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Strontium Ranelate: State of the Art

Strontium ranelate is a new antiosteoporotic treatment that has an original mechanism of action on bone turnover. Preclinical studies have shown that strontium ranelate decreases bone resorption and increases bone formation, resulting in an increase in bone mass. In Phase III studies in postmenopausal osteoporotic women, strontium ranelate (2 g/day) reduced the risk of vertebral fracture by 41% (p ≤ 0.001) and the risk of nonvertebral fracture by 16% (p = 0.04) over 3 years. Strontium ranelate safety was considered to be good. Strontium ranelate 2 g/day is a new and effective therapeutic option in postmenopausal osteoporosis.

Strontium ranelate is a new antiosteoporotic treatment that has an original mechanism of action on bone turnover. Preclinical studies have shown that strontium ranelate decreases bone resorption and increases bone formation, resulting in an increase in bone mass. In Phase III studies in postmenopausal osteoporotic women, strontium ranelate (2 g/day) reduced the risk of vertebral fracture by 41% (p ≤ 0.001) and the risk of nonvertebral fracture by 16% (p = 0.04) over 3 years. Strontium ranelate safety was considered to be good. Strontium ranelate 2 g/day is a new and effective therapeutic option in postmenopausal osteoporosis.
Osteoporosis is characterized by an increase in bone fragility due to low bone mass and deterioration of bone architecture, occurring after menopause and during aging, and leading to an increased risk of fractures. The bone loss results from an imbalance between resorption and formation, these two activities being coupled in normal skeleton. Optimal treatment of osteoporosis would increase trabecular and cortical bone mass and decrease the risk of fracture.
Strontium is a bone-seeking element, closely related to calcium. Under experimental conditions strontium ranelate is able to increase bone formation and decrease bone resorption, resulting in an increase in bone mass. In this paper, the mode of action of strontium ranelate, its efficacy, and its safety in postmenopausal osteoporotic patients are reviewed.

Bone formation
Canalis and colleagues studied the effects of strontium ranelate in vitro on rat calvaria bone cells, a model that allows the evaluation of osteoblastic activity [1]. In organ culture, strontium ranelate (10 -3 M) enhances the replication of preosteoblastic cells by 30-50% after 24 h and by 60% after 96 h of treatment. Strontium ranelate (10 -³ M) enhances DNA synthesis by threeto fourfold in preosteoblastic cells. This effect was less consistent with mature osteoblastic cells. Strontium ranelate (10 -³ M) also stimulates the synthesis of collagen and noncollagenic proteins by 35% at 24 h by osteoblasts. The effect was specific for strontium since neither calcium nor sodium salts were able to induce similar effects [1]. Under these experimental conditions, strontium ranelate is able to increase both cell replication and bone formation in vitro.

Bone resorption
Strontium ranelate (1 mM) caused a dosedependent decrease in bone resorption (measured by calcium release) in vitro in mouse calvariae. The addition of calcium had no effect [2]. Strontium ranelate decreases the activity of mouse osteoclasts in organ culture, measured by the pit assay [3]. In a model of differentiated osteoclasts (chicken bone marrow cultures), preincubation bone slices with strontium ranelate induced a dose-dependent inhibition of boneresorbing activity from 32% at 10 -4 M to 66% at 10 -3 M (p < 0.05). A longer incubation (10 -3 M) induces a greater inhibition of bone-resorbing activity (73%, p < 0.05) [3].
In summary, experimental studies show that strontium ranelate decreases the activity of osteoclasts and bone resorption in vitro.

Intact animals
Strontium ranelate is able to increase bone mass in intact animals (mice, rats and monkeys) using high doses and long-term treatments. In intact adult mice, administration of strontium ranelate (200, 600 and 1800 mg/kg/day for 104 weeks) dose-dependently increased the trabecular volume by 25 and 59% in animals treated with strontium ranelate 600 and 1800 mg/kg/day, respectively. Strontium ranelate increased the osteoblastic surface by 131%, decreased the osteoclastic surface (-52%) and decreased the osteoclast number (-30% in females treated with 600 mg/kg/day and -47% in the group treated with 1800 mg/kg/day) [4]. Ammann and colleagues confirmed these results: the 2-year effects of strontium ranelate were studied in intact female rats with different doses of strontium ranelate (0, 225, 450 and 900 mg/kg/day). Strontium ranelate significantly increased the bone mass of the vertebral body (which contains the largest proportion of trabecular bone) and of the femur (which contains mainly cortical bone) in animals receiving the highest dose (900 mg/kg/day). In this study, strontium ranelate improved the bone strength of both the vertebral body and the femur. Total alkalin phosphatase, a marker of bone formation activity, was increased in treated animals [5]. The activity of strontium ranelate has been studied in intact adult monkeys (Macaca fascicularis), treated (100, 275 and 750 mg/kg/day) for 6 months. Bone resorption, assessed by histomorphometric indices, was dose-dependently decreased (-77% for osteoclast number at highest dose tested). In contrast, strontium ranelate increased the histomorphometric indices of bone formation [6].

