Strontium (Sr) ranelate is composed of two atoms of stable strontium combined with ranelic acid, which acts as carrier and dissociates after ingestion. Unlike other drugs used in the management of osteoporosis, Sr has a dual effect on bone remodelling. It has the ability to stimulate bone formation by osteoblasts, a property shared with bone-forming agents, and can inhibit bone resorption by osteoclasts, as do antiresorptive medications. The precise molecular mechanism is elusive, but, as Sr is a divalent cation, closely resembling calcium in its atomic and ionic properties, it has been hypothesized that Sr could act as an agonist of the extracellular calcium-sensing receptor that is expressed by osteoblasts in all stages of their development and could form the basis of the known anabolic effects of calcium in bone [37, 38].
One of the key elements in the cross-talk between osteoblasts and osteoclasts is the receptor activator of NF-kappaB (RANK) ligand (RANKL) and osteoprotegerin (OPG) system. The OPG–RANKL ratio is decisive for bone resorption, and a decrease in the ratio has been described in osteoporosis associated with the menopause, glucocorticosteroid use and inflammatory diseases (e.g. rheumatoid and hormone therapy for breast and prostate
cancer). Strontium enhances OPG expression and downregulates RANKL expression in rats [39]. Apart from possible interference with the OPG–RANKL system, Sr interferes directly with osteoclasts by inhibiting cell differentiation and enhancing apoptosis [40, 41]. As calcium receptor (CaR) is involved in both osteoclast differentiation and apoptosis, strontium effects on osteoclast may also be CaR mediated. In vivo experiments in animals show increased markers of bone formation, decreased markers of bone resorption, increased bone diameter, enhanced bone mass on dual X-ray absorptiometry (DXA) and improved microarchitecture assessed by histomorphometry [42, 43].
The efficacy of Sr has been assessed in two large multicentre, randomized, double- blind, placebo-controlled trials. The Spinal Osteoporosis Therapeutic Intervention (SOTI) trial studied its effects on the risk of vertebral fracture in 1649 osteoporotic post-menopausal women aged, on average, 70 years [44]. The Treatment of Peripheral Osteoporosis (TROPOS) trial studied the effects on the risk of non-vertebral fractures in 5091 osteoporotic post-menopausal women aged 74 years (or 70 years with one risk factor for fracture) [45]. Sr reduces the risk of new vertebral fracture by 49% at 1 year, 41% at 3 years and 33% over 4 years based on intent-to-treat analysis. Non-vertebral fracture risk was reduced by an average of 15% throughout the 5-year study (RR 0.85, 95% CI 0.73–0.99). A subsequent subgroup analysis on 1977 women aged over 74 years at high risk of hip fracture revealed reduction in risk of hip fracture by 36% (RR 0.64, 95% CI 0.41–0.99) [46]. Although these results were obtained in a post hoc analysis, it is worth remembering that no other trial has been conducted so far versus placebo during 5 years with non-vertebral fracture incidence as an end-point. A preplanned pooling of data from both SOTI and TROPOS trials has demonstrated significant treatment effects in the elderly (women aged 80–100 years). In this subgroup, compared with placebo, Sr reduced the incidence of vertebral fractures by 59% after 1 year and 32% after 3 years. The reduction in non-vertebral fractures was 41% and 31% after 1 and 3 years, respectively. The 2006 Cochrane review included a total of four trials, three of which investigated the effects of Sr in a treatment population and one in a prevention population [47]. In osteoporotic, post-menopausal women a 37% reduction in vertebral fractures (two trials, n = 5082, RR 0.63, 95% CI 0.56–0.71) and a 14% reduction in non-vertebral fractures (two trials, n = 6572, RR 0.86, 95% CI 0.75–0.98) was demonstrated over a 3-year period (Table 13.1). An increase in BMD at all sites was shown. The decrease in fracture rates observed with strontium is of a similar magnitude to that described for oral bisphosphonates and was classified as ‘silver’ evidence. Administration of Sr resulted in increased levels of serum bone alkaline phosphatase (+8.1%) and a decrease in serum telopeptide of type I collagen (–12.2%) from the third month. These changes are moderate, but opposite and concomitant, and support the potential dual action of the drug.
Diarrhoea is a common adverse event, generally seen during the first 3 months of treatment. It was reported in the original trial and subsequently during systematic review (RR 1.38%, 95% CI 1.02–1.87). The trial data showed a slight increase in annual incidence of venous thromboembolism (VTE; 0.9% vs. 0.6%) at 3 years, and remained unchanged since the third year. This excess risk is also seen on systematic review: VTE OR 1.5; 95% CI 1.1–2.1. No underlying potential mechanism has been postulated as there is no known interaction between strontium and parameters of haemostasis. Although regulatory authorities have not considered a history of VTE as a contraindication to the use of the drug, caution should be used in patients at increased risk including those with a past history. During post-marketing surveillance, cases of hypersensitivity syndrome (i.e. drug rash with eosinophila and systemic symptoms [DRESS syndrome]) have been reported. This typically occurs 2–6 weeks after initiating therapy and presents with skin reaction, fever, systemic upset, hypereosinophilia, hepatic abnormality and renal impairment. Because of potential fatal outcome linked to the syndrome, treatment should be discontinued immediately and permanently in case of skin rash developing on the drug.
Strontium ranelate is available as a powder (2-g sachet). Strontium and ranelic acid are both eliminated unchanged, the latter excreted almost exclusively by the gut. The absorption of strontium is reduced by food, milk and dairy products. It should therefore be administered between meals, ideally taken at bedtime, preferably 2 hours after eating. No dosage adjustment is needed in relation to age or in patients with mild-to-moderate renal impairment. It is not recommended in severe renal impairement with creatinine clearance below 30 ml/min.
It is worth knowing that because of greater attenuation of X-rays by strontium, BMD measurements over-estimate actual BMD changes. In clinical practice, increase in BMD probably reflects compliance to therapy and is likely to translate to reduced fracture risk, as the SOTI and TROPOS pooled data analysis showed that the higher the increase in femoral neck BMD the lower the incidence of vertebral fracture. Another question is the persistence of the gain in BMD after stopping treatment. In SOTI, treated patients were randomized at the end of the fourth year to either placebo or Sr for the final year. In those who switched from Sr to placebo, there was a significant decrease in BMD at the spine and hip by 3.2% and 2.5%, respectively. This decrease mimics the observed increase in annual BMD during the first year of treatment; probably reflecting clearance of Sr from the bone and the change in bone remodelling induced by stopping therapy.
Based on existing evidence, Sr has a role where there is a high risk of either vertebral and/ or non-vertebral fracture, especially in the very elderly with high hip fracture risk. Caution needs to be taken in patients at risk of VTE and in the interpretation of bone densitometry measurements. The treating physician should be aware of hypersensitivity to the drug, which, although extremely rare, can be occasionally fatal.