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Protelos: Nonvertebral and hip antifracture efficacy in postmenopausal osteoporosis
Bone 38 (2006) S23 – S27
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Protelos: Nonvertebral and hip antifracture efficacy in postmenopausal osteoporosis S. Adami ⁎ Rheumatology Rehabilitation Unit of the University of Verona, Valeggio sul Mincio, Italy Received 31 May 2005; accepted 23 August 2005 Available online 24 January 2006
Abstract Strontium ranelate is a new treatment for postmenopausal osteoporosis, simultaneously increasing bone formation and decreasing bone resorption, thus rebalancing bone turnover in favor of bone formation. Strontium ranelate was demonstrated to significantly reduce the relative risk of vertebral fracture whatever the severity of the disease. In the TReatment Of Peripheral OSteoporosis (TROPOS) study, the incidence of nonvertebral and hip fractures, following treatment with strontium ranelate (Protelos®, Servier) at a dosage of 2 g/day orally, was assessed over a 3-year period. In this double-blind, placebo-controlled trial, 5091 women with postmenopausal osteoporosis were assigned to either strontium ranelate (n = 2479) or placebo (n = 2453) treatment. Overall, the reduction in risk for nonvertebral fractures in patients treated with strontium ranelate was 16% (P = 0.04) and for major fractures (hip, wrist, pelvis and sacrum, ribs and sternum, clavicle and humerus), it was 19% (P = 0.031), compared with those treated with placebo. Women with osteoporosis and aged 74 years or more who were treated with strontium ranelate (n = 982) had a 36% reduction in risk of hip fracture (P = 0.046) over 3 years compared with those treated with placebo (n = 995). The difference in bone mineral density between groups was 8.2% for femoral neck and 9.8% for total hip at 3 years. The incidence of adverse events was comparable between groups. The study demonstrates that strontium ranelate treatment offers a safe and effective means of reducing the risk of nonvertebral and hip fractures in postmenopausal women with osteoporosis. © 2005 Published by Elsevier Inc. Keywords: Strontium ranelate; Osteoporosis; Nonvertebral fractures; Hip fractures; Postmenopausal
Introduction Bone remodeling continues into adult life, and the enhanced bone fragility, in postmenopausal women with osteoporosis, arises from a mismatch between bone resorption and bone formation. Currently, most agents available for the treatment of osteoporosis inhibit bone resorption, but, within months, this is accompanied by a reduction in bone formation [1,2]. On the other hand, some available agents act by stimulating bone formation which is associated with an increase in bone resorption [3]. Evidence from in vitro and in vivo studies suggests that strontium ranelate, an innovative orally active drug, has a different action on the two processes of bone turnover such that bone formation increases while bone resorption decreases, thus rebalancing bone turnover in favor of bone formation [4]. In STRATOS ⁎ Fax: +39 045 79 52 000. E-mail address: [email protected]. 8756-3282/$ - see front matter © 2005 Published by Elsevier Inc. doi:10.1016/j.bone.2005.08.028
(STRontium Administration for the Treatment of OSteoporosis), it was demonstrated that strontium ranelate 2 g/day was the effective dose for preventing bone loss in postmenopausal osteoporosis with a good tolerability profile [5]. A huge development program was then instigated to assess the effects of strontium ranelate (Protelos®, Servier), at a daily dose of 2 g, in reducing the relative risk (RR) of fracture in women with postmenopausal osteoporosis. This program began with FIRST (Fracture International Run-in for Strontium ranelate Trial) starting the normalization of the calcium and vitamin D status of potential candidates for the SOTI (Spinal Osteoporosis Therapeutic Intervention) or TROPOS (TReatment of Peripheral OSteoporosis) trials [6]. Treatment with strontium ranelate reduced the RR of new vertebral fractures by 49% in the first year and by 41% over 3 years, in the SOTI clinical trial of 1649 postmenopausal women [7]. In this report, we present evidence from the TROPOS randomized, double-blind, placebo-controlled clinical trial on
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the efficacy and safety of Protelos® (strontium ranelate) in preventing nonvertebral and hip fractures [8]. Materials and methods Study subjects Postmenopausal, ambulatory women of 74 years of age or more, or 70 to 74 years with an additional risk factor (i.e., history of osteoporotic fracture after menopause, resident in a retirement home, frequent falls or a maternal history of osteoporotic fractures of the hip, spine, or wrist) were recruited at 75 centers in 11 European countries and in Australia. In addition, these women had to have a femoral neck bone mineral density (BMD) of ≤0.6 g/cm2 (measured with Hologic instruments), corresponding to a T score b−2.5. Women with diseases interfering with bone metabolism and those using antiosteoporotic agents (bisphosphonates taken for more than 14 days within the previous year, estrogen, calcitonin, fluoride salts, calcitriol or 1-alpha-vitamin D taken for more than 1 month during the previous 6 months) were excluded. Patients were told of the nature, purpose and duration of the study and given the opportunity to ask questions. They were informed that they were free to withdraw from the study at any time. On this basis, all participants gave written informed consent prior to being enrolled in the study. The study was approved by the Institutional Review Boards.