Animal models of osteoporosis
Ovariectomy and immobilization are two relevant means to obtain an animal model of osteoporosis in rats. In ovariectomized rats, trabecular bone loss induced by estrogen deficiency is due to an increase in bone resorption, which predominates over bone formation. Administration of strontium ranelate (77, 154 and 308 mg/kg/day for 60 days) 3 months after ovariectomy reduces the trabecular bone loss, measured by dual x-ray absorptiometry (DXA), with positive effects on other bone parameters (bone ash weight, bone mineral content and histomorphometric indices) [7]. Trabecular bone volume measured by histomorphometry on the tibial metaphysis is decreased by 46% in ovariectomized rats, corrected by estrogen, and 30-36% higher in animals treated with strontium ranelate than in untreated animals. Histomorphometric and biochemical analyses showed that strontium ranelate decreased bone resorption but not bone formation, indicating that strontium ranelate can have a distinct action on these two activities [7,8].
Skeletal immobilization in adult rats induces trabecular bone loss resulting from an increase in bone resorption associated with a decrease in bone formation. Administration of strontium ranelate (50, 200 and 800 mg/kg/day for 10 days) partially reduced bone loss at the highest dose, as shown by increased bone mineral density (BMD) (4%) and trabecular bone volume (13 and 19% for 200 and 800 mg/kg/day, respectively) compared with untreated immobilized rats. These effects, observed at the highest dose (800 mg/kg/day), were thought to be related to inhibition of bone resorption, as shown by urinary hydroxyproline levels similar as those of non-immobilized control rats, and histomorphometric indices of bone resorption. A significant increase in serum alkaline phosphatase activity was observed (p < 0.05) [9].

Effects of strontium ranelate on bone mineralization
Bone mineralization has been carefully assessed in preclinical studies because of the potential deleterious bone effects of strontium, previously investigated during use in hemodialyzed patients and in a rat model of renal failure. These deleterious effects have been linked to the use of strontium-contaminated dialysis fluid. In the bone tissue of treated animals, strontium ranelate is mainly absorbed onto the crystal surface and substitutes a weak part of the calcium in the hydroxyapatite crystal. Strontium ranelate administered in intact rats at a high dose (800 mg/kg/day) did not modify mineralization, even after 2 years of treatment, as assessed by histomorphometry performed at the proximal tibia. Analysis of the hydroxyapatite crystals formed under treatment with strontium ranelate showed that there was no significant change in the crystal lattice parameters or cohesion properties of the mineral crystals [5]. These results confirmed previous studies in which the degree of mineralization of bone was not modified [10]. Marie and colleagues treated intact mice for 104 weeks with different doses of strontium ranelate (200, 600 and 1800 mg/kg/day) [11]. Over 104 weeks, even at the highest dose (1800 mg/kg/day), strontium ranelate didn't alter bone mineralization. Iliac crest bone biopsies performed at 24, 36 or 48 months in 20 women receiving the therapeutic dose of strontium ranelate 2 g/day in Phase III trials confirmed these results: none of the biopsies showed evidence of osteomalacia or any sign of a primary mineralization defect [12]. These data, associated with the proven efficacy of strontium ranelate in elderly women, are reassuring. Strontium ranelate is not recommended in patients with creatinine clearance below 30 ml/min. Strontium ranelate: state of the art -DRUG EVALUATION

Summary
In vitro and animal studies show that strontium ranelate can stimulate bone formation and decrease bone resorption. There is no experimental evidence that strontium ranelate is associated with alteration of bone mineralization, even after prolonged exposure. The underlying mechanism of action at the cellular level is not yet known; the interaction between strontium and a calcium-sensing receptor is currently being studied [13,14], as small changes in homeostasis parameters, without any clinical consequence, are observed in clinical studies. Whether strontium ranelate is able to dissociate bone formation and bone resorption in osteoporotic patients is unknown. This mechanism is suggested by the results of biochemical markers, but as yet there is no evidence of that from the histomorphometric data in treated patients.

