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Endocrine Care |
Hôpital Edouard Herriot (P.J.M., P.D.D.), 69437 Lyon, France; Cantonal Hospital (D.O.S.), 1211 Geneva 14, Switzerland; Centre Hospitalo-Universitaire (J.L.S.), 80030 Amiens, France; University of Florence (M.L.B.), 50139 Florence, Italy; University of Rome (C.A.), 00161 Rome, Italy; Health Center (R.L.), 04-736 Warsaw, Poland; Hillerød Hospital (S.P.-N.), 3400 Hillerød, Denmark; Hôpital Lariboisière (M.C.d.V.), 75475 Paris, France; Hospital Candelaria (A.R.), 38010 Santa Cruz de Tenerife, Spain; and Centre Hospitalo-Universitaire (J.Y.R.), 4020 Liège, Belgium
Address all correspondence and requests for reprints to: Pierre J. Meunier, M.D., Hôpital Edouard Herriot, 69437 Lyon Cedex 03, France. E-mail: . Meunier{at}lyon151.inserm.fr
Abstract
The aim of the strontium ranelate (SR) for treatment of osteoporosis (STRATOS) trial was to investigate the efficacy and safety of different doses of SR, a novel agent in the treatment of postmenopausal osteoporosis. A randomized, multicenter, double-blind, placebo-controlled trial was undertaken in 353 osteoporotic women with at least one previous vertebral fracture and a lumbar T-score <-2.4. Patients were randomized to receive placebo, 0.5 g, 1 g, or 2 g SR/d for 2 yr. The primary efficacy endpoint was lumbar bone mineral density (BMD), assessed by dual-energy x-ray absorptiometry. Secondary outcome measures included femoral BMD, incidence of new vertebral deformities, and biochemical markers of bone metabolism. Lumbar BMD, adjusted for bone strontium content, increased in a dose-dependent manner in the intention-to-treat population: mean annual slope increased from 1.4% with 0.5 g/d SR to 3.0% with 2 g/d SR, which was significantly higher than placebo (P < 0.01). There was a significant reduction in the number of patients experiencing new vertebral deformities in the second year of treatment with 2 g/d SR [relative risk 0.56; 95% confidence interval (0.35; 0.89)]. In the 2 g/d group, there was a significant increase in serum levels of bone alkaline phosphatase, whereas urinary excretion of cross-linked N-telopeptide, a marker of bone resorption, was lower with SR than with placebo. All tested doses were well tolerated; the 2 g/d dose was considered to offer the best combination of efficacy and safety. In conclusion, SR therapy increased vertebral BMD and reduced the incidence of vertebral fractures.
AT MENOPAUSE, ACCELERATION of bone turnover leads to an imbalance between bone resorption and bone formation, resulting in postmenopausal bone loss. Osteoporosis is considered to be the main cause of fractures in postmenopausal women and as such represents an important (and potentially preventable) health problem.
Most compounds currently available for the treatment of osteoporosis (e.g. estrogens, bisphosphonates, calcitonin, selective ER modulators) are bone resorption inhibitors (1) Thus, the challenge for the clinical scientist is to identify new molecules capable either of increasing bone formation, or both stimulating bone formation and inhibiting resorption, without altering the mechanical properties of bone. Moreover, to date, none of these resorption inhibitors has shown a complete suppression of new fractures. New therapeutic agents are currently under investigation. One of them is strontium ranelate (SR), a compound containing the organic acid, ranelic acid, and two atoms of stable strontium.
Strontium is a bone-seeking element. Results of animal and human studies have suggested that SR may be useful for the treatment of osteoporosis in humans, without the risk of altering the bone mineral. SR has been shown to stimulate bone formation in growing rats (2). Canalis et al. (3) showed that SR stimulated bone formation in organ and cell cultures of rat calvariae, and that this effect may be related to an increase in osteoprogenitor cell replication. SR also inhibited bone resorption in vitro in mouse calvariae and isolated rat osteoclast cultures (4). In ovariectomized rats, SR prevented bone loss by reducing bone resorption, whereas bone formation remained elevated (5). The exact mechanism by which SR exerts these effects is not definitely understood, but may include stimulation of osteoblast proliferation and inhibition of osteoclast formation (6). Not only modifying bone cell activities, strontium, which is a divalent cation-like calcium may participate in bone mineralization with the same physical properties than calcium. In monkeys, 13-wk treatment with SR at doses up to 750 mg/kg·d did not produce any major modifications in bone mineral at the crystal level (7). A double-blind, placebo-controlled, dose-finding study in early postmenopausal women showed that 1 g of SR daily for 2 yr prevented from the decrease in lumbar bone mineral density (BMD) observed in the placebo group (8).
The phase II, randomized, 2-yr trial reported here, the strontium ranelate (SR) for treatment of osteoporosis (STRATOS) trial, was conducted to establish the minimal dose of SR effective for the treatment of postmenopausal vertebral osteoporosis. BMD of the lumbar spine was used as the primary endpoint. This is the commonly accepted primary endpoint in phase II studies evaluating the dose response of treatment developed to decrease the risk of fracture in postmenopausal osteoporosis (9, 10). A 5–10% increase in lumbar BMD may lead to expect a 30–50% decrease in the relative risk of vertebral fracture. Secondary endpoints, such as the number of patients with new vertebral deformities after 1 and 2 yr of treatment and biochemical markers of bone metabolism, were also analyzed.
Patients and Methods
Study population
We studied Caucasian women, 45–78 yr old, nonobese [body mass index (BMI) 
30 kg/m2], who were at least 12 months postmenopausal and who had established vertebral osteoporosis. Vertebral osteoporosis was defined as at least one vertebral (T4–L5) fracture occurring under no or minimal trauma, and a lumbar spinal BMD below a threshold equivalent to the published 85th percentile of a group of women with osteoporotic fractures (11), corresponding to a T-score of -2.4.
Exclusion criteria were: more than two x-ray documented vertebral crushed fractures between L1 and L4; documented secondary osteoporosis; osteomalacia; severe scoliosis (>20 degree); Paget’s disease; evolving cancer, multiple myeloma or bone metastasis; life expectancy under 2 yr; renal insufficiency (creatinine >120 µmol/liter); liver insufficiency (prothrombin time <70%); alcohol intake 160 g or more pure alcohol/d; treatment with calcitonin, estrogen, corticosteroids, anabolic steroids or vitamin D more than 800 IU/d within the previous 3 months; treatment with phosphorus, thiazide diuretics or calcium more than 500 mg/d within the previous month; treatment with etidronate or pamidronate for more than 30 d; any treatment with another bisphosphonate. Treatment with etidronate or pamidronate for 15–30 d required a 3-month washout period; treatment with fluoride for more than 2 months required a 5-yr washout, and treatment with fluoride for less than 2 months required a 3-month washout. The protocol was reviewed by independent Ethics Committees in each participating country and by a Comité Consultatif de Protection des Personnes dans la Recherche Biomédicale in France. All patients gave written informed consent.
Study design
The study was a randomized, parallel-group, double-blind, placebo-controlled trial carried out in 31 centers in nine European countries. Patients were randomly assigned to receive placebo (PL), or SR 0.5 g, 1 g, or 2 g/d (PL, SR 0.5 g, SR 1 g, and SR 2 g groups, respectively), as two identical tablets, twice daily. Treatments were randomized within each center, and patients were allocated to the treatment groups by block permutation (block size = 4). Each center was given entire blocks and consecutive therapeutic unit numbers were allocated to patients in chronological order. For analyses performed on interim data at 6 months, the code was available only to the biostatistician, and results were issued only by treatment group; no individual patient data listings were issued. To enable BMD data at 12 months to be adjusted for the presence of strontium in the bone, the plasma, urinary, and bone strontium levels were transferred to the data manager, the biostatistician, and the person in charge of pharmacokinetics, who was not involved in the clinical part of the study.
All patients received supplementary calcium (500 mg/d) and vitamin D (vitamin D3 800 IU/d) throughout the study to ensure that patients affected by severe osteoporosis received a minimum level of active treatment (12). During the study period, patients were not allowed to receive any of the treatments specified in the exclusion criteria.
Study visits were scheduled at selection (month -1) and at months (M) 0, 1, 3, 6, 9, 12, 18, and 24. Patient compliance was assessed from unused tablets returned at study visits, and from drug concentration measurements (by Y. Mauras, Center Hospitalier Regional Universitaire, Angers, France).
The primary efficacy endpoint was lumbar BMD measured by dual-energy x-ray absorptiometry (DXA) at M12 (principal analysis) and M24 (final analysis). The main outcome measurement was the BMD (measured and adjusted) annual slope, expressed as percentage variation from baseline. Secondary efficacy outcome measurements were femoral neck BMD (FN-BMD) annual slope (%), changes in biochemical markers of bone formation and resorption, and the number of patients with new vertebral deformities at M12 and M24.
Investigations
DXA analysis of BMD was performed using four different brands of apparatus, depending on local availability. The same apparatus was used throughout the study for individual patients, and an external multicenter cross-calibration was performed using an external spine phantom. Measured values were normalized to a reference apparatus (13). Any metal with an atomic number higher than that of calcium (Z = 20) will attenuate x-rays to a greater extent than calcium, which may lead to an overestimation of the bone mineral content and BMD measured by DXA scanning techniques and expressed in calcium hydroxyapatite equivalent. The influence increases with the atomic number due to the effects on radiation attenuation. Strontium attenuates more x-rays than calcium, due to its higher atomic number (Z = 38) than calcium (14). Measurements of lumbar BMD were therefore adjusted for bone strontium content (BSC), as follows.
At months 12 and 24, iliac crest bone biopsies were collected (see below) and submitted to chemical analysis. BSC of these biopsies was then used to establish linear regressions between iliac crest BSC and strontium plasma exposures from baseline to months 12 and 24 (AUCP[M0–M12], AUCP[M0–M24]):
BSCiliac crestM12 = a x AUCP[M0–M12]
where a, the slope estimate, = 0.0079 (SD = 0.0008; R2 = 0.863); AUC, area under the curve
BSCiliac crestM24 = b x AUCP[M0–M24]
where b = 0.0052 (SD = 0.0002; R2 = 0.893)
From these slopes, iliac crest BSC at months 12 and 24 were estimated from strontium plasma exposure for patients for whom no biopsy was available.
Lumbar BSC was then estimated from iliac BSC using the relationship:
BSCvertebrae = BSCiliac crest x 0.61 (SE = 0.0170; 95% CI [0.57; 0.65]; R2 = 0.9931)
established in a recent study in monkeys, which found that BSC is highly correlated between different skeletal sites (15).
Adjusted lumbar BMD was then calculated from measured lumbar BMD using the following equation, which allows for an adjustment of 10% (derived from in vitro studies, in which a strontium concentration of 1% was found to induce a 10% overestimation of BMD expressed in calcium hydroxyapatite equivalent):
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Biochemical markers of bone metabolism were assayed in a central laboratory (P. D. Delmas, Lyon, France), and included: bone alkaline phosphatase (assayed by immunoradiometric assay; IRMA); total serum osteocalcin (IRMA); procollagen (ELISA); and pyridinolines (ELISA). Indicators of plasma calcium homeostasis were also assessed, including plasma and urinary calcium (by plasma emission spectrophotometry; P. Allain, Angers, France), PTH and 25-hydroxyvitamin D (IRMA; P. D. Delmas, Lyon, France), and 1,25-dihydroxyvitamin D (IRMA; J. M. Kaufman, Ghent, Belgium).
Spinal radiographs were obtained at the M1, M12, and M24 visits. Quantitative morphometric radiological assessments were performed centrally (J. L. Sebert, Amiens, France). A decrease of at least 20% in one of the ratios of the vertebral heights was taken to indicate a vertebral deformity.
In some centers, a transiliac bone biopsy after tetracycline double-labeling was carried out after 1 and/or 2 yr of treatment in consenting patients, to assess BSC and histomorphometric parameters. Paired blind readings were made in two central laboratories (P. J. Meunier, Lyon, France; and M. C. de Vernejoul, Paris, France).
Safety measurements
Clinical examinations were performed at each study visit. Any symptoms, signs and/or diseases detected after the first visit were reported as adverse events. Standard hematology and biochemistry tests were performed at all visits.
Statistical analyses
It was planned to include 65 patients per treatment group, to ensure 90% power to detect a difference in lumbar BMD annual slope of 4%, with an SD of 6%, between placebo and one SR dose in a one-tailed situation with a type I error rate of 5%. This presupposed a treatment withdrawal rate of 20% in the first year.
Statistical analyses were performed in the intention-to-treat population on primary and secondary efficacy criteria at M12 and M24. All the results reported here are those for the ITT populations, unless otherwise stated.
Annual slopes of lumbar BMD were expressed as percent variations relative to baseline, and compared between groups using a one-way ANOVA followed by a Dunnett test in case of significant group-effect. Other outcomes were assessed using analysis of covariance, the Kruskal-Wallis test, Cochran-Mantel-Haenzel test, 
2 test, Fisher’s exact test, or the paired sample t test (two-tailed type I/error rate 5%), as appropriate. Statistical tests were performed using SAS.
Results
Patient characteristics
A total of 353 patients were randomized to one of four treatment groups, and 272 patients (77.1%) completed the study. Among the 78 patients who prematurely discontinued treatment, 55 withdrew because of adverse events: 14, 15, 15, and 11 from the PL, SR 0.5 g, SR 1 g, and SR 2 g groups, respectively. Twenty-three patients prematurely discontinued due to nonmedical reasons. and three patients were lost to follow-up (Fig. 1
). There were no significant differences between treatment groups with regard to the rates of withdrawal, or the reasons for withdrawal.
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. There were no significant differences between groups at baseline with regard to demographic data or disease factors, with the exception of BMI, for which there was a significant difference between the SR 1 g and SR 2 g groups. This difference was considered to be neither clinically relevant nor likely to have an impact on efficacy assessment. At baseline, there were no significant differences between groups with regard to lumbar BMD (Table 1) or FN-BMD values, or to biochemical markers of bone metabolism (data not shown). There were also no significant clinically relevant differences between the randomized population (n = 353), the per-protocol (PP) population (n = 237), and the 64 patients with a bone biopsy evaluable at M24 (data not shown). Compliance with treatment was high in all groups (mean global compliance 93 ± 13%), with no relevant differences between groups.
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Measured lumbar BMD increased at M12 and M24 in a dose-dependent way (Fig. 2A), with mean annual slopes ranging from 2.86% for the SR 0.5 g group to 7.32% for the SR 2 g group. However, as explained in Patients and Methods, it was necessary to adjust the measured BMD values for the presence of strontium in the bone. Seventeen satisfactory bone biopsies were available at M12, and a further 64 at M24. The results from these biopsies were used to calculate adjustment factors according to time (M12 or M24) and treatment group (data not shown). All treatment groups showed increases in adjusted lumbar BMD at 12 months, and further increases at 24 months, and the mean changes in adjusted BMD from baseline for all treatment groups are shown in Fig. 2B. The mean annual slopes of the percentage change in adjusted lumbar BMD are shown in Table 2. There was a significant group effect (P < 0.001), and the SR 2 g group was significantly different from placebo (P < 0.01). When the analysis was repeated using a larger adjustment factor for BSC, calculated using the upper 95% confidence limits of the coefficients used in determining the factor, the pattern of changes was similar and they remained significant (Table 2).
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. As expected, FN-BMD tended to decrease over time in the PL group, reflecting the lack of relevant effects of the calcium and vitamin D supplements received by these patients. In the SR treatment groups, FN-BMD increased in a dose-dependent way (Fig. 2C); however, these values have not been adjusted for the presence of strontium in the bone, because it was not possible to estimate the BSC of the femoral neck.
The proportion of patients experiencing new vertebral deformities (not including worsening of existing deformities), identified by x-ray morphometry, was reduced by SR therapy, the effect becoming significant (P = 0.01) during the second year of the study (Table 3). The incidence of new vertebral deformities increased in the PL group during yr 2 relative to yr 1, whereas it decreased in the SR 0.5 g and SR 2 g groups during this period, and remained fairly constant in the SR 1 g group. For the SR 0.5 g and SR 2 g groups, the relative risks of experiencing a new deformity in the second year, compared with placebo, were 0.51 [95% confidence intervals (CI): (0.31; 0.84)] and 0.56 [95% CI: (0.35; 0.89)], respectively. Thus, the proportion of patients having an incident fracture during the second year was reduced by about 44% in the SR 2 g group compared with the PL group. The relative risk of a new deformity over the entire 2-yr period, compared with placebo, was 0.71 [95% (CI 0.49; 1.02)] and 0.77 [95% CI (0.54; 1.09)], respectively.
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With regard to plasma calcium homeostasis, a slight dose-dependent decrease in plasma calcium levels (<2% in the SR 2 g group) was observed in the groups treated with SR. Serum levels of PTH, 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D did not change in any of the groups, and no inhibitory effect of SR on vitamin D hydroxylation was detected.
Bone histomorphometry revealed no sign of osteomalacia in the SR-treated groups. In particular, there was no increase in osteoid thickness and no relevant decreases in mineralizing surface or mineral apposition rate compared with placebo (data not shown).
Safety
The frequency of emergent adverse events (i.e. events not present at baseline and events present at baseline that worsened during the treatment period) is shown in Table 4. Most (82%) were mild to moderate in severity. There was no difference between groups in the incidence of emergent adverse events (P = 0.707, Fisher’s exact test), in particular of gastrointestinal disorders. Eight patients died (three, four, and one in the PL, SR 0.5 g, and SR 1 g groups, respectively). None of these deaths was considered by the investigators to be related to treatment.
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Discussion
This study is the first to demonstrate antiosteoporotic efficacy of SR in a controlled clinical trial. Treatment of postmenopausal women with established osteoporosis using SR 2 g daily for 2 yr resulted in an increase in lumbar BMD of about 3%/yr (adjusted for the presence of strontium), significantly higher than with placebo. The rate of increase in BMD was almost the same during the second year of treatment as during the first year. This compares favorably with results from trials of other antiresorptive treatments (e.g. hormone replacement therapy and bisphosphonates), which at therapeutic doses for osteoporosis have commonly shown increases in BMD of 4–10% at 2 or 3 yr (1, 16, 17), with 70–80% of the increase occurring during the first year.
A dose-dependent increase in unadjusted femoral neck BMD was also seen with SR, which became significantly different from placebo at doses of 1 and 2 g/d after 2 yr of treatment. It was not possible to adjust femoral neck BMD for BSC as no correlation has been established between femoral neck BSC and iliac crest BSC.
The robustness of these results is demonstrated by the adjustment of lumbar BMD for a larger BSC adjustment factor (calculated using the upper 95% CI of the coefficients). Even when using this larger adjustment factor, a dose- dependent increase in lumbar BMD was seen with SR, which was significantly different from placebo at the SR 2 g dose after 2 yr of treatment.
The incidence of new vertebral fractures occurring in those receiving placebo during the first and second years of the study was high (34% and 47%, respectively), reflecting the fact that this study population (all of whom had vertebral fractures at baseline) were at high risk of subsequent fractures. On average, each patient in the present study had an average of 2.75 fractures at baseline, with 18% of the participants having more than three vertebral fractures. A similar percentage of new vertebral fractures has been reported in another study of postmenopausal women with one or more vertebral fractures at baseline who received placebo for 1 yr (18).
Because of the long cycle of remodeling in osteoporosis, the effects of antiosteoporotic agents may not be fully realized during the first year of treatment (19). As expected, therefore, the reduction in incidence of new vertebral fractures, as determined by morphometry, was not significant compared with placebo during the first year of the study in any treatment group. Fracture incidence did decrease significantly, however, in the second treatment year, in the SR 0.5 g (relative risk = 0.51) and SR 2 g (relative risk = 0.56) groups, compared with placebo. There was no clear effect of dose on the reduction in incidence of fractures, but the study was not powered to demonstrate such an effect. The incidence of fractures is reported as the incidence of women experiencing a new vertebral fracture, as recommended by current European (9), and American guidelines (20). Our results are comparable with those reported for the selective estrogen receptor modulator raloxifene (21) and the bisphosphonates alendronate (22), etidronate (16) and risedronate (23). Although our study was not powered to show an effect on fractures because the number of patients had been calculated to demonstrate an effect on lumbar BMD, these data are encouraging, and justify the decision to run a phase III program.
The challenge in research on osteoporosis is to develop a drug that will stimulate bone formation and inhibit resorption without altering the mechanical properties of bone. The results presented here show that SR 2 g/d increased serum bone alkaline phosphatase and concomitantly decreased NTX pyridinoline excretion. These findings are consistent with previous reports of experimental studies that SR is able to stimulate bone formation and inhibit bone resorption concomitantly, thus allowing sustained increases in BMD (2, 3, 4, 5). An agent that is able to uncouple bone metabolism could provide a more sustained, long-term increase in bone mass than treatments that inhibit resorption without preventing a corresponding decrease in bone formation.
As has previously been reported (24), SR was found to have no negative impact on bone mineralization.
Overall, SR was extremely well tolerated over the 2-yr study period, its tolerability profile being equivalent to that of placebo. Indeed, the highest number of treatment-related adverse events per patient was reported in the placebo group. There was also no evidence that SR affects any hematological variables or blood biochemistry parameters, with the exception of a significant, but transient, increase in the musculoskeletal isoenzyme of creatine phosphokinase with SR 1 g and 2 g. This change had no clinical relevance, and there were no changes in PTH, 25-hydroxyvitamin D or 1,25-hydroxyvitamin D levels.
In conclusion, SR is a promising new agent for the treatment of postmenopausal osteoporosis. This study also showed that SR was well tolerated and that a dose of 2 g daily offered the best combination of efficacy and safety. Extensive phase III trials using a dose of 2 g daily are currently underway.
Acknowledgments
The following investigators participated in the trial:
Belgium: J. Y. Reginster, Liège; P. Geusens and I. Dequeker, Diepenbeek/Pellenberg.
Denmark: S. Pors Nielsen, Hillerød; O. H. Sørensen, Copenhagen.
France: P. J. Meunier,1 Lyon; C. Alexandre, St Etienne; M. Audran, Angers; C. L. Benhamou, Orléans; P. Bourgeois, Paris; A. Daragon, Rouen; D. Goldberg and D. Kuntz, Paris; Y. Pawlotsky, Rennes; J. M. Ristori, Clermont-Ferrand; D. Rolland, Bourges; C. Zarnitsky, Le Havre; G. Ziegler, Nice.
Germany: E. Minne, Bad-Pyrmont.
Hungary: J. Szucs and G. Balint, Budapest.
Italy: C. V. Albanese, Rome; M. Passeri, Parma; S. Ortolani, Milan; M. L. Brandi, Florence.
Poland: R. Lorenc, Warsaw.
Spain: J. Gonzalez, Santander; H. Rico, Madrid; A. Roces, Tenerife.
UK: A. Bhalla, Bath; D. Fogelman, London; A. Woolf, Truro.
Footnotes
1 *International study coordinator 
Funding for this study was provided by Servier. Statistical analyses were carried out by François Gavini of the Biometry Division of Servier.
Results of this study have been presented in part at the following congresses and published as abstracts: World Congress on Osteoporosis, Amsterdam, The Netherlands, 1996 [Meunier PJ, Slosman D, Delmas PD, Sebert JL, Albanese C, Brandi ML, Lorenc, R, Sorensen OH, de Vernejoul MC, Provvedini DM, Tsouderos, Y, Reginster, JY. The strontium salt S 12911: a new candidate for the treatment of osteoporosis. Osteoporos Int 6(Suppl 1):241(Abstract PTu 634)]; 19th Annual Meeting of the American Society for Bone and Mineral Research, Cincinnati, Ohio, 1997 [Meunier PJ, Slosman D, Delmas PD, Sebert JL, Albanese C, Brandi ML, Lorenc R, Beck-Jensen JE, de Vernejoul MC, Provvedini DM, Tsouderos Y, Reginster JY. Strontium ranelate as a treatment of vertebral osteoporosis. J Bone Miner Res 12(Suppl 1):129 (Abstract 107)].
Abbreviations: AUC, Area under the curve; BMD, bone mineral density; BMI, body mass index; BSC, bone strontium content; CI, confidence interval; DXA, dual-energy x-ray absorptiometry; FN, femoral neck; IRMA, immunoradiometric assay; M, month; NTX, cross-linked N- telopeptide; PL, placebo; SR, strontium ranelate; STRATOS, strontium ranelate for treatment of osteoporosis.
Received September 24, 2001.
Accepted February 14, 2002.
References
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