Study design Subjects were initially subjected to a run-in period of between 2 weeks and 6 months to start to normalize their calcium and vitamin D status (FIRST study). All women received daily supplements of elemental calcium (0, 500 or 1000 mg) such that their total daily intake was above 1000 mg. Vitamin D was administered at 800 IU for patients with a serum 25-hydroxyvitamin D lower than 45 nmol/L and 400 IU for all others. If the 25-OH vitamin D level was lower than 30 nmol/L, then the duration of the run-in was at least 3 months. Calcium and vitamin D supplementation was maintained throughout the study at a dose determined during this run-in period. At the end of the run-in period, patients were randomly assigned to receive either 2 g/day of strontium ranelate or placebo for 5 years. Patients were able to take the study drug once daily at bedtime or twice daily (one sachet half an hour before breakfast and one at bedtime): almost 90% of patients took the drug once daily at bedtime. The incidence of nonvertebral fractures over a 3-year treatment period was the main evaluation criterion. Nonvertebral fractures were defined as fractures occurring at a nonvertebral site, with fractures of the coccyx, skull, jaw, face, ankle and phalanx (fingers and toes) not considered as related to osteoporosis and not taken into account in the analysis. The incidence of major nonvertebral fractures was one of the secondary end points. These fractures were defined as fractures located at the hip, wrist, pelvis and sacrum, ribs/sternum, clavicle or humerus. Patients were asked to attend visits on a regular basis: at baseline, month 3, month 6 and then every 6 months until the end of the study. During the study, nonvertebral fractures were reported by the study investigators based on written documentation provided and documented in the source document (radiograph, radiological report, hospitalization/ emergency department report). Only documented fractures were taken into account in the statistical analysis. BMD was measured by dual energy X-ray absorptiometry (DXA) at baseline and at 6-monthly intervals at the proximal femur and total hip, and scans were analyzed centrally. Quality control throughout the study included serial measurements of a spine phantom and daily quality controls [9]. Blood and urine samples were stored at −80°C and centrally analyzed. Biochemical tests were performed using standard methods. Serum parathyroid hormone (PTH) concentrations were measured using an immunoradiometric assay (N-tact®, Diasorin; laboratory reference range: 10–65 pg/mL), 25hydroxyvitamin D using a radioimmunoassay (Diasorin; laboratory reference range: 7.5–101.0 nmol/L) and 1,25-dihydroxyvitamin D with a radioreceptor assay (Diasorin).
Statistical analyses Unless otherwise stated, all analyses were performed on data obtained at baseline and until the last patient completed 3 years of follow-up to comply with international guidelines [10,11]. Antifracture efficacy, for nonvertebral fractures, was analyzed for the intention-to-treat (ITT) population, defined as patients who had received at least one sachet of medication and with at least one postbaseline assessment of nonvertebral fracture occurrence. Major nonvertebral fractures were analyzed for the ITT population. Hip fracture incidence was analyzed for a post-hoc ITT subgroup of osteoporotic patients, aged ≥74 years (femoral neck BMD T score of −2.4 according to National Health And Nutrition Examination Survey [NHANES] III). Safety was assessed for all patients who had received a least one sachet of strontium ranelate. The TROPOS trial was implemented in 1996, which was prior to the release of the first European Committee for Medicinal Products for Human Use (CHMP) guidelines on osteoporosis in 1997. This study was powered to evaluate the RR of nonvertebral fractures between groups. However, although nonvertebral (primary end point) major osteoporosis-related fractures and hip fractures were documented separately and individually analyzed as requested in the CHMP guidelines issued in 2001 (CPMP/EW/552/95 rev 1), this study was not designed or powered to demonstrate antifracture efficacy at individual sites. The post-hoc subgroup of osteoporotic patients aged 74 years or more was analyzed to comply with this CHMP guidelines (2001). The incidence of patients experiencing nonvertebral fractures was assessed according to the Kaplan–Meier method, and a Cox model was used to compare groups and to estimate the RR and 95% confidence interval (CI). Simultaneous adjustments for influential covariates were carried out for age, femoral neck BMD, body mass index and country. A type one error rate was set at 5% (twosided). A step-down hierarchical procedure was performed, based on the increasing treatment effect over time, for percentage changes from baseline in BMD at each visit. The two groups were compared using a one-sided Student's t test at each visit with a type one error rate of 2.5%. The P values correspond to a two-sided t test at the 5% threshold (one-sided P values were doubled).
Results New nonvertebral fractures Of the patients who were recruited to the study, 97% (4932 patients) formed the ITT population as defined in the above paragraph. Strontium ranelate was administered to 2479 patients, and 2453 patients received placebo (Table 1). The baseline characteristics were similar in the two groups with mean ages of 77 years (Table 2), and the overall duration of treatment was 906 ± 471 days (mean ± SD) corresponding to a mean global compliance of 82%. Table 1 Overview of study populations in the TReatment Of Peripheral OSteoporosis (TROPOS) study Study population n
Strontium ranelate
Placebo
Excluded
Total
Randomized Safety Intention to treat Completed follow-up at 3 years Osteoporotic patients aged 74 years or more
2554 2526 2479 1687
2537 2503 2453 1633
n/a 62 a 97 b 1612 c
5091 5029 4932 3320
982
995
n/a
1977
n/a = not applicable. a Patients excluded from randomized set as no treatment intake. b Patients excluded from safety set as no assessment of nonvertebral fracture. c 1587 patients withdrew, and 25 were lost to follow-up.