Pharmacokinetic properties of strontium ranelate
Strontium ranelate is made up of 2 atoms of stable strontium and a molecule of ranelic acid. Pharmacokinetic properties have been assessed in young men and healthy postmenopausal women [101]. After an oral dose of strontium ranelate 2 g, the absolute bioavaibility of strontium is 25% (range 19-27%). Maximum concentrations are reached 3 h after administration. Simultaneous intake of food or calcium reduces the bioavailability of strontium ranelate by 60-70%. It is recommended to administer strontium ranelate once a day at bedtime, 2 h after dinner. Food and calcium intake should be avoided just before and after intake of strontium ranelate. There are no data showing that serum strontium levels are useful for monitoring treatment. Strontium ranelate has a strong affinity for bone tissue and in particular for newly formed bone, as determined from biopsies of postmenopausal women with osteoporosis over a period of 2 (STRontium Administration for Treatment of OSteoporosis [STRATOS] study) and 3 years (Phase III population) [12,15]. Bone concentrations do not increase linearly, reaching a plateau after 3 years of treatment. Strontium ranelate and ranelic acid are essentially excreted via the kidneys. There are no pharmacokinetic data in patients with severe renal impairment [101].

Prevention of postmenopausal bone loss
Strontium ranelate was administered to 160 early postmenopausal women (mean age 54 years) during a 24-month, double-blind, placebo-controlled study. Doses of 125, 500 and 1000 mg/day p.o. were compared with placebo; all women received 500 mg of calcium. The mean T-score was -1.4 +/-1.4; 20% of women were lost in follow-up. In the group receiving strontium ranelate 1000 mg/day (n = 40), lumbar BMD significantly increased (5.5 vs -0.75% in the placebo group). The gain of femur BMD was significantly higher (3.2%) in the strontium ranelate group compared to the placebo group (-0.88%) [16]. The percentage of withdrawals due to adverse reactions was similar in the two groups.

Efficacy of strontium ranelate in the treatment of postmenopausal osteoporosis Phase II study
Three doses of strontium ranelate (0.5, 1 and 2 g) were assessed in 353 osteoporotic women during a double-blind, placebo-controlled dose-response study [15]. All patients received calcium (500 mg) and vitamin D, 72 patients received the 2 g (which is the marketed dosing), and 78 patients received the placebo. After 2 years, in the group receiving strontium ranelate 2 g/day, the gain of lumbar BMD was significantly higher compared to placebo (13.6%). The annual increase in lumbar BMD was 7.3%, significantly different from placebo (p < 0.001). There was a significant reduction in the number of patients experiencing new vertebral fracture during the second year in the group receiving 2 g/day (relative risk [RR], 0.56; 95% confidence interval [CI], 0.35-0.89). The safety was comparable for patients receiving placebo and for those receiving strontium ranelate 2 g/day [15]. The study demonstrates a large increase in BMD during strontium ranelate treatment. Part of this increase might be a consequence of the anabolic effect of the treatment. But this change can also be explained by the artifactual change induced by strontium ranelate itself, the atomic number of strontium being higher than that of calcium (Z = 38 vs Z = 20). Any metal with an atomic number higher than that of Ca will influence bone density measurements. Strontium ranelate attenuates x-rays more than calcium does. This may lead to an overestimation of BMD measured by DXA, which is proportional to the strontium content. Formulae have been derived to correct the artificial elevation observed for the spine, but not for the hip [17]. According to these estimates, the artifactual part may account for 50% of the BMD change at 3 years. These formulae are not relevant in clinical practice and only the measured BMD should be used.

Phase III studies
The efficacy of strontium ranelate (2 g/day) has been assessed in two multicenter, randomized, double-blind, placebo-controlled trials, scheduled to last for 5 years. The Spinal Osteoporosis Therapeutic Intervention (SOTI) trial studied the effects of strontium ranelate on the risk of vertebral fractures. The Treatment of Peripheral Osteoporosis (TROPOS) trial studied the effect of strontium ranelate on the risk of nonvertebral fractures. These studies were preceded by a short run-in trial called FIRST (Fracture International Run-in Strontium ranelate Trial), aimed at obtaining the normalisation of the calcium/vitamin D status. More than 9000 patients participated in FIRST, and 6540 were followed in the 3-year Phase III trials. The analysis was performed with the intention-to-treat (ITT) population.

