Dr Reginster serves as a consultant for Amgen, Eli Lilly and Company, GlaxoSmithKline, Merck, Negma, NPS Pharmaceuticals, Novartis, Nycomed, Roche, Servier, Theramex, and Wyeth. He serves as a speaker for Analis, Eli Lilly and Company, Geneverier, IBSA, Merck, Sharpe & Dohme, Novartis, Roche, and Standard de Liege. All other authors state that they have no conflicts of interest.
Vertebral Fracture Risk Reduction With Strontium Ranelate in Women With Postmenopausal Osteoporosis Is Independent of Baseline Risk Factors
Article first published online: 3 JAN 2006
Copyright © 2006 ASBMR
Journal of Bone and Mineral Research
Volume 21, Issue 4, pages 536–542, April 2006
How to Cite
Roux, C., Reginster, J.-Y., Fechtenbaum, J., Kolta, S., Sawicki, A., Tulassay, Z., Luisetto, G., Padrino, J.-M., Doyle, D., Prince, R., Fardellone, P., Sorensen, O. H. and Meunier, P. J. (2006), Vertebral Fracture Risk Reduction With Strontium Ranelate in Women With Postmenopausal Osteoporosis Is Independent of Baseline Risk Factors. J Bone Miner Res, 21: 536–542. doi: 10.1359/jbmr.060101
- Issue published online: 4 DEC 2009
- Article first published online: 3 JAN 2006
- Manuscript Revised: 29 DEC 2005
- Manuscript Accepted: 29 DEC 2005
- Manuscript Received: 28 APR 2005
- strontium ranelate;
- risk factors;
- vertebral fracture
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 ≥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.
Osteoporosis and its consequent increase in fracture risk is a major health problem for postmenopausal women.(1) The disease is currently managed with a range of therapies that decrease bone resorption(2–4) or increase bone formation.(5) The response to treatment may depend on the patient's characteristics such as initial BMD(6) and osteoporotic status(7) or be independent of such factors.(8) Strontium ranelate is an orally active agent, which has been shown to both increase bone formation and reduce bone resorption in vitro and in animal models(9,10) and to improve bone architecture and bone resistance in rats.(11) In two large multinational studies of postmenopausal women with osteoporosis, a 3-year treatment with strontium ranelate 2 g/day orally was shown to reduce significantly the risk of vertebral and nonvertebral fractures by 41% over 3 years in the Spinal Osteoporosis Therapeutic Intervention (SOTI) study(12) and 16% in the Treatment of Peripheral Osteoporosis (TROPOS) study,(13) with a 36% reduction of risk of hip fracture in a high-risk population of the TROPOS study (a posteriori analysis performed in a subgroup of osteoporotic women with age ≥ 74 years).(13) The bone formation measured by bone alkaline phosphatase was increased compared with placebo, whereas the intensity of bone resorption measured by serum C-telopeptide crosslinks (sCTX) was decreased,(12) suggesting that strontium ranelate may dissociate bone formation and bone resorption. Among the different types of osteoporotic fractures, the clinical significance of vertebral fractures is now recognized because of the link between these fractures and increased mortality,(14,15) pain, disability, and impairment of quality of life.(16,17)
The aim of these analyses was to assess the efficacy of strontium ranelate according to the determinants of vertebral fracture and thus to determine which patients would benefit from this treatment.
MATERIALS AND METHODS
Data from the SOTI study(12) and the TROPOS study(13) were used for this study. These randomized, double-blind, placebo-controlled clinical trials have been presented in detail previously.(12,13) Before inclusion either in the SOTI or in the TROPOS study depending of the inclusion criteria, patients were subjected to a run-in study to initiate normalization of their calcium and vitamin D status.(12,13)
In SOTI, 1649 patients were enrolled; they were included in the study if they were 50 years old or more and postmenopausal for at least 5 years, had had at least one vertebral fracture confirmed by spinal X-rays, and had a lumbar spine BMD of 0.840 g/cm2 or less (measured with Hologic devices).