S. Adami / Bone 38 (2006) S23–S27
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Table 2 Baseline characteristics of the intention-to-treat population and of osteoporotic patients aged 74 years or more in the TReatment Of Peripheral OSteoporosis (TROPOS) study
Intention-to-treat population (ITT) N Mean age ± SD (years) Prevalent osteoporotic fracture (vertebral or nonvertebral) (%) Mean time since menopause ± SD (years)
Strontium ranelate
Placebo
2479 76.7 ± 5.0 55.4
2453 76.8 ± 5.0 54.2
28.4 ± 7.3
28.5 ± 7.5
ITT subset of osteoporotic patients aged 74 years or more N 982 Mean age ± SD (years) 79.7 ± 4.6 Prevalent osteoporotic 58.8 fracture (vertebral or nonvertebral) (%) Mean time since 31.4 ± 7.0 menopause ± SD (years)
995 79.5 ± 4.4 57.4
31.6 ± 7.0
In these patients, the mean duration of the run-in period was 101 ± 52 (mean ± SD) days. Using the Kaplan–Meier method, the incidence of patients experiencing at least one new nonvertebral fracture over 36 months of study was 11.2% in the strontium ranelate group and 12.9% in the placebo group. There was a significant 16% reduction in risk of all nonvertebral fractures in the strontium ranelate group compared with the placebo group (RR, 0.84; 95% CI [0.702; 0.995]; P = 0.04). The incidence of patients experiencing at least one new major nonvertebral fracture over 36 months of study was 8.7% in the strontium ranelate group and 10.4% in the placebo group: the reduction in RR was 19%, (RR, 0.81; 95% CI [0.66; 0.98]; P = 0.031). Hip fractures Among the patients included in the ITT population, a subset of osteoporotic patients, aged 74 years or more, was made: there were 1977 of these patients, and they were treated with either strontium ranelate (n = 982) or placebo (n = 995). They had similar baseline characteristics, and their mean age was 80 years (Table 2). The mean overall duration of treatment of these patients was 838 ± 485 days (mean ± SD) corresponding to a mean global compliance of 80%. The incidence of patients experiencing at least one hip fracture over the 36 months of the study was 4.3% in the strontium ranelate group and 6.4% in the placebo group. When these patients were treated with strontium ranelate, they had a relative reduction of 36% (RR, 0.64; 95% CI [0.412; 0.997]; P = 0.046) in the risk of hip fracture compared with those treated with placebo (Fig. 1). Bone mineral density Data from BMD measurements showed an increase of 5.1% at the femoral neck and 7.1% at the total hip (P b 0.001 for each)
Fig. 1. Cumulative incidence over time of osteoporotic patients aged 74 or more with at least one incident osteoporosis-related hip fracture in the intention-totreat population.
for patients in the strontium ranelate group at 3 years. As BMD decreased in the placebo group over 3 years, the increases in the strontium ranelate group compared with placebo were more pronounced at 8.2% (95% CI [7.7;8.7]; P b 0.001) and 9.8% (95% CI [9.3;10.4]; P b 0.001) for the femoral neck and hip, respectively. The strontium distribution in bone accounts for approximately 50% of these BMD increases. Safety Treatment with strontium ranelate was well tolerated, and the overall incidence of adverse events, serious adverse events and withdrawals due to adverse events was well balanced between groups (Table 3). By considering adverse events one by one, the incidence of nausea, diarrhea, dermatitis and eczema and headaches was reported significantly more in the strontium ranelate group. Concerning nausea and diarrhea, the incidence in both groups was similar after 3 months. The upper gastrointestinal tolerance was particularly good in the strontium ranelate group in which the incidence of gastritis was comparable to that of the placebo group. In the strontium ranelate group, a significant slight decrease in serum calcium and a significant slight increase in serum phosphorus were observed in comparison to the placebo group. In addition, a slight decrease in parathyroid hormone was observed in both groups, being more pronounced in the
Table 3 Adverse events in the TReatment Of Peripheral Osteoporosis (TROPOS) study Strontium ranelate N 2479 Adverse events n (%) 2179 (87.9) Serious adverse events n (%) 612 (24.7) Withdrawals due to 600 (24.2) adverse events n (%) Most commonly reported in the strontium ranelate group Nausea a 178 (7.2) Diarrheaa 166 (6.7) Dermatitis and eczema 136 (5.5) Headache 84 (3.4) a
After 3 months, there was no more difference between groups.
