Strontium ranelate—Data on vertebral and nonvertebral fracture efficacy and safety: Mechanism of action

Strontium ranelate is a novel therapy for the treatment of postmenopausal osteoporosis with actions to reduce bone resorption and increase bone formation. In vitro, strontium ranelate has anabolic and antiresorptive activity, increasing collagen and non-collagen protein synthesis, enhancing pre-osteoblast differentiation, inhibiting osteoclast differentiation, and reducing osteoclast function. In animal models, the increase in bone density is closely correlated with increases in biomechanical bone strength. Histomorphometry demonstrates reduced osteoclast surfaces with increased bone formation. Clinical trials in postmenopausal women have demonstrated 3-year fracture efficacy. Reductions in vertebral fracture were seen in patients with and without prevalent vertebral fracture. Nonvertebral fractures were also significantly reduced. In a subgroup of patients at high risk for hip fracture, there was a significant reduction in hip fracture risk. Strontium ranelate is well tolerated with nausea, diarrhea, headache, and dermatitis more frequent in treated patients only for the first 3 months of therapy. Together, these data suggest that strontium ranelate is a well-tolerated and effective therapy for postmenopausal osteoporosis reducing vertebral and nonvertebral fracture by a novel dual antiresorptive and anabolic action on bone.     

Vertebral fracture risk reduction with strontium ranelate in women with postmenopausal osteoporosis is independent of baseline risk factors.

Strontium ranelate (2 g/day) was studied in 5082 postmenopausal women. A reduction in incident vertebral fracture risk by 40% was shown after 3 years. This effect was independent of age, initial BMD, and prevalent vertebral fractures. INTRODUCTION: Strontium ranelate is an orally active treatment able to decrease the risk of vertebral and hip fractures in osteoporotic postmenopausal women. The aim of this study was to assess the efficacy of strontium ranelate according to the main determinants of vertebral fracture risk: age, baseline BMD, prevalent fractures, family history of osteoporosis, baseline BMI, and addiction to smoking. MATERIALS AND METHODS: We pooled data of two large multinational randomized double-blind studies with a population of 5082 (2536 receiving strontium ranelate 2 g/day and 2546 receiving a placebo), 74 years of age on average, and a 3-year follow-up. An intention-to-treat principle was used, as well as a Cox model for comparison and relative risks. RESULTS: The treatment decreased the risk of both vertebral (relative risk [RR] = 0.60 [0.53-0.69] p < 0.001) and nonvertebral (RR = 0.85 [0.74-0.99] p = 0.03) fractures. The decrease in risk of vertebral fractures was 37% (p = 0.003) in women <70 years, 42% (p < 0.001) for those 70-80 years of age, and 32% (p = 0.013) for those > or = 80 years. The RR of vertebral fracture was 0.28 (0.07-0.99) in osteopenic and 0.61 (0.53-0.70) in osteoporotic women, and baseline BMD was not a determinant of efficacy. The incidence of vertebral fractures in the placebo group increased with the number of prevalent vertebral fractures, but this was not a determinant of the effect of strontium ranelate. In 2605 patients, the risk of experiencing a first vertebral fracture was reduced by 48% (p < 0.001). The risk of experiencing a second vertebral fracture was reduced by 45% (p < 0.001; 1100 patients). Moreover, the risk of experiencing more than two vertebral fractures was reduced by 33% (p < 0.001; 1365 patients). Family history of osteoporosis, baseline BMI, and addiction to smoking were not determinants of efficacy. CONCLUSIONS: This study shows that a 3-year treatment with strontium ranelate leads to antivertebral fracture efficacy in postmenopausal women independently of baseline osteoporotic risk factors.     

Effects of long-term strontium ranelate treatment on vertebral fracture risk in postmenopausal women with osteoporosis

Summary

Vertebral fractures are a major adverse consequence of osteoporosis. In a large placebo-controlled trial in postmenopausal women with osteoporosis, strontium ranelate reduced vertebral fracture risk by 33% over 4 years, confirming the role of strontium ranelate as an effective long-term treatment in osteoporosis.