The vertebral fracture incidence was the main efficacy criterion of SOTI study. Over the 3-year double-blind controlled study period, 139 patients in the strontium ranelate group (20.9%) and 222 patients in the placebo group (32.8%) had at least one new vertebral fracture (i.e., a 41% relative risk [RR] reduction; RR = 0.59; 95% CI, 0.48; 0.73; p < 0.001).(12) Nonvertebral fractures occurred in 234 women (112 in strontium ranelate group and 122 in placebo group), without a significant difference in incidence between the two groups (RR = 0.90; 95%CI, 0.69;1.17).(12)
In TROPOS, 5091 patients were enrolled and were eligible if they were ≥74 years of age (or were between 70 and 74 years of age with one additional fracture risk factor, i.e., history of osteoporotic fracture after menopause, residence in a retirement home, frequent falls, or a maternal history of osteoporotic fractures at the hip, spine, or wrist), had been postmenopausal for at least 5 years, and had a femoral neck BMD ≤ 0.600 g/cm2 (measured with Hologic devices). The incidence of nonvertebral fractures was the main efficacy criterion of this study. In the ITT population, strontium ranelate treatment was associated with a 16% reduction in all nonvertebral fractures over a 3-year follow-up period (RR = 0.84; 95%CI, 0.702; 0.995; p = 0.04); 233 patients in the strontium ranelate group (11.0%) and 276 patients in the placebo group (12.9%) had at least one new nonvertebral fracture. The RR of experiencing a major nonvertebral fracture (defined as fractures of hip, wrist, pelvis and sacrum, ribs-sternum, clavicle, or humerus, a predetermined secondary endpoint decided by an Advisory Board) was reduced by 19% in strontium ranelate–treated patients in comparison with the placebo group (RR = 0.81; 95% CI, 0.66; 0.98; p = 0.031). Among osteoporotic women ≥74 years of age (n = 1977), the RR reduction for hip fracture was 36% (RR = 0.64; 95%CI, 0.412; 0.997; p = 0.046). The effect on vertebral fracture incidence was a secondary criterion efficacy in TROPOS; over the 3 years, the RR of experiencing a new vertebral fracture in treated women was 0.61 (95% CI, 0.51–0.73; p < 0.001) in patients with spinal X-rays (not mandatory in the TROPOS study).(13)
Because the study design, centers, BMD central reading center, and X-ray central reading center were common to both SOTI and TROPOS studies, a predetermined analysis of pooled data was performed to increase the assessment of the treatment effect estimate compared with the individual phase III studies. The pooled data from the SOTI and TROPOS studies are the basis of this study.
In both SOTI and TROPOS studies, patients were randomly assigned to receive 2 g/day of strontium ranelate (two sachets a day of powder that they mixed with water) or placebo for 3 years. Subjects were instructed to take the study drug once daily, at bedtime, or twice daily (one sachet 30 minutes before breakfast and one at bedtime). Most patients (>90%) chose the once daily regimen. Throughout both studies, subjects received daily calcium supplements at lunchtime (up to 1000 mg of elemental calcium, depending on their dietary calcium intake), and vitamin D (400–800 IU depending on the baseline serum concentration of 25 hydroxyvitamin D).
Assessment of outcomes
The assessment of vertebral fractures and BMD was similar in the SOTI and TROPOS studies.
Three lateral radiographs of the spine (thoracic and lumbar radiographs and an image of the thoracolumbar junction) were obtained at baseline and annually, according to standardized procedures. At baseline, anteroposterior radiographs of the spine were also obtained. All radiographs were assessed at a central facility; central readers were told the time sequence of each radiograph but were unaware of the treatment assignment. The semiquantitative visual assessment of each vertebra, from T4 to L4, was performed by the same reader throughout the study. The semiquantitative grading scale was as follows: grade 0, normal; grade 1, a decrease in the height of any vertebra of 20–25%; grade 2, a decrease of 25–40%; grade 3, a decrease of 40% or more.(18) For primary analysis, a new vertebral fracture was defined by a change in the score of a vertebra from grade 0 at baseline to a subsequent grade of 1 or more.
BMD at the lumbar spine and proximal femur was measured by DXA at baseline and at 6-month intervals (using Hologic densitometers). All the scans were analyzed centrally, and a quality control of all the devices was conducted throughout the study.(19) Results in this study were those without adjustment for the strontium content of the bone. For patient diagnostic categorization, lumbar spine and femoral neck BMD T scores were calculated using a reference database (D.O. Slosman, Geneva, Switzerland). Baseline BMD T score was used to categorize patients into those with osteopenia and those with osteoporosis. Osteopenia was defined as a BMD >2.5 SD below the young adult mean value at both sites and less than or equal to −1 (−2,5 < T score ≤ −1) at lumbar or femoral neck level, and osteoporosis was defined as a BMD <2.5 SD below the young adult mean value (T score < −2.5) at at least one of the two sites.
Efficacy analysis was based on an intention-to-treat principle by the use of a full analysis set defined as randomized patients having taken at least one sachet of treatment with a baseline and at least one postbaseline spinal radiographs.
The incidence of patients experiencing a vertebral fracture was estimated according to Kaplan-Meier method (product limit estimate of the probability of fracture), and a Cox model was used to compare groups and to estimate the RR of experiencing a new vertebral fracture and its 95% CI. p values were given according to the likelihood ratio test.
Homogeneity of the treatment effect across levels of risk factors was assessed for all the factors (through the treatment × factor interaction). Likelihood ratio test was performed comparing both models with and without the interaction term.
