therapeutic option for the treatment of the osteoporosis.
Strontium and the Bone Density Increase
The strontium ranelate is the pharmaceutical form of strontium that has been most extensively studied in clinical trials — it consists of two strontium atoms (as Sr2+) complexed with the ranelic acid ligand, which enhances the intestinal absorption and the bioavailability of the strontium. The strontium ranelate was approved in the European Union for the treatment of the osteoporosis in 2004, based on the evidence from two large phase III RCTs — the SOTI trial (Spinal Osteoporosis Therapeutic Intervention) and the TROPOS trial (Treatment of Peripheral Osteoporosis) — which together enrolled more than 10,000 postmenopausal women with the osteoporosis and demonstrated that the strontium ranelate at 2g daily reduced the risk of the vertebral fractures by 41% (SOTI) and the risk of the non-vertebral fractures by 14% (TROPOS) compared to placebo. These findings are among the most impressive fracture reduction results achieved by any osteoporosis treatment, and they established the strontium ranelate as one of the most effective therapeutic options for the treatment of the osteoporosis in postmenopausal women.
The mechanism by which strontium increases the bone density involves the incorporation of the strontium into the bone matrix during the bone remodelling process — the strontium atoms are taken up by the osteoblasts and incorporated into the newly forming bone matrix in place of the calcium atoms, and this strontium-substituted bone matrix has a higher mineral density than the normal bone matrix. Additionally, strontium has been shown to stimulate the differentiation and the activity of the osteoblasts (the bone-forming cells) and to inhibit the differentiation and the activity of the osteoclasts (the bone-resorbing cells), through the modulation of the calcium-sensing receptor (CaSR) signalling in these cells. When the strontium binds to the CaSR on the osteoblasts, it stimulates the bone formation, and when it binds to the CaSR on the osteoclasts, it inhibits the bone resorption — this dual effect on the bone remodelling cells explains the unique ability of strontium to increase the bone mass (rather than merely preventing the bone loss) that is not shared by the bisphosphonate drugs or by the other antiresorptive agents.
Strontium and the Fracture Risk Reduction
The fracture risk reduction that is achieved by the strontium ranelate is one of the most important therapeutic outcomes in the management of the osteoporosis — the fractures (particularly the hip fractures and the vertebral fractures) are the most serious complications of the osteoporosis, and they are associated with a high mortality rate (20-30% in the first year after a hip fracture), a high rate of the morbidity (many patients never regain their pre-fracture functional status), and a high cost to the healthcare system. The strontium ranelate has been shown to reduce the hip fracture risk by approximately 36% in the TROPOS trial (in the subgroup of patients who were at highest risk), and this reduction in the hip fracture risk is one of the most impressive outcomes achieved by any osteoporosis treatment. However, it should be noted that the strontium ranelate was withdrawn from the market in the European Union in 2017 (and it has never been approved in the United States by the FDA) because of the concerns about the cardiovascular safety (particularly the increased risk of the myocardial infarction and the venous thromboembolism) that were identified in the post-marketing surveillance data.
Practical Application
For general strontium supplementation (in the absence of the strontium ranelate, which is no longer available as a pharmaceutical product), the evidence-based approach is to supplement with 2-4mg of strontium daily (as the strontium citrate or strontium gluconate form), which is the dose range that has been used in the studies of the strontium supplementation for the bone health. However, it should be noted that the strontium supplements that are available in the market are not the same as the strontium ranelate that was used in the clinical trials, and their efficacy and safety have not been established by rigorous clinical trials. The strontium should not be used as a substitute for the established osteoporosis medications (bisphosphonates, denosumab, teriparatide) without the supervision of a physician who can monitor the bone density, the fracture risk, and the potential adverse effects (including the cardiovascular risk). For comprehensive bone health support, strontium pairs well with the calcium and the vitamin D (which are essential for the bone mineralisation), with the vitamin K2 (which directs the calcium to the bone and away from the soft tissues by activating the osteocalcin and the matrix Gla protein), and with the weight-bearing exercise programme (which is the most effective non-pharmacological intervention for the maintenance of the bone mass).
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