SOTI study
The SOTI trial included 1649 postmenopausal women aged on average 70 years with osteoporosis, defined by a T-score of -2.5 or more and/or at least one prevalent vertebral fracture (this last criterion being present in 87.5% of included patients).
The primary efficacy analysis was the incidence of patients with new vertebral fracture after 36 months. Strontium ranelate reduced the risk of a new vertebral fracture by 49% over 1 year, compared with placebo (RR, 0.51; 95% CI, 0.36-0.74; p ≤ 0.001). The benefit over 3 years of strontium ranelate was a reduction of 41% (RR, 0.59; 95% CI, 0.48-0.73; p ≤ 0.001) [12]. The incidence of vertebral fractures at 3 years was 32.8% in the placebo group. This high incidence is linked to the characteristics of the included patients, who were at high risk of fracture (baseline spine T-score = -3.6 and 2.2 vertebral fractures on average). The risk of clinical vertebral fracture was reduced by 52% after 1 year of treatment (RR, 0.48; 95% CI, 0.29-0.80; p = 0.003) and by 38% after 3 years, as compared with the placebo group (RR, 0.62; 95% CI, 0.47-0.83; p ≤ 0.001). The number of patients that need to be treated during 3 years to prevent one vertebral fracture was nine (95% CI, [6][7][8][9][10][11][12][13][14]. There was no decrease in the risk of peripheral fractures (RR, 0.90, 95% CI 0.69-1.17) in the SOTI trial. At 3 years, the lumbar spine BMD had increased in the patients treated with strontium ranelate compared with the placebo group (12.7 vs -1.3%, p ≤ 0.001). The gain of femur BMD was also significant (8.3% compared with the placebo group, p < 0.001). Administration of strontium ranelate (2 g/day) resulted in an increase in levels of serum bone alkaline phosphatase compared with the placebo group from the third month (8.1%, p < 0.001), and this difference persisted at each assessment during 3 years, while the serum telopeptide of Type I collagen decreased from the third month (-12.2% of treatment related difference, p < 0.001) with concentrations that were 5% below baseline values at 2 years. The changes are modest, as compared with the changes reported with antiresorptive therapies, but are in parallel with the experimental data [12].

TROPOS study
Efficacy on nonvertebral fractures has been evaluated in the TROPOS trial, which included 5091 osteoporotic postmenopausal women aged 74 years (or 70 years with one additional risk factor of osteoporotic fracture) [18]. The primary efficacy analysis was incidence of patients with at least one osteoporotic peripheral fracture over time.
The TROPOS study showed a significant reduction in the risk of nonvertebral fractures (16%, p = 0.04), (RR, 0.84; 95% CI, 0.702-0.995) in the group treated with strontium ranelate over the 3-year study, compared with placebo. The RR was reduced by 19% for major fragility fractures (hip, wrist, pelvis and sacrum, ribs and sternum, clavicle, and humerus) (p = 0.031) in strontium-ranelate-treated patients, compared with the placebo group. In the whole population, there was no effect on the risk of hip fractures (RR, 0.85; 95% CI, 0.61-1.19; p = 0.33) [18]. An a posteriori analysis was performed on a subgroup of patients (n = 1977) at high risk of hip fracture (age ≥74 years and T-score ≤-3, corresponding to T-score < -2.4, according to National Health And Nutrition Examination Study [NHANES] reference). Over 3 years of treatment, strontium ranelate reduced the risk of hip fracture in this subgroup by 36% compared with the placebo group (RR, 0.64; 95% CI, 0.412-0.997; p = 0.046) [18]. The efficacy of strontium ranelate in reducing the risk of vertebral fracture (secondary efficacy end point) was confirmed in this study, with a reduction in risk of 39% (RR, 0.61; 95% CI, 0.51-0.73; p ≤ 0.001) over 3 years in the 3640 patients with available x-rays.
Strontium ranelate: state of the art -DRUG EVALUATION At 3 years, the BMD in the strontium ranelate group had increased from baseline by 5.7% at the femoral neck and 7.1% at the total hip (p ≤ 0.001), as compared with the placebo group.

Integrated analysis of efficacy
A preplanned pooled analysis of SOTI and TROPOS has been performed, including 6551 patients (3295 receiving strontium ranelate) [101]. The integrated analysis of efficacy (IAE) was an opportunity to check for antifracture efficacy of strontium ranelate in elderly patients, a population in whom the risk of fracture is very high. In 443 patients over 80 years old, strontium ranelate reduces the incidence of vertebral fracture by 32% over 3 years. There was no data on hip fracture risk in this subgroup analysis.
In patients with baseline lumbar and/or femoral BMD in the osteopenic range without prevalent vertebral fracture (n = 176), strontium ranelate reduces the risk of a first vertebral fracture by 72% over 3 years.

Safety
In the Phase III SOTI study, tolerability was similar in the strontium ranelate and placebo groups. The most common adverse events consisted of nausea and diarrhea (6.1 vs 3.6% in the placebo group). The difference between the two groups disappeared after the first 3 months [12]. In the TROPOS study, conducted in women of 77 years old on average, nausea (7.2 vs 4.4%), diarrhea (6.7 vs 5.0%), headache (3.4 vs 2.4%) and dermatitis and eczema (5.5 vs 4.1%) were reported more commonly in the strontium ranelate group, but, again, only during the first 3 months of treatment, with no difference for gastrointestinal disorders between groups afterwards [18]. As antiosteoporotic drugs are administered to a large number of women, it is important to check for adverse events in the largest population as possible in Phase III studies. That is why the safety data to be considered are from the pooled SOTI and TROPOS data (IAE). For adverse events having an incidence higher than 2%, only nausea and diarrhea were different between strontium ranelate and placebo. There was a small and transient rise in serum creatine phosphokinase concentration, which had no clinical consequence during the studies [101]. An increase in venous thromboembolism (RR, 1.5, 95% CI, 1.1-2.1) was observed over 3 years in the strontium ranelate group (0.9%), in comparison with the placebo group (0.6%). For pulmonary embolism, the excess risk was similar between groups (RR, 1.7, 95% CI, 1.0-3.1). In women aged 80 years or over, the tolerability profile of strontium ranelate was comparable to that of the whole population, although pulmonary embolism, thrombosis and stenosis were reported by 12 patients the in strontium ranelate group versus 3 in the placebo group [101]. Nervous system disorders had a very low incidence, and were reported with higher frequency in patients treated with strontium ranelate, compared with placebo: disturbances in consciousness (2.5 vs 2.0%), seizures (0.3 vs 0.1%), and memory loss (2.4 vs 1.9%) [101]. There is no underlying mechanism linked to metabolism of strontium ranelate to explain these observations.

Expert commentary
Strontium ranelate is a new antiosteoporotic treatment with an original mechanism of action. Experimental studies showed a dual mechanism of action, increasing bone formation and decreasing bone resorption. The efficacy of strontium ranelate in the treatment of postmenopausal osteoporosis is based on a 36-month analysis of two large placebo-controlled trials in postmenopausal osteoporotic women. Strontium ranelate (2 g/day) reduces the risk of vertebral fractures by 40-50% (primary end point of SOTI study) and the risk of nonvertebral fractures by 16% (primary end point of TROPOS study). Benefit for hip fracture has been shown in a post hoc analysis of a subpopulation of TROPOS (age > 74 years, T-score ≤ -3). The safety of strontium ranelate has been studied in a large population of elderly and very elderly women and is considered as good. Nausea and diarrhea may occur at the beginning of treatment, without serious gastrointestinal events. However, the excess of venous thromboembolism events requires a targeted surveillance, especially in case of previous history of venous thromboembolism and in older women. No mechanism has been elucidated for these events and further surveillance is necessary. There are no data on the association of strontium ranelate with other antiosteoporotic drugs, and the efficacy of strontium ranelate in patients previously treated with antiresorptive therapies is unknown.
Five-year data from the SOTI and TROPOS trials will be available soon. It is expected that these data will confirm the antivertebral and antiperipheral fracture efficacy of strontium ranelate, and clarify the safety data.

Conclusion
Strontium ranelate is a new option in the treatment of postmenopausal osteoporosis. The clinical benefit is underpinned by experimental data showing increased bone formation and decreased bone resorption. Strontium ranelate (2 g/day) reduces both the risk of vertebral fracture over 1 and 3 years (with a similar magnitude to that demonstrated for the other antiosteoporotic treatments), and the risk of nonvertebral fracture. Strontium ranelate safety is good but caution must be used in patients at increased risk of venous thromboembolism.

Executive summary
• Strontium ranelate is a new antiosteoporotic treatment that has, under experimental conditions, an original mechanism of action, increasing bone formation and decreasing bone resorption. • Strontium ranelate (2 g/day) reduces the risk of vertebral fractures by 40-50% (SOTI study) over 1 and 3 years in osteoporotic postmenopausal women. • Strontium ranelate (2 g/day) decreases the risk of nonvertebral fractures by 16% (TROPOS study). • Strontium ranelate safety is good but the excess of venous thromboembolism events requires a targeted surveillance, and precautions for use in patients at increased risk of venous thromboembolism. • Long-term data (5 and 7 years) are expected to confirm the antifracture efficacy and the safety of long-term treatment with strontium ranelate. • Efficacy of strontium ranelate in association with or after antiresorptive treatment should be studied.

Bibliography
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