A population of 5082 women is the basis of this study (Fig. 1). Baseline characteristics of the population are in Table 1: there was no significant difference between the patients given 2 g/day strontium ranelate (N = 2536) and those given placebo (N = 2546). Over the 3-year study period, 15.0% patients in the strontium ranelate group and 23.7% patients in the placebo group had at least one new vertebral fracture (i.e., a 40% lower risk; RR = 0.60; 95% CI, 0.53–0.69; p < 0.001). In the same period, there was a 15% lower risk of a nonvertebral fracture in the strontium ranelate group than in the placebo group (incidence, 11.6% versus 13.1%; RR = 0.85; 95% CI, 0.74–0.99; p = 0.03).
Age and risk of vertebral fracture
Mean age of the population was 74.0 ± 6.2 (SD) years. We categorized age in three subgroups: <70 years (N = 750), 70–80 years (N = 3437), and ≥80 years (N = 895).
Over the 3-year follow-up period, in each subgroup of age, there was a decrease in risk of incident vertebral fracture in the strontium ranelate group relative to placebo, and there was no treatment-by-age interaction (p = 0.652). The RR reduction was 37% (p = 0.003) in the younger women (<70 years), 42% (p < 0.001) in women 70–80 years of age, and 32% (p = 0.013) in the elderly (i.e., women ≥80 years of age; Table 2).
Baseline BMD and risk of vertebral fracture
In patients receiving placebo, the RR for developing new vertebral fractures was inversely related to baseline BMD: new vertebral fracture occurred in 24.1% of osteoporotic (N = 2462) and 12% of osteopenic patients (N = 84), respectively. These proportions were 15.4% (N = 2444) and 3.6% (N = 92) in the patients treated with strontium ranelate. Thus, the decrease in vertebral fracture risk fracture was significantly reduced in the strontium ranelate group compared with the placebo group regardless of the baseline BMD (Table 2). The treatment-by-baseline T score interaction was not significant (p = 0.646). The risk of experiencing a new vertebral fracture was lower in patients treated with strontium ranelate having a higher measured BMD, thus indicating that the prognostic value of measured BMD is maintained with strontium ranelate (Fig. 2).
Prevalent vertebral fractures and risk of vertebral fracture
Among the 5082 patients (2 of whom without any information on prevalent vertebral fracture), 2605 had no prevalent vertebral fracture, including 189 patients of the SOTI study who were reclassified as having no prevalent vertebral fracture by central readers. In these 2605 patients, mean lumbar T score was −2.70 ± 1.53 and mean femoral neck T score was −2.97 ± 0.56. The incidence of the first vertebral fracture was 14.4% in the placebo group and 7.5% in the strontium ranelate group (i.e., a reduction in risk of 48%; p < 0.001; Table 2).
There was an increase in the incidence of vertebral fractures according to the number of prevalent vertebral fractures in the placebo group: 25.2% in patients having only one prevalent vertebral fracture (1110 patients in total, 577 in the placebo group), and 40.3% in patients having two or more prevalent vertebral fractures (1365 patients in total, 683 in the placebo group). In each of those subgroups, there was a decrease in risk of incident vertebral fracture in the strontium ranelate group relative to placebo (Table 2), and the treatment-by-prevalent vertebral fracture interaction was not significant (p = 0.256).
Prevalent nonvertebral fractures and risk of vertebral fractures
Among the 1871 women who had a prevalent nonvertebral fracture at baseline, 910 had no vertebral fracture (485 in the strontium ranelate group and 425 in the placebo group). In this subgroup, over the 3-year study period, 40 patients in the strontium ranelate group (9.1%) and 62 patients (16.7%) in the placebo group had at least one first vertebral fracture (i.e., a 46% relative risk reduction in vertebral fracture in the strontium ranelate group compared with placebo over 3 years of treatment; RR = 0.54; 95% CI, 0.366; 0.810; p = 0.002). The treatment-by-prevalent nonvertebral fractures interaction was not significant (p = 0.859).
Family history of osteoporosis and risk of vertebral fractures
Among the 5082 patients, 1714 patients had a family history of osteoporosis corresponding to history of hip, vertebrae, and/or wrist fractures (871 in the strontium ranelate group and 843 in the placebo group). In this subgroup, over the 3-year study period, 122 patients in the strontium ranelate group (15.3%) and 168 patients (21.9%) in the placebo group had at least one vertebral fracture. There was a 31% RR reduction in vertebral fracture in the strontium ranelate group compared with placebo over 3 years of treatment (RR = 0.69; 95% CI, 0.547; 0.873; p = 0.002), whereas in the subgroup without a family history of osteoporosis (3355 patients), there was a 44% RR reduction in vertebral fracture (RR = 0.56; 95% CI, 0.475; 0.664; p < 0.001; Table 2). The treatment-by-family history of osteoporosis interaction was not significant (p = 0.359).