Placebo 2453 2181 (88.9) 599 (24.4) 530 (21.6)
108 (4.4) 123 (5.0) 108 (4.4) 59 (2.4)
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strontium ranelate group. These changes were not associated with clinical sign or symptom. No changes were observed in serum 25-hydroxyvitamin D or 1,25-dihydroxyvitamin D levels at the end of the study compared with baseline. Discussion Most previous clinical studies of antiosteoporosis agents have used vertebral fractures as the primary efficacy end point. The TROPOS study was primarily designed to assess the incidence of nonvertebral fractures following strontium ranelate treatment in a double-blind, placebo-controlled trial. The only previous study in which a registered antiosteoporosis drug was assessed using a nonvertebral site as a primary end point was the HIP (Hip Intervention Program) study with risedronate [12]. The risk of major nonvertebral osteoporotic fractures was reduced by 20% in women receiving risedronate (pooled 2.5 mg and 5 mg doses) compared with those receiving placebo. Our results with strontium ranelate show a similar efficacy, with a reduction of 19% in the risk of major nonvertebral fractures. The risk of all nonvertebral fractures was also reduced. In the VERTNA (Vertebral Efficacy with Risedronate Therapy, North America), there was a reduction in nonvertebral fractures (clavicle, humerus, wrist, pelvis, hip or leg), but this was not evident in the VERT-MN (multinational) study [13,14]. Studies in which the efficacy of antiosteoporosis agents in preventing nonvertebral fractures is assessed are more complex than those in which vertebral fractures are investigated; factors such as the propensity to fall, visual impairment and reduced mobility are likely to influence the outcome. In the FIT (Fracture Intervention Trial) study, with the antiresorptive agent alendronate, there was no significant reduction in the risk of nonvertebral fracture in the population as a whole. However, significant reductions were reported in subgroups of patients with a prevalent fracture or femoral neck BMD T score of less than −2.5 SD [15,16]. Although the original study was not powered to measure a reduction in the risk of hip fracture, we assessed the RR of this type of fracture, following strontium ranelate treatment, in osteoporotic patients aged 74 years or more. This was an appropriate population for this study as the incidence of hip fracture rises exponentially after the age of 74 years [17]. The reduction in risk of hip fracture (36%) in patients treated with strontium ranelate was consistent with that observed in the HIP trial with risedronate. In TROPOS, there were significant increases in the femoral neck and hip BMD following strontium ranelate (2 g/day) treatment consistent with what has previously been observed [7]. The decrease in serum calcium and parathyroid hormone and the significant increase in serum phosphorus observed in the strontium ranelate group in comparison to the placebo group could be associated with activation of calcium-sensitive receptors by strontium. Such activation has been demonstrated in vitro [18,19]. These changes were not observed to have any clinical consequences.
Strontium ranelate was well tolerated over 3 years of treatment and especially at the upper gastrointestinal level. In conclusion, oral administration of strontium ranelate (2 g/ day) significantly reduced the risk of nonvertebral and hip fractures. Over the 3-year study period, strontium ranelate was well tolerated. These results confirm that strontium ranelate is an effective first-line treatment not only for reducing the risk of osteoporosis-related vertebral fractures but also of nonvertebral and hip fractures risks, in postmenopausal women.
References [1] Parfitt AM, Mundy GR, Roodman GD, Hughes DE, Boyce BF. A new model for the regulation of bone resorption, with particular reference to the effects of bisphosphonates. J Bone Miner Res 1996;11:150–9. [2] Eastell R. Treatment of postmenopausal osteoporosis. N Engl J Med 1998;338:736–46. [3] Dobnig H, Sipos A, Jiang Y, Fahrleitner-Pammer A, Ste-Marie LG, Gallagher JC, et al. Early changes in biochemical markers of bone formation correlate with improvements in bone structure during Teriparatide therapy. J Clin Endocrinol Metab 2005;90:3970–7. [4] Marie PJ, Hott M, Modrowski D, De Pollack C, Guillemain J, Deloffre P, et al. An uncoupling agent containing strontium prevents bone loss by depressing bone resorption and maintaining bone formation in estrogendeficient rats. J Bone Miner Res 1993;8:607–15. [5] Meunier PJ, Slosman DO, Delmas PD, Sebert JL, Brandi ML, Lorenc ACR, et al. Strontium ranelate: dose-dependent effects in established postmenopausal vertebral osteoporosis—A 2-year randomised placebocontrolled trial. J Clin Endocrinol Metab 2002;87:2060–6. [6] Meunier PJ, Reginster JY. Design and methodology of the phase 3 trials for the clinical development of strontium ranelate in the treatment of women with postmenopausal osteoporosis. Osteoporos Int 2003;14(Suppl 3): S66–76. [7] Meunier PJ, Roux C, Seeman E, Ortolani S, Badurski JE, Spector T, et al. The effects of strontium ranelate on the risk of vertebral fracture in women with postmenopausal osteoporosis. N Engl J Med 2004;350:459–68. [8] Reginster JY, Seeman E, De Vernejoul C, Adami S, Compston J, Phenekos C, et al. Strontium ranelate reduces the risk of nonvertebral fractures in postmenopausal women with osteoporosis treatment of peripheral osteoporosis (TROPOS) study. J Clin Endocrinol Metab 2005;90: 2816–22. [9] Slosman D, Provvedini DM, Meunier PJ, Delmas PD, Sebert JL, De Vernejoul MC, et al. The use of different dual X-ray absorptiometry brands in a multicenter clinical trial. J Clin Densitom 1999;2:37–44. [10] Committee for Proprietary Medicinal Products. Note for guidance on post menopausal osteoporosis in women Rev. 1 (CPMP adopted January 2001). [11] FDA, Draft Guidance Postmenopausal Osteoporosis. Preclinical and clinical evaluation of agents used in the prevention and treatment of postmenopausal osteoporosis (Issued 4/1994). [12] McClung MR, Geusens P, Miller PD, Zippel H, Bensen WG, Roux C, et al. Effect of risedronate on the risk of hip fracture in elderly women. Hip Intervention Program Study Group. N Engl J Med 2001; 344:333–40. [13] Reginster JY, Minne HW, Sorensen OH, Hooper M, Roux C, Brandi ML, et al. Randomized trial of the effects of risedronate on vertebral fractures in women with established post-menopausal osteoporosis. Vertebral Efficacy with Risedronate Therapy (VERT) Study Group. Osteoporos Int 2000;11:83–91. [14] Harris ST, Watts NB, Genant HK, McKeever CD, Hangartner T, Keller M, et al. Effects of risedronate treatment on vertebral and nonvertebral fractures in women with postmenopausal osteoporosis. JAMA 1999; 282:1344–52. [15] Black DM, Cummings SR, Karpf DB, Cauley JA, Thompson DE, Nevitt MC, et al. Randomised trial of the effect of alendronate on risk of fracture
S. Adami / Bone 38 (2006) S23–S27 in women with existing vertebral fractures, Fracture Intervention Trial Research Group. Lancet 1996;348:1535–41. [16] Cummings SR, Black DM, Thompson DE, Applegate WB, Barrett-Connor E, Musliner TA, et al. Effect of alendronate on risk of fracture in women with low bone density but without vertebral fractures: results from the Fracture Intervention Trial. JAMA 1998;280:2077–82. [17] Donaldson LJ, Cook A, Thompson RG. Incidence of fractures in a
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geographically defined population. J Epidemiol Community Health 1990;44:241–5. [18] Coulombe J, Faure H, Robin B, Tsouderos Y, Ruat M. Activation of the rat and mouse cation-sensing receptor by strontium ranelate and its modulation by extracellular calcium. Osteoporos Int 13 (Suppl 1) P70MO. [19] Pi M, Quarles LD. A novel cation-sensing mechanism in osteoblasts is a molecular target for strontium. J Bone Miner Res 2004;19:862–9.
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Protelos: Nonvertebral and hip antifracture efficacy in postmenopausal osteoporosis S. Adami ⁎ Rheumatology Rehabilitation Unit of the University of Verona, Valeggio sul Mincio, Italy Received 31 May 2005; accepted 23 August 2005 Available online 24 January 2006
Abstract Strontium ranelate is a new treatment for postmenopausal osteoporosis, simultaneously increasing bone formation and decreasing bone resorption, thus rebalancing bone turnover in favor of bone formation. Strontium ranelate was demonstrated to significantly reduce the relative risk of vertebral fracture whatever the severity of the disease. In the TReatment Of Peripheral OSteoporosis (TROPOS) study, the incidence of nonvertebral and hip fractures, following treatment with strontium ranelate (Protelos®, Servier) at a dosage of 2 g/day orally, was assessed over a 3-year period. In this double-blind, placebo-controlled trial, 5091 women with postmenopausal osteoporosis were assigned to either strontium ranelate (n = 2479) or placebo (n = 2453) treatment. Overall, the reduction in risk for nonvertebral fractures in patients treated with strontium ranelate was 16% (P = 0.04) and for major fractures (hip, wrist, pelvis and sacrum, ribs and sternum, clavicle and humerus), it was 19% (P = 0.031), compared with those treated with placebo. Women with osteoporosis and aged 74 years or more who were treated with strontium ranelate (n = 982) had a 36% reduction in risk of hip fracture (P = 0.046) over 3 years compared with those treated with placebo (n = 995). The difference in bone mineral density between groups was 8.2% for femoral neck and 9.8% for total hip at 3 years. The incidence of adverse events was comparable between groups. The study demonstrates that strontium ranelate treatment offers a safe and effective means of reducing the risk of nonvertebral and hip fractures in postmenopausal women with osteoporosis. © 2005 Published by Elsevier Inc. Keywords: Strontium ranelate; Osteoporosis; Nonvertebral fractures; Hip fractures; Postmenopausal
Introduction Bone remodeling continues into adult life, and the enhanced bone fragility, in postmenopausal women with osteoporosis, arises from a mismatch between bone resorption and bone formation. Currently, most agents available for the treatment of osteoporosis inhibit bone resorption, but, within months, this is accompanied by a reduction in bone formation [1,2]. On the other hand, some available agents act by stimulating bone formation which is associated with an increase in bone resorption [3]. Evidence from in vitro and in vivo studies suggests that strontium ranelate, an innovative orally active drug, has a different action on the two processes of bone turnover such that bone formation increases while bone resorption decreases, thus rebalancing bone turnover in favor of bone formation [4]. In STRATOS ⁎ Fax: +39 045 79 52 000. E-mail address: [email protected]. 8756-3282/$ - see front matter © 2005 Published by Elsevier Inc. doi:10.1016/j.bone.2005.08.028
(STRontium Administration for the Treatment of OSteoporosis), it was demonstrated that strontium ranelate 2 g/day was the effective dose for preventing bone loss in postmenopausal osteoporosis with a good tolerability profile [5]. A huge development program was then instigated to assess the effects of strontium ranelate (Protelos®, Servier), at a daily dose of 2 g, in reducing the relative risk (RR) of fracture in women with postmenopausal osteoporosis. This program began with FIRST (Fracture International Run-in for Strontium ranelate Trial) starting the normalization of the calcium and vitamin D status of potential candidates for the SOTI (Spinal Osteoporosis Therapeutic Intervention) or TROPOS (TReatment of Peripheral OSteoporosis) trials [6]. Treatment with strontium ranelate reduced the RR of new vertebral fractures by 49% in the first year and by 41% over 3 years, in the SOTI clinical trial of 1649 postmenopausal women [7]. In this report, we present evidence from the TROPOS randomized, double-blind, placebo-controlled clinical trial on
S24
S. Adami / Bone 38 (2006) S23–S27
the efficacy and safety of Protelos® (strontium ranelate) in preventing nonvertebral and hip fractures [8]. Materials and methods Study subjects Postmenopausal, ambulatory women of 74 years of age or more, or 70 to 74 years with an additional risk factor (i.e., history of osteoporotic fracture after menopause, resident in a retirement home, frequent falls or a maternal history of osteoporotic fractures of the hip, spine, or wrist) were recruited at 75 centers in 11 European countries and in Australia. In addition, these women had to have a femoral neck bone mineral density (BMD) of ≤0.6 g/cm2 (measured with Hologic instruments), corresponding to a T score b−2.5. Women with diseases interfering with bone metabolism and those using antiosteoporotic agents (bisphosphonates taken for more than 14 days within the previous year, estrogen, calcitonin, fluoride salts, calcitriol or 1-alpha-vitamin D taken for more than 1 month during the previous 6 months) were excluded. Patients were told of the nature, purpose and duration of the study and given the opportunity to ask questions. They were informed that they were free to withdraw from the study at any time. On this basis, all participants gave written informed consent prior to being enrolled in the study. The study was approved by the Institutional Review Boards.
Study design Subjects were initially subjected to a run-in period of between 2 weeks and 6 months to start to normalize their calcium and vitamin D status (FIRST study). All women received daily supplements of elemental calcium (0, 500 or 1000 mg) such that their total daily intake was above 1000 mg. Vitamin D was administered at 800 IU for patients with a serum 25-hydroxyvitamin D lower than 45 nmol/L and 400 IU for all others. If the 25-OH vitamin D level was lower than 30 nmol/L, then the duration of the run-in was at least 3 months. Calcium and vitamin D supplementation was maintained throughout the study at a dose determined during this run-in period. At the end of the run-in period, patients were randomly assigned to receive either 2 g/day of strontium ranelate or placebo for 5 years. Patients were able to take the study drug once daily at bedtime or twice daily (one sachet half an hour before breakfast and one at bedtime): almost 90% of patients took the drug once daily at bedtime. The incidence of nonvertebral fractures over a 3-year treatment period was the main evaluation criterion. Nonvertebral fractures were defined as fractures occurring at a nonvertebral site, with fractures of the coccyx, skull, jaw, face, ankle and phalanx (fingers and toes) not considered as related to osteoporosis and not taken into account in the analysis. The incidence of major nonvertebral fractures was one of the secondary end points. These fractures were defined as fractures located at the hip, wrist, pelvis and sacrum, ribs/sternum, clavicle or humerus. Patients were asked to attend visits on a regular basis: at baseline, month 3, month 6 and then every 6 months until the end of the study. During the study, nonvertebral fractures were reported by the study investigators based on written documentation provided and documented in the source document (radiograph, radiological report, hospitalization/ emergency department report). Only documented fractures were taken into account in the statistical analysis. BMD was measured by dual energy X-ray absorptiometry (DXA) at baseline and at 6-monthly intervals at the proximal femur and total hip, and scans were analyzed centrally. Quality control throughout the study included serial measurements of a spine phantom and daily quality controls [9]. Blood and urine samples were stored at −80°C and centrally analyzed. Biochemical tests were performed using standard methods. Serum parathyroid hormone (PTH) concentrations were measured using an immunoradiometric assay (N-tact®, Diasorin; laboratory reference range: 10–65 pg/mL), 25hydroxyvitamin D using a radioimmunoassay (Diasorin; laboratory reference range: 7.5–101.0 nmol/L) and 1,25-dihydroxyvitamin D with a radioreceptor assay (Diasorin).
Statistical analyses Unless otherwise stated, all analyses were performed on data obtained at baseline and until the last patient completed 3 years of follow-up to comply with international guidelines [10,11]. Antifracture efficacy, for nonvertebral fractures, was analyzed for the intention-to-treat (ITT) population, defined as patients who had received at least one sachet of medication and with at least one postbaseline assessment of nonvertebral fracture occurrence. Major nonvertebral fractures were analyzed for the ITT population. Hip fracture incidence was analyzed for a post-hoc ITT subgroup of osteoporotic patients, aged ≥74 years (femoral neck BMD T score of −2.4 according to National Health And Nutrition Examination Survey [NHANES] III). Safety was assessed for all patients who had received a least one sachet of strontium ranelate. The TROPOS trial was implemented in 1996, which was prior to the release of the first European Committee for Medicinal Products for Human Use (CHMP) guidelines on osteoporosis in 1997. This study was powered to evaluate the RR of nonvertebral fractures between groups. However, although nonvertebral (primary end point) major osteoporosis-related fractures and hip fractures were documented separately and individually analyzed as requested in the CHMP guidelines issued in 2001 (CPMP/EW/552/95 rev 1), this study was not designed or powered to demonstrate antifracture efficacy at individual sites. The post-hoc subgroup of osteoporotic patients aged 74 years or more was analyzed to comply with this CHMP guidelines (2001). The incidence of patients experiencing nonvertebral fractures was assessed according to the Kaplan–Meier method, and a Cox model was used to compare groups and to estimate the RR and 95% confidence interval (CI). Simultaneous adjustments for influential covariates were carried out for age, femoral neck BMD, body mass index and country. A type one error rate was set at 5% (twosided). A step-down hierarchical procedure was performed, based on the increasing treatment effect over time, for percentage changes from baseline in BMD at each visit. The two groups were compared using a one-sided Student's t test at each visit with a type one error rate of 2.5%. The P values correspond to a two-sided t test at the 5% threshold (one-sided P values were doubled).
Results New nonvertebral fractures Of the patients who were recruited to the study, 97% (4932 patients) formed the ITT population as defined in the above paragraph. Strontium ranelate was administered to 2479 patients, and 2453 patients received placebo (Table 1). The baseline characteristics were similar in the two groups with mean ages of 77 years (Table 2), and the overall duration of treatment was 906 ± 471 days (mean ± SD) corresponding to a mean global compliance of 82%. Table 1 Overview of study populations in the TReatment Of Peripheral OSteoporosis (TROPOS) study Study population n
Strontium ranelate
Placebo
Excluded
Total
Randomized Safety Intention to treat Completed follow-up at 3 years Osteoporotic patients aged 74 years or more
2554 2526 2479 1687
2537 2503 2453 1633
n/a 62 a 97 b 1612 c
5091 5029 4932 3320
982
995
n/a
1977
n/a = not applicable. a Patients excluded from randomized set as no treatment intake. b Patients excluded from safety set as no assessment of nonvertebral fracture. c 1587 patients withdrew, and 25 were lost to follow-up.
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Table 2 Baseline characteristics of the intention-to-treat population and of osteoporotic patients aged 74 years or more in the TReatment Of Peripheral OSteoporosis (TROPOS) study
Intention-to-treat population (ITT) N Mean age ± SD (years) Prevalent osteoporotic fracture (vertebral or nonvertebral) (%) Mean time since menopause ± SD (years)
Strontium ranelate
Placebo
2479 76.7 ± 5.0 55.4
2453 76.8 ± 5.0 54.2
28.4 ± 7.3
28.5 ± 7.5
ITT subset of osteoporotic patients aged 74 years or more N 982 Mean age ± SD (years) 79.7 ± 4.6 Prevalent osteoporotic 58.8 fracture (vertebral or nonvertebral) (%) Mean time since 31.4 ± 7.0 menopause ± SD (years)
995 79.5 ± 4.4 57.4
31.6 ± 7.0
In these patients, the mean duration of the run-in period was 101 ± 52 (mean ± SD) days. Using the Kaplan–Meier method, the incidence of patients experiencing at least one new nonvertebral fracture over 36 months of study was 11.2% in the strontium ranelate group and 12.9% in the placebo group. There was a significant 16% reduction in risk of all nonvertebral fractures in the strontium ranelate group compared with the placebo group (RR, 0.84; 95% CI [0.702; 0.995]; P = 0.04). The incidence of patients experiencing at least one new major nonvertebral fracture over 36 months of study was 8.7% in the strontium ranelate group and 10.4% in the placebo group: the reduction in RR was 19%, (RR, 0.81; 95% CI [0.66; 0.98]; P = 0.031). Hip fractures Among the patients included in the ITT population, a subset of osteoporotic patients, aged 74 years or more, was made: there were 1977 of these patients, and they were treated with either strontium ranelate (n = 982) or placebo (n = 995). They had similar baseline characteristics, and their mean age was 80 years (Table 2). The mean overall duration of treatment of these patients was 838 ± 485 days (mean ± SD) corresponding to a mean global compliance of 80%. The incidence of patients experiencing at least one hip fracture over the 36 months of the study was 4.3% in the strontium ranelate group and 6.4% in the placebo group. When these patients were treated with strontium ranelate, they had a relative reduction of 36% (RR, 0.64; 95% CI [0.412; 0.997]; P = 0.046) in the risk of hip fracture compared with those treated with placebo (Fig. 1). Bone mineral density Data from BMD measurements showed an increase of 5.1% at the femoral neck and 7.1% at the total hip (P b 0.001 for each)
Fig. 1. Cumulative incidence over time of osteoporotic patients aged 74 or more with at least one incident osteoporosis-related hip fracture in the intention-totreat population.
for patients in the strontium ranelate group at 3 years. As BMD decreased in the placebo group over 3 years, the increases in the strontium ranelate group compared with placebo were more pronounced at 8.2% (95% CI [7.7;8.7]; P b 0.001) and 9.8% (95% CI [9.3;10.4]; P b 0.001) for the femoral neck and hip, respectively. The strontium distribution in bone accounts for approximately 50% of these BMD increases. Safety Treatment with strontium ranelate was well tolerated, and the overall incidence of adverse events, serious adverse events and withdrawals due to adverse events was well balanced between groups (Table 3). By considering adverse events one by one, the incidence of nausea, diarrhea, dermatitis and eczema and headaches was reported significantly more in the strontium ranelate group. Concerning nausea and diarrhea, the incidence in both groups was similar after 3 months. The upper gastrointestinal tolerance was particularly good in the strontium ranelate group in which the incidence of gastritis was comparable to that of the placebo group. In the strontium ranelate group, a significant slight decrease in serum calcium and a significant slight increase in serum phosphorus were observed in comparison to the placebo group. In addition, a slight decrease in parathyroid hormone was observed in both groups, being more pronounced in the
Table 3 Adverse events in the TReatment Of Peripheral Osteoporosis (TROPOS) study Strontium ranelate N 2479 Adverse events n (%) 2179 (87.9) Serious adverse events n (%) 612 (24.7) Withdrawals due to 600 (24.2) adverse events n (%) Most commonly reported in the strontium ranelate group Nausea a 178 (7.2) Diarrheaa 166 (6.7) Dermatitis and eczema 136 (5.5) Headache 84 (3.4) a
After 3 months, there was no more difference between groups.
Placebo 2453 2181 (88.9) 599 (24.4) 530 (21.6)
108 (4.4) 123 (5.0) 108 (4.4) 59 (2.4)
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strontium ranelate group. These changes were not associated with clinical sign or symptom. No changes were observed in serum 25-hydroxyvitamin D or 1,25-dihydroxyvitamin D levels at the end of the study compared with baseline. Discussion Most previous clinical studies of antiosteoporosis agents have used vertebral fractures as the primary efficacy end point. The TROPOS study was primarily designed to assess the incidence of nonvertebral fractures following strontium ranelate treatment in a double-blind, placebo-controlled trial. The only previous study in which a registered antiosteoporosis drug was assessed using a nonvertebral site as a primary end point was the HIP (Hip Intervention Program) study with risedronate [12]. The risk of major nonvertebral osteoporotic fractures was reduced by 20% in women receiving risedronate (pooled 2.5 mg and 5 mg doses) compared with those receiving placebo. Our results with strontium ranelate show a similar efficacy, with a reduction of 19% in the risk of major nonvertebral fractures. The risk of all nonvertebral fractures was also reduced. In the VERTNA (Vertebral Efficacy with Risedronate Therapy, North America), there was a reduction in nonvertebral fractures (clavicle, humerus, wrist, pelvis, hip or leg), but this was not evident in the VERT-MN (multinational) study [13,14]. Studies in which the efficacy of antiosteoporosis agents in preventing nonvertebral fractures is assessed are more complex than those in which vertebral fractures are investigated; factors such as the propensity to fall, visual impairment and reduced mobility are likely to influence the outcome. In the FIT (Fracture Intervention Trial) study, with the antiresorptive agent alendronate, there was no significant reduction in the risk of nonvertebral fracture in the population as a whole. However, significant reductions were reported in subgroups of patients with a prevalent fracture or femoral neck BMD T score of less than −2.5 SD [15,16]. Although the original study was not powered to measure a reduction in the risk of hip fracture, we assessed the RR of this type of fracture, following strontium ranelate treatment, in osteoporotic patients aged 74 years or more. This was an appropriate population for this study as the incidence of hip fracture rises exponentially after the age of 74 years [17]. The reduction in risk of hip fracture (36%) in patients treated with strontium ranelate was consistent with that observed in the HIP trial with risedronate. In TROPOS, there were significant increases in the femoral neck and hip BMD following strontium ranelate (2 g/day) treatment consistent with what has previously been observed [7]. The decrease in serum calcium and parathyroid hormone and the significant increase in serum phosphorus observed in the strontium ranelate group in comparison to the placebo group could be associated with activation of calcium-sensitive receptors by strontium. Such activation has been demonstrated in vitro [18,19]. These changes were not observed to have any clinical consequences.
Strontium ranelate was well tolerated over 3 years of treatment and especially at the upper gastrointestinal level. In conclusion, oral administration of strontium ranelate (2 g/ day) significantly reduced the risk of nonvertebral and hip fractures. Over the 3-year study period, strontium ranelate was well tolerated. These results confirm that strontium ranelate is an effective first-line treatment not only for reducing the risk of osteoporosis-related vertebral fractures but also of nonvertebral and hip fractures risks, in postmenopausal women.
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