Introduction

Osteoporotic vertebral fractures are associated with increased mortality, morbidity, and loss of quality-of-life (QoL). Strontium ranelate (2 g/day) was shown to prevent bone loss, increase bone strength, and reduce vertebral and peripheral fractures. The preplanned aim of this study was to evaluate long-term efficacy and safety of strontium ranelate.

Methods

A total of 1,649 postmenopausal osteoporotic women were randomized to strontium ranelate or placebo for 4 years, followed by a 1-year treatment-switch period for half of the patients. Primary efficacy criterion was incidence of patients with new vertebral fractures over 4 years. Lumbar bone mineral density (BMD) and QoL were also evaluated.

Results

Over 4 years, risk of vertebral fracture was reduced by 33% with strontium ranelate (risk reduction?=?0.67, p?<?0.001). Among patients with two or more prevalent vertebral fractures, risk reduction was 36% (p?<?0.001). QoL, assessed by the QUALIOST®, was significantly better (p?=?0.025), and patients without back pain were greater (p?=?0.005) with strontium ranelate than placebo over 4 years. Lumbar BMD increased over 5 years in patients who continued with strontium ranelate, while it decreased in patients who switched to placebo. Emergent adverse events were similar between groups.

Conclusion

In this 4- and 5-year study, strontium ranelate is an effective and safe treatment for long-term treatment of osteoporosis in postmenopausal women.     

A review of strontium ranelate and its effect on DXA scans.

Strontium ranelate is a new orally administered agent for the treatment of women with postmenopausal osteoporosis that reduces the risk of vertebral and nonvertebral fractures. This review article examines the evidence for the antifracture efficacy and safety of strontium ranelate treatment and discusses the effect of DXA scans, biochemical markers of bone turnover, and bone histology. In the SOTI trial, three years treatment with strontium ranelate led to a 41% reduction in vertebral fracture risk (relative risk [RR]=0.59; 95% CI: 0.48-0.73; p<0.001), while in the TROPOS study there was a 16% reduction in nonvertebral fractures (RR=0.84; 95% CI 0.702-0.995; p=0.04). Compared with alternative osteoporosis therapies, strontium ranelate treated patients show large increases in BMD coupled with comparatively modest changes in biochemical markers of bone turnover and bone histology. While the large BMD changes provide a useful way of monitoring patients' response to treatment, it is important to appreciate that much of the increase is a purely physical effect due to the increased attenuation of X-ray when some of the calcium in bone is replaced by strontium. Strontium ranelate is a useful addition to the range of antifracture treatments available for treating postmenopausal women with osteoporosis and is the only treatment proven to be effective at preventing both vertebral and nonvertebral fractures in women aged 80 yr and older.     

Dual effect of strontium ranelate: stimulation of osteoblast differentiation and inhibition of osteoclast formation and resorption in vitro

Strontium ranelate is a newly developed drug that has been shown to significantly reduce the risk of vertebral and non-vertebral fractures, including those of the hip, in postmenopausal women with osteoporosis. In contrast to other available treatments for osteoporosis, strontium ranelate increases bone formation and decreases resorption. In this study, the dual mode of action of strontium ranelate in bone was tested in vitro, on primary murine osteoblasts and osteoclasts derived from calvaria and spleen cells, respectively. We show that strontium ranelate treatment, either continuously or during proliferation or differentiation phases of mouse calvaria cells, stimulates osteoblast formation. Indeed after 22 days of continuous treatment with strontium ranelate, the expression of the osteoblast markers ALP, BSP and OCN was increased, and was combined with an increase in bone nodule numbers. On the other hand, the number of mature osteoclasts strongly decreased after strontium ranelate treatment. Similarly to previous studies, we confirm that osteoclasts resorbing activity was also reduced but we found that strontium ranelate treatment was associated with a disruption of the osteoclast actin-containing sealing zone. Therefore, our in vitro assays performed on primary murine bone cells confirmed the dual action of strontium ranelate in vivo as an anabolic agent on bone remodeling. It stimulates bone formation through its positive action on osteoblast differentiation and function, and decreases osteoclast differentiation as well as function by disrupting actin cytoskeleton organization.     

Maintenance of antifracture efficacy over 10?years with strontium ranelate in postmenopausal osteoporosis

Summary

In an open-label extension study, BMD increased continuously with strontium ranelate over 10?years in osteoporotic women (P?P?Introduction Strontium ranelate has proven efficacy against vertebral and nonvertebral fractures, including hip, over 5?years in postmenopausal osteoporosis. We explored long-term efficacy and safety of strontium ranelate over 10?years.

Methods

Postmenopausal osteoporotic women participating in the double-blind, placebo-controlled phase 3 studies SOTI and TROPOS to 5?years were invited to enter a 5-year open-label extension, during which they received strontium ranelate 2?g/day (n?=?237, 10-year population). Bone mineral density (BMD) and fracture incidence were recorded, and FRAX? scores were calculated. The effect of strontium ranelate on fracture incidence was evaluated by comparison with a FRAX?-matched placebo group identified in the TROPOS placebo arm.

Results

The patients in the 10-year population had baseline characteristics comparable to those of the total SOTI/TROPOS population. Over 10?years, lumbar BMD increased continuously and significantly (P?P?Conclusions Long-term treatment with strontium ranelate is associated with sustained increases in BMD over 10?years, with a good safety profile. Our results also support the maintenance of antifracture efficacy over 10?years with strontium ranelate.     

Monitoring strontium ranelate therapy in patients with osteoporosis

Purpose  The purpose of this study was to review the monitoring of strontium ranelate osteoporosis therapy. Methods  The method used in this study was comprehensive literature review with clinical perspectives. Results  Changes in bone turnover markers (BTM) or bone mineral density (BMD) have been documented in osteoporosis clinical trials. However, neither BMD nor BTM changes fully explain the observed fracture risk reduction in treated patients. If changes in BMD or BTM on therapy would be easily discernable in individual patients, and were strongly associated with fracture risk reduction, monitoring individuals would be more useful. BMD changes in patients on strontium ranelate are of a greater magnitude and hence can be easily determined in an individual patient. In addition, there exists a better correlation between fracture risk reduction and increases in BMD. Conclusions  The strong correlation between measured BMD increases and fracture risk reduction in patients on strontium ranelate therapy will be of clinical benefit to physicians wishing to evaluate both treatment persistence and fracture risk reduction.     

Cost-effectiveness of strontium ranelate in the treatment of male osteoporosis

Summary

The results of this study suggest that, under the assumption of same relative risk reduction of fractures in men as for women, strontium ranelate could be considered a cost-effective strategy compared with no treatment for the treatment of osteoporotic men from a Belgian healthcare payer perspective.

Introduction

This study was conducted to estimate the cost-effectiveness of strontium ranelate in the treatment of osteoporotic men.

Methods

A previously validated Markov microsimulation model was adapted to estimate the cost (€2,010) per quality-adjusted life-year (QALY) gained of strontium ranelate compared with no treatment. Similar efficacy data on lumbar spine and femoral neck bone mineral density (BMD) between men with osteoporosis at high risk of fracture (MALEO Trial) and postmenopausal osteoporotic women (pivotal SOTI, TROPOS trials) supports the assumption, in the base-case analysis, of the same relative risk reduction of fractures in men as for women. Analyses were conducted, from a Belgian healthcare payer perspective, in the population from the MALEO Trial who is a men population with a mean age of 73 years, and BMD T-score ≤?2.5 or prevalent vertebral fracture (PVF).

Results

In the MALEO population, strontium ranelate compared with no treatment was estimated at €49,798 and €25,584 per QALY gained using efficacy data from the intent-to-treat analysis and the per-protocol analysis including only adherent patients, respectively. In men with a BMD T-score ≤?2.5 or with PVF, the cost per QALY gained of strontium ranelate fall below thresholds of €45,000 and €25,000 per QALY gained based on efficacy data from the entire population of the clinical trial and from the per-protocol analyses, respectively.

Conclusions

The results of this study suggest that, under the assumption of same relative risk reduction of fractures in men as for women, strontium ranelate could be considered cost-effective compared with no treatment for male osteoporosis.     

Strontium ranelate: New data on fracture prevention and mechanisms of action

Osteoporosis treatments need to combine an unequivocally demonstrated reduction of fractures, at various skeletal sites, long-term safety, and a user-friendly profile that optimizes therapeutic adherence. Strontium ranelate is the first compound to simultaneously decrease bone resorption and stimulate bone formation. Its anti-fracture efficacy at various skeletal sites has been established for as long as 5 years through studies of the highest methodological standards. Increases in bone mineral density observed after 1 year of treatment are predictive of the long-term fracture efficacy, suggesting for the first time in osteoporosis that bone densitometry can be used as a monitoring tool. Due to a positive risk/benefit ratio, strontium ranelate is now considered as a first-line treatment in the management of osteoporosis.     

The cost-effectiveness of strontium ranelate in the UK for the management of osteoporosis

Summary

The cost-effectiveness of strontium ranelate was compared to no treatment in UK women using the FRAX® algorithm for fracture risk assessment. At a willingness-to-pay of £30,000 per quality-adjusted life-year (QALY), strontium ranelate was generally cost-effective in women with prior fracture at the threshold of osteoporosis from an age of 65 years.

Introduction

The objectives of the study were to estimate the cost-effectiveness of strontium ranelate in the UK for the treatment of osteoporosis and to establish intervention thresholds for treatment using the FRAX® tool.

Methods

The cost-effectiveness of strontium ranelate was compared to no treatment in postmenopausal women with clinical risk factors for fracture using a lifetime simulation model based on Markov cohort methodology that incorporated the features of FRAX®.

Results

At a threshold of £30,000 per QALY, strontium ranelate was generally cost-effective in women from an age of 65 years with prior fracture at the threshold of osteoporosis (i.e., a T-score of ?2.5 SD) and in women with a prior fracture (and no information on bone mineral density) from the age of 65 years. At a threshold of £20,000, strontium ranelate became cost-effective at a 10-year fracture probability of 25.7% and at 16.9% with a threshold of £30,000 for a QALY.

Conclusions

Strontium ranelate is a cost-effective agent for the treatment of established osteoporosis in women over the age of 65 years. Cost-effective scenarios were also found for the prevention and treatment of fractures associated with osteoporosis, in younger women with additional clinical risk factors.     

Strontium Ranelate Reduces the Risk of Vertebral Fractures in Patients With Osteopenia

Many fractures occur in women with moderate fracture risk caused by osteopenia. Strontium ranelate was studied in 1431 postmenopausal women with osteopenia. Vertebral fracture risk reduction of 41–59% was shown depending on the site and fracture status at baseline. This is the first report of antivertebral fracture efficacy in women with vertebral osteopenia. Introduction: Women with osteoporosis are at high risk for fracture. However, more than one half of all fractures in the community originate from the larger population at more moderate risk of fracture caused by osteopenia. Despite this, evidence for antifracture efficacy in these persons is limited. The aim of this study was to determine whether strontium ranelate, a new drug that reduces fracture risk in women with osteoporosis, is also effective in women with osteopenia. Materials and Methods: Data from the Spinal Osteoporosis Therapeutic Intervention study (SOTI; n = 1649) and the TReatment Of Peripheral OSteoporosis (TROPOS; n = 5091) were pooled to evaluate the antivertebral fracture efficacy of strontium ranelate in women with lumbar spine (LS) osteopenia with any BMD value at the femoral neck (FN; N = 1166) and in 265 women with osteopenia at both sites (intention‐to‐treat analysis). The women were randomized to strontium ranelate 2 g/d orally or placebo for 3 yr. Results: No group differences were present in baseline characteristics that may influence fracture outcome independent of therapy. In women with LS osteopenia, treatment reduced the risk of vertebral fracture by 41% (RR = 0.59; 95% CI, 0.43–0.82), by 59% (RR = 0.41; 95% CI, 0.17–0.99) in the 447 patients with no prevalent fractures, and by 38% (RR = 0.62; 95% CI, 0.44–0.88) in the 719 patients with prevalent fractures. In women with osteopenia at both sites, treatment reduced the risk of fracture by 52% (RR = 0.48; 95% CI, 0.24–0.96). Conclusions: Strontium ranelate safely reduces the risk of vertebral fractures in women with osteopenia with or without a prevalent fracture.     