Baseline BMI and risk of vertebral fractures
Median baseline BMI of the population was 25.46 kg/m2: 2508 patients with a baseline BMI ≤ 25.46 kg/m2 (1251 in the strontium ranelate and 1257 in the placebo groups) and 2497 with a baseline BMI > 25.46 kg/m2 (1244 in the strontium ranelate and 1253 in the placebo groups). Over the 3-year follow-up period, in each of those two groups, there was a decrease in risk of incident vertebral fracture in the strontium ranelate group relative to placebo, and there was no treatment-by-age interaction (p = 0.658). The RR reduction was 37% in the group of women with a baseline BMI ≤ 25.46 kg/m2 (RR = 0.63; 95% CI, 0.526; 0.765; p < 0.001); 181 patients in the strontium ranelate group (16.1%) and 278 patients (24.6%) in the placebo group had at least one vertebral fracture. The RR reduction was 44% in women with a baseline BMI > 25.46 kg/m2 (RR = 0.56; 95% CI, 0.458; 0.684; p < 0.001); 153 patients in the strontium ranelate group (13.6%) and 258 patients (22.9%) in the placebo group had at least one vertebral fracture (Table 2). The treatment-by-baseline BMI interaction was not significant (p = 0.658).
Addiction to smoking and risk of vertebral fractures
Addiction to smoking was defined as past history of smoking and current use of tobacco. Among the 5082 patients, 451 patients had smoked or are still currently smoking (231 in the strontium ranelate group and 220 in the placebo group). Over the 3-year study period, 34 patients in the strontium ranelate group (16.3%) and 51 patients (25.9%) in the placebo group had at least one vertebral fracture, i.e., a 40% RR reduction in vertebral fracture in the strontium ranelate group compared with placebo over 3 years of treatment (RR = 0.60; 95% CI, 0.386; 0.920; p = 0.018), whereas in the subgroup without smoking (4631 patients), there was a 40% RR reduction in vertebral fracture (RR = 0.60; 95% CI, 0.523; 0.695; p < 0.001; Table 2). The treatment-by-addiction to smoking interaction was not significant (p = 0.998).
This study shows that the efficacy of a 3-year treatment with strontium ranelate on the risk of vertebral fractures is independent of the existence of main risk factors for such fractures.
The number and burden of fractures are increasing as age advances in relation with increased longevity. This is particularly the case in those >80 years of age, a group at highest absolute risk for fracture. Very few data are available in this population. In our study, 26.5% of women ≥80 years of age had at least one vertebral fracture in the 3-year follow-up. Age was not a determinant of the reduction of vertebral fracture risk by strontium ranelate. Prevalent vertebral fractures are a strong risk factor for both vertebral and nonvertebral incident fractures.(20,21) In the placebo group, the risk of vertebral fracture in women with one prevalent vertebral fracture was 1.8 times that of women without prevalent vertebral fractures, whereas for women with at least two prevalent vertebral fractures, the risk was 2.8 times higher. Among postmenopausal women sustaining an osteoporotic vertebral fracture, 20% of patients will fracture again within the following 12 months.(22) Thus, it is relevant to prevent the first vertebral fracture in women with low BMD. Because of the design of the study, we had a suitable group for analysis of prevention of the first vertebral fracture in a population with a low spine BMD. The risk of such a first vertebral fracture was reduced by strontium ranelate by 48%. This result reinforces the relevance of the identification of high-risk women to intervene before progressive and debilitating vertebral and spine deformities.
The effect of strontium ranelate did not vary by baseline BMD. Moreover, a significant vertebral antifracture effect of strontium ranelate was observed in a subset of 176 women with osteopenia, although the event rate was low in this subgroup. Whereas BMD is a major determinant of fracture risk, a proportion of fractures occurs in women with T scores greater than −2.5. Based on the commonly used definition of osteoporosis (T score < −2.5), the proportion of fractures attributable to osteoporosis is modest, ranging from 10% to 44% in women ≥65 years of age.(23) Not all osteopenic women must be treated, but improved methods of risk assessment should identify those women with osteopenia who have a high fracture probability and in whom a treatment is indicated.
Strontium ranelate increases BMD, because of both the atomic number of strontium(24) and the effect of the drug in increasing bone mass.(11) The prognostic value of the measured BMD is maintained with strontium ranelate (Fig. 2), and the fracture risk in this population is driven by the absolute value of BMD at both baseline and follow-up.
This study showed that a 3-year treatment with strontium ranelate leads to antivertebral fracture efficacy in postmenopausal women with a large spectrum of risk for such fractures.
- 112004 Strontium ranelate improves bone resistance by increasing bone mass and improving architecture in intact female rats. J Bone Miner Res 19: 2012–2020., , , , ,Direct Link: