In the SOTI and TROPOS trials, the incidence of adverse events, serious adverse events, and withdrawals due to adverse events was similar in the strontium ranelate and placebo groups [137, 138]. During the first 3 months of treatment, nausea, diarrhea, headache, dermatitis, and eczema were more frequently associated with strontium ranelate compared to placebo, but, thereafter, there was no difference in incidence between strontium

Epoxomicin concentration ranelate and placebo groups concerning nausea and diarrhea. In pooled data from the SOTI and TROPOS trials, there was an apparent increased risk of venous thromboembolism in the strontium ranelate group (0.6% vs. 0.9% per year), although the annual

incidence was similar in the strontium ranelate and placebo groups in the individual trials [122, 129]. A recently published study used the UK General Practice Research Database to assess the risk of several recently reported adverse events linked to the use of strontium ranelate for osteoporosis in postmenopausal women [139]. Age-adjusted rate ratios for venous thromboembolism, gastrointestinal disturbance, BLZ945 manufacturer minor skin complaint, and memory loss were 1.1 (95% CI, 0.2–5.0), 3.0 (95% CI, 2.3–3.8), 2.0 (95% CI, 1.3–3.1), and 1.8 (95% CI, 0.2–14.1), respectively. No cases of ONJ, Stevens–Johnson syndrome, or drug rash with eosinophilia and systemic symptoms were found. Recently, the postmarketing experience of patients treated with strontium ranelate reported cases of the drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome (<20 for 570,000 patient-years of exposure) [138]. This incidence is in the vicinity of what has been previously reported as severe skin reactions, with most of the other currently marketed antiosteoporosis medications. A causative Tryptophan synthase link has not been firmly established, as strontium is a trace element naturally present in the human body, and ranelic acid is

poorly absorbed. Due to the possible fatality linked to this syndrome, however, it seems reasonable to discontinue immediately strontium ranelate and other concomitant treatment known to induce such a syndrome in case of suspicious major skin disorders Nirogacestat in vitro occurring within 2 months of treatment initiation [140] and to introduce adapted treatment and follow-up to avoid systemic symptoms. Anecdotic cases of alopecia were also reported, but no causative link was formally established [141]. Strontium ranelate is not indicated in patients with severe kidney failure (i.e., with creatinine clearance below 30 ml/min). New therapeutic perspectives Blockade of the RANK—RANK ligand (RANKL) pathway The discovery of the OPG—RANK ligand (RANKL)—RANK system has allowed unraveling the mechanisms whereby osteoblastic cells regulate bone resorption.