Results of indirect and mixed treatment comparison of fracture efficacy for osteoporosis treatments: a meta-analysis

Summary

Network meta-analysis techniques (meta-analysis, adjusted indirect comparison, and mixed treatment comparison [MTC]) allow for treatment comparisons in the absence of head-to-head trials. In this study, conditional estimates of relative treatment efficacy derived through these techniques show important differences in the fracture risk reduction profiles of marketed pharmacologic therapies for postmenopausal osteoporosis.

Introduction

This study illustrates how network meta-analysis techniques (meta-analysis, adjusted indirect comparison, and MTC) can provide comparisons of the relative efficacy of postmenopausal osteoporosis therapies in the absence of comprehensive head-to-head trials.

Methods

Source articles were identified in MEDLINE; EMBASE; Cochrane Central Register of Controlled Trials (CENTRAL) via Wiley Interscience; and Cumulative Index to Nursing and Allied Health Literature (CINAHL) between April 28, 2009 and November 4, 2009. Two reviewers identified English-language articles reporting randomized controlled trials (RCTs) with on-label dosing of marketed osteoporosis agents and fracture endpoints. Trial design, population characteristics, intervention and comparator, fracture outcomes, and adverse events were abstracted for analysis. Primary analyses included data from RCTs with fracture endpoints. Sensitivity analyses also included studies with fractures reported through adverse event reports. Meta-analysis compared fracture outcomes for pharmacological therapies vs. placebo (fixed and random effects models); adjusted indirect comparisons and MTC assessed fracture risk in postmenopausal women treated with denosumab vs. other agents.

Results

Using data from 34 studies, random effects meta-analysis showed that all agents except etidronate significantly reduced the risk of new vertebral fractures compared with placebo; denosumab, risedronate, and zoledronic acid significantly reduced the risk for nonvertebral and hip fracture, while alendronate, strontium ranelate, and teriparatide significantly reduced the risk for nonvertebral fractures. MTC showed denosumab to be more effective than strontium ranelate, raloxifene, alendronate, and risedronate in preventing new vertebral fractures.

Conclusions

The conditional estimates of relative treatment efficacy indicate that there are important differences in fracture risk reduction profiles for marketed pharmacological therapies for postmenopausal osteoporosis.     

Strontium ranelate treatment improves trabecular and cortical intrinsic bone tissue quality, a determinant of bone strength.

Beside its influence on determinants of bone strength (geometry, microarchitecture), which is likely to be related to a cellular effect, strontium ranelate improves bone tissue quality as evaluated by nanoindentation, increasing elastic modulus, hardness, and dissipated energy in vertebrae of rats treated for 104 wk with daily dose from 0 to 900 mg/kg. INTRODUCTION: We previously showed that strontium ranelate treatment improves the mechanical properties of the vertebral body and long bone midshaft in intact rats. The increased energy to failure obtained with strontium ranelate is essentially caused by an increase in plastic energy, suggesting that bone formed during treatment can withstand greater deformation before fracture. In the bone mineral phase, strontium is mainly located in the hydrated shell and could thus potentially influence intrinsic bone tissue quality. MATERIALS AND METHODS: To study whether strontium ranelate treatment could positively influence intrinsic bone tissue quality (elastic modulus, hardness, and dissipated energy), nanoindentation tests were performed at the level of trabecular nodes and cortex under physiological or dry conditions in vertebrae of rats treated for 104 wk with strontium ranelate at a daily dose of 0, 225, 450, or 900 mg/kg (n = 12 per group). Ex vivo microCT measurements and axial compression tests of adjacent vertebral bodies were also performed. Significance of difference was evaluated using ANOVA. RESULTS: In agreement with previous results, strontium ranelate (900 mg/kg/d) [corrected] increased versus controls in maximal load (+23%), total energy (+71%), and plastic energy (+143%). At the level of trabecular bone, strontium ranelate treatment resulted in a significant increase in elastic modulus (+15.1%, p < 0.01), hardness (+11.5%, p < 0.05), and dissipated energy (+16.2%, p < 0.001) versus controls in physiological, but not in dry, conditions. The effect was less pronounced in cortex. CONCLUSIONS: These results show for the first time a direct action of strontium ranelate on bone tissue quality. Beside its shown influence on classical determinants of bone strength (geometry, microarchitecture), which is likely to be related to a cellular effect, strontium ranelate improves bone tissue quality. This could contribute to the increase in bone strength and thus be involved in the reduction of fracture risk in postmenopausal osteoporotic patients treated with strontium ranelate.     

Increased bone strength is associated with improved bone microarchitecture in intact female rats treated with strontium ranelate: a finite element analysis study

Strontium ranelate has been previously shown to act on bone metabolism and to be effective in postmenopausal osteoporosis treatment by preventing vertebral and non-vertebral fractures. Animal studies explicitly demonstrated that bone strength was improved with strontium ranelate treatment, but the contribution of either improved bone microarchitecture or intrinsic quality of the bone tissue is not clear. Therefore, the purpose of this research was to address this issue by using the unique capability of finite element (FE) analysis to integrate both intrinsic bone quality properties from nano-indentation and microarchitecture measured by micro-computed tomography (μCT). The two groups included intact female Fischer rats fed a normal diet (controls, N=12) or a diet containing strontium ranelate (900mg/kg/day; N=12) for a period of 104weeks. The L(5) vertebra was scanned by μCT and a morphological analysis of the vertebral body was performed. Subsequently, those μCT data were the basis of FE models with added virtual endcaps that simulated axial compression tests. The FE models were solved with the vertebral bodies only and repeated with the vertebral processes intact. In the initial stages, the intrinsic bone properties were kept constant between the control and the treated animals in order to independently study the impact of microarchitectural changes on bone strength. Morphological data indicated a significant improvement in bone microarchitecture associated with strontium ranelate compared to controls, including a 40% (p<0.01) higher trabecular thickness, a 28% (p<0.01) higher cortical thickness, and no significant change in the number of trabeculae (p=0.56). The poor correlation of bone strontium content against bone volume fraction (BV/TV) (R(2)=0.013, p=0.74) and BMD (R(2)=0.153, p=0.23) indicated that the morphological data were not biased by the presence of strontium in bone. The FE simulations demonstrated a 22% (p<0.01) increase of stiffness and 29% (p<0.01) increase in strength compared to controls. The magnitudes were greater, but the relative differences were similar when the entire intact vertebra was modeled compared to the vertebral body alone. Adjusting the FE models to account for differences in intrinsic bone tissue quality between control and treated animals resulted in an even higher bone strength with strontium ranelate. Furthermore, load transfer in strontium ranelate treated animals shifted from an equal distribution between cortical and trabecular compartments to more load being supported by the trabecular bone (a shift of 8%, p<0.02). Tissue-level stresses were reduced on average (-7%, p<0.01) and more homogeneously distributed. Together, these findings indicated that, independently from bone strontium content, microarchitectural adaptations played a major role in the increased bone strength associated with strontium ranelate exposure and that the changes in load distribution resulted in patterns that were more favorable to resisting fracture.     

Prospective assessment of thoracic kyphosis in postmenopausal women with osteoporosis

We attempt to assess quantitatively thoracic kyphosis and its influence on incident fractures and quality of life over three years in postmenopausal women with osteoporosis and the effect of strontium ranelate on thoracic kyphosis progression. This study was performed on women with postmenopausal osteoporosis from the Spinal Osteoporosis Therapeutic Intervention (SOTI) and Treatment of Peripheral Osteoporosis (TROPOS) studies. Vertebral fractures were assessed on lateral thoracic radiographs performed at baseline and at three years according to standardized procedure. Kyphosis index (KI, %), was defined as the percentage ratio between the maximum depth of thoracic curvature and the height measured from the T4 to the T12 vertebrae. Baseline characteristics of the 3218 patients (1594 strontium ranelate, 1624 placebo) were mean age 73.3 years, spine bone mineral density (BMD) T‐score (L2–4) ?3.1, femoral neck T‐score ?3.0, and KI 25.4%. In the placebo group, patients with the highest baseline KI experienced significantly more vertebral fractures than those with medium KIs [relative risk (RR) = 1.53; 95% confidence interval (CI) 1.19–1.96, p < .001) or the lowest KIs (RR = 1.70, 95%CI 1.32–2.21, p < .001), even after adjusting for the presence of prevalent fractures, age, body mass index (BMI), and BMD. There was no difference in the risk of nonvertebral fractures according to baseline KI. Three‐year changes in quality‐of‐life physical scores reflected significantly better status for patients in the lowest tertile of KI compared with those in the highest at baseline. Over three years, the KI increased for all patients, indicating worsening of thoracic kyphosis, whatever the presence of prevalent or incident vertebral fractures. This KI progression was lower in the strontium ranelate group than in the placebo group. Thoracic kyphosis is a risk factor for vertebral fractures over three years and influences physical capacity changes in postmenopausal women with osteoporosis. Thoracic kyphosis progression over three years is lower in a subgroup of strontium ranelate–treated patients compared with placebo‐treated patients. © 2010 American Society for Bone and Mineral Research     

Strontium ranelate inhibits bone resorption while maintaining bone formation in alveolar bone in monkeys (Macaca fascicularis)

Strontium ranelate (S12911) has previously been shown to stimulate bone formation and inhibit bone resorption in rats. To determine whether strontium ranelate affects normal bone remodeling, we studied the effect of strontium ranelate on alveolar bone in monkeys. Strontium ranelate, at dosages of 100, 275, and 750 mg/kg per day, or vehicle, were given by gavage to 31 normal adult monkeys (Macaca fascicularis) (15 males, 16 females), aged 3-4 years. Treatment for 6 months with strontium ranelate resulted in an increase in plasma strontium concentration. Histomorphometric analyses of indices of bone formation and resorption were determined in standardized areas of alveolar bone. Treatment with strontium ranelate decreased the histomorphometric indices of bone resorption (osteoclast surface and number) with a maximal significant effect at the highest dose tested. In contrast to this inhibitory effect on bone resorption, strontium ranelate maintained bone formation. Although the amount of osteoid tended to increase, strontium ranelate, even at the highest dose, had no deleterious effect on bone mineralization, as evaluated by mineral apposition rate and osteoid thickness. These findings show that strontium ranelate decreases indices of bone resorption while maintaining bone formation in the alveolar bone in monkeys.     

Drug combination strategies for osteoporosis

Several medications are effective in reducing the incidence of osteoporotic fractures. Vertebral and nonvertebral fractures can be reduced by 30-65% by administering anticatabolic agents (e.g. raloxifene, alendronate, and risedronate) or anabolic agents (e.g. the active parathyroid hormone fragment teriparatide and strontium ranelate). These medications were investigated in placebo-controlled randomized trials in vast populations. Study extensions provided information on long-term efficacy and safety. However, the best strategy for using these medications in high-risk individuals remains unclear. For instance, the relative merits of starting with an anabolic agent or on an anticatabolic agent have not been compared. The patient's age, severity of the osteoporosis (bone mineral density and risk factor profile), specific characteristics of each medication, and patient preferences regarding drug-dosing modalities should be considered. Compliance must be evaluated regularly. Whereas minimal treatment durations have been determined, optimal durations remain incompletely evaluated and should be determined on a case-by-case basis according to the severity of the bone disease and to the treatment response in terms of clinical features and bone mineral density. Synchronous and t treatment combinations have been evaluated. Disappointing results were obtained with synchronous parathyroid hormone and bisphosphonate therapy. In contrast, the parathyroid hormone-bisphosphonate sequence holds promise for the treatment of severe postmenopausal osteoporosis with at least two vertebral fractures. However, little is known about potential synergies among medications in terms of fracture risk reduction. Synchronous and sequential regimens have not been compared in randomized clinical trials, and such trials would be extraordinarily difficult to design. Nevertheless, available data allow a number of suggestions regarding treatment strategies. The most important step is deciding to start effective treatment (raloxifene, bisphosphonate, teriparatide, or strontium ranelate) in patients at risk for fractures. Patients should be given detailed information on potential benefits and long-term treatment modalities.     

Strontium ranelate improves bone strength in ovariectomized rat by positively influencing bone resistance determinants

Summary  Treatment of adult ovariectomized (OVX) rats with strontium ranelate prevented vertebral biomechanics degradation as a result of the prevention of bone loss and micro-architecture deterioration associated to an effect on intrinsic bone material quality. Strontium ranelate influenced the determinants of bone strength by prevention of ovariectomy-induced changes which contribute to explain strontium ranelate antifracture efficacy. Introduction  Strontium ranelate effects on the determinants of bone strength in OVX rats were evaluated. Methods  Adult female Sprague–Dawley rats were OVX, then treated daily for 52 weeks with 125, 250, or 625 mg strontium ranelate/kg. Bone strength, mass, micro-architecture, turnover, and intrinsic quality were assessed. Results  Strontium ranelate prevented ovariectomy-induced deterioration in mechanical properties with energy necessary for fracture completely maintained vs. SHAM at 625 mg/kg/day, which corresponds to the clinical dose. This was related to a dose-dependent effect on bone volume, higher trabeculae number, and lower trabecular separation in strontium ranelate vs. OVX. Load and energy required to induce lamella deformation were higher with strontium ranelate than in OVX and in SHAM, indicating that the bone formed with strontium ranelate is able to withstand greater damage before fracture. Bone formation was maintained high or even increased in strontium ranelate as shown by mineralizing surfaces and alkaline phosphatase while strontium ranelate led to reductions in deoxypyridinoline. Conclusion  Strontium ranelate administered at 625 mg/kg/day for 52 weeks prevented OVX-induced biomechanical properties deterioration by influencing the determinants of bone strength: it prevented bone loss and micro-architecture degradation in association with an effect on intrinsic bone quality. These beneficial effects on bone contribute to explain strontium ranelate antifracture efficacy.     

Strontium ranelate prevents quality of life impairment in post-menopausal women with established vertebral osteoporosis

Summary

Strontium ranelate reduces the risk of fracture in post-menopausal osteoporotic women with prevalent fractures for whom quality of life is severely impaired. The SOTI study, which used the SF-36® questionnaire and disease-specific QUALIOST® module, demonstrated that treatment with strontium ranelate improved osteoporotic women’s quality of life compared with placebo.

Introduction

The Spinal Osteoporosis Therapeutic Intervention (SOTI) study demonstrated the effect of orally administered strontium ranelate versus placebo on the incidence of new vertebral fractures and compared impact on quality of life (QoL).

Methods

QoL was assessed 6 monthly over 3 years using the QUALIOST® and SF-36® questionnaires in post-menopausal osteoporotic women with prevalent fracture taking strontium ranelate or placebo 2 g/day. A total of 1,240 women were included (strontium ranelate: n?=?618 and placebo: n?= 622).

Results

The QUALIOST® total score decreased in the strontium ranelate group, indicating preserved QoL compared with a deterioration in the placebo group (P?=?0.016). Strontium ranelate patients had reduced QUALIOST® emotional and physical dimension scores (P?=?0.019 and 0.032, respectively, versus placebo), indicating beneficial effects on emotional and physical functioning. There was a trend towards better SF-36® scores in the strontium ranelate group, although there were no significant between-group differences. More strontium ranelate patients (+ 31%) were free from back pain over 3 years versus placebo (P?=?0.005), with a significant effect from the first year of treatment (P?=?0.023).

Conclusion

Strontium ranelate has beneficial effects on QoL in women with post-menopausal osteoporosis compared with placebo.     

A meta-analysis of the effect of strontium ranelate on the risk of vertebral and non-vertebral fracture in postmenopausal osteoporosis and the interaction with FRAX?

Summary  

The aim of the present study was to determine the efficacy of strontium ranelate as a function of baseline fracture risk. Treatment with strontium ranelate was associated with a significant 31% decrease in all clinical osteoporotic fractures (vertebral fractures included). Hazard ratios for the effect of strontium ranelate on the fracture outcome did not change significantly with increasing fracture probability.