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Strontium ranelate treatment increases osteoprotegerin serum levels in postmenopausal osteoporotic women
Bone 50 (2012) 1201–1202
Contents lists available at SciVerse ScienceDirect
Bone journal homepage: www.elsevier.com/locate/bone
Letter to the Editor Strontium ranelate treatment increases osteoprotegerin serum levels in postmenopausal osteoporotic women
women treatment with SrRan, support Peng and colleagues' hypothesis that OPG might be a primary mediator of SrRan opposite effects on bone resorption and formation.
Dear Editor, Conflict of interest In the September Epub issue of BONE [1], Peng et al. suggested that osteoprotegerin (OPG) plays an important role in the cross-talking between osteoclasts and osteoblasts in response to strontium ranelate (SrRan) treatment. This elegant, in vitro, study confirms previous results published by the same group suggesting that OPG deficiency attenuates strontium-mediated inhibition of osteoclastogenesis and bone resorption [2]. SrRan is prescribed for the management of postmenopausal osteoporosis, following two large clinical trials which demonstrated its ability to reduce vertebral and non-vertebral fractures [3,4]. A dual mode of action for SrRan, concomitantly reducing bone resorption and stimulating bone formation was extensively described in several preclinical studies [5]. In the above-referenced clinical trials, bone turnover markers, i.e. serum bone-specific alkaline phosphatase (sbALP), serum C-terminal propeptide of type I procollagen (sPICP), urinary N-telopeptide cross-links (uNTX) and serum type I collagen C-telopeptide (sCTX1) variations supported a dissociated effect on osteoblasts (promoted) and osteoclasts (inhibited [3,4,6]. However, the mechanism though which SrRan uncouples in vivo bone resorption from bone formation remains to be fully elucidated. Assuming that the determinant role of OPG described by Peng et al. [1,2] also occurs in vivo, significant variations in serum OPG would be anticipated, in osteoporotic patients, during treatment with SrRan. Therefore, OPG levels were measured in 2335 patients from the population of the TROPOS study [4] who had available blood samples at baseline and after 3, 6, 12, 24 and 36 months. Blood samples were collected under fasting conditions at each visit and immediately centrifuged, and serum was stored at − 80 °C until measurement. Serum OPG levels were measured using the ELISA from Immundiagnostik, Germany. This sandwich-type ELISA is an assay for the direct determination of OPG levels in serum, plasma and urine using two highly specific antibodies against OPG. The method was validated by our laboratory; the detection limit was estimated at 0.43 pmol/L, the within-assay precision b6% and the inter-assay variability b15%. At baseline, no significant differences were observed between the strontium ranelate group (5.50 ± 1.82 pmol/L) and the placebo group (5.52 ± 1.87 pmol/L) for OPG serum levels. At the third month of therapy, the serum OPG concentration was higher in the strontium ranelate group than in the placebo group, with a mean (SD) difference between groups of 0.15 (0.03) pmol/L (2.6%, p b 0.001), and this difference persisted at each evaluation during the 3 years (all p b 0.001). After 3 years, a mean (SD) difference between the two groups of 0.24 (0.05) pmol/L (3.7%, p b 0.001) was observed. The levels of OPG observed in this study remained within normal ranges. In conclusion, these results, showing a significant and persistent increase in OPG serum concentrations, in osteoporotic post-menopausal 8756-3282/$ – see front matter © 2012 Elsevier Inc. All rights reserved. doi:10.1016/j.bone.2011.12.024
Jean-Yves Reginster Consulting fees or paid advisory boards: Servier, Novartis, Negma, Lilly, Wyeth, Amgen, GlaxoSmithKline, Roche, Merckle, Nycomed, NPS, Theramex, UCB. Lecture fees when speaking at the invitation of a commercial sponsor: Merck Sharp and Dohme, Lilly, Rottapharm, IBSA, Genevrier, Novartis, Servier, Roche, GlaxoSmithKline, Teijin, Teva, EbeweePharma, Zodiac, Analis, Theramex, Nycomed, Novo-Nordisk. Grant support from industry: Bristol Myers Squibb, Merck Sharp & Dohme, Rottapharm, Teva, Lilly, Novartis, Roche, GlaxoSmithKline, Amgen, Servier. Olivier Bruyere Grant research: GlaxoSmithKline, IBSA, Merck Sharp & Dohme, Theramex, Novartis, Pfizer, Rottapharm, Servier. Consulting or lecture fees: IBSA, Rottapharm, Servier. Reimbursement for attending meetings: IBSA, Merck Sharp & Dohme, Novartis, Pfizer, Rottapharm, Theramex, Servier. Julien Collette has no conflict of interest. References [1] Peng S, Liu XS, Huang S, Li Z, Pan H, Zhen W, Luk KD, Guo XE, Lu WW. The cross-talk between osteoclasts and osteoblasts in response to strontium treatment: involvement of osteoprotegerin. Bone 2011;49:1290–8. [2] Peng S, Liu XS, Zhou G, Li Z, Luk KD, Guo XE, Lu WW. Osteoprotegerin deficiency attenuates strontium-mediated inhibition of osteoclastogenesis and bone resorption. J Bone Miner Res 2011;26:1272–82. [3] Meunier PJ, Roux C, Seeman E, Ortolani S, Badurski JE, Spector TD, Cannata J, Balogh A, Lemmel EM, Pors-Nielsen S, Rizzoli R, Genant HK, Reginster JY. The effects of strontium ranelate on the risk of vertebral fracture in women with postmenopausal osteoporosis. N Engl J Med 2004;350:459–68. [4] Reginster JY, Seeman E, De Vernejoul MC, Adami S, Compston J, Phenekos C, Devogelaer JP, Curiel MD, Sawicki A, Goemaere S, Sorensen OH, Felsenberg D, Meunier PJ. 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. [5] Marie PJ, Felsenberg D, Brandi ML. How strontium ranelate, via opposite effects on bone resorption and formation, prevents osteoporosis. Osteoporos Int 2011;22: 1659–67. [6] Bruyere O, Collette J, Reginster JY. The effects of strontium ranelate on biochemical markers of bone turnover and their relationship with bone mineral density. Osteoporos Int 2010;21:1039–40.
J.Y. Reginster Bone and Cartilage Metabolism Research Unit and Department of Public Health Sciences, CHU Centre-Ville, Policliniques L. Brull, University of Liège, Liège, Belgium Corresponding author at: Bone and Cartilage Metabolism Research Unit, CHU Centre-Ville, Policliniques L. Brull, Quai Godefroid Kurth 45 (9ème étage), 4020 Liege, Belgium. Fax: +32 4 270 32 53. E-mail address: [email protected].
1202
Letter to the Editor
O. Bruyere Department of Public Health Sciences, CHU Sart Tilman, University of Liège, Liège, Belgium Fax: +32 4 366 28 12. E-mail address: [email protected].
J. Collette Bone and Cartilage Markers Laboratory, Unilab Lg, CHU Sart Tilman, University of Liège, Liège, Belgium Fax: +32 4 270 32 53. E-mail address: [email protected].
Contents lists available at SciVerse ScienceDirect
Bone journal homepage: www.elsevier.com/locate/bone
Letter to the Editor Strontium ranelate treatment increases osteoprotegerin serum levels in postmenopausal osteoporotic women
women treatment with SrRan, support Peng and colleagues' hypothesis that OPG might be a primary mediator of SrRan opposite effects on bone resorption and formation.
Dear Editor, Conflict of interest In the September Epub issue of BONE [1], Peng et al. suggested that osteoprotegerin (OPG) plays an important role in the cross-talking between osteoclasts and osteoblasts in response to strontium ranelate (SrRan) treatment. This elegant, in vitro, study confirms previous results published by the same group suggesting that OPG deficiency attenuates strontium-mediated inhibition of osteoclastogenesis and bone resorption [2]. SrRan is prescribed for the management of postmenopausal osteoporosis, following two large clinical trials which demonstrated its ability to reduce vertebral and non-vertebral fractures [3,4]. A dual mode of action for SrRan, concomitantly reducing bone resorption and stimulating bone formation was extensively described in several preclinical studies [5]. In the above-referenced clinical trials, bone turnover markers, i.e. serum bone-specific alkaline phosphatase (sbALP), serum C-terminal propeptide of type I procollagen (sPICP), urinary N-telopeptide cross-links (uNTX) and serum type I collagen C-telopeptide (sCTX1) variations supported a dissociated effect on osteoblasts (promoted) and osteoclasts (inhibited [3,4,6]. However, the mechanism though which SrRan uncouples in vivo bone resorption from bone formation remains to be fully elucidated. Assuming that the determinant role of OPG described by Peng et al. [1,2] also occurs in vivo, significant variations in serum OPG would be anticipated, in osteoporotic patients, during treatment with SrRan. Therefore, OPG levels were measured in 2335 patients from the population of the TROPOS study [4] who had available blood samples at baseline and after 3, 6, 12, 24 and 36 months. Blood samples were collected under fasting conditions at each visit and immediately centrifuged, and serum was stored at − 80 °C until measurement. Serum OPG levels were measured using the ELISA from Immundiagnostik, Germany. This sandwich-type ELISA is an assay for the direct determination of OPG levels in serum, plasma and urine using two highly specific antibodies against OPG. The method was validated by our laboratory; the detection limit was estimated at 0.43 pmol/L, the within-assay precision b6% and the inter-assay variability b15%. At baseline, no significant differences were observed between the strontium ranelate group (5.50 ± 1.82 pmol/L) and the placebo group (5.52 ± 1.87 pmol/L) for OPG serum levels. At the third month of therapy, the serum OPG concentration was higher in the strontium ranelate group than in the placebo group, with a mean (SD) difference between groups of 0.15 (0.03) pmol/L (2.6%, p b 0.001), and this difference persisted at each evaluation during the 3 years (all p b 0.001). After 3 years, a mean (SD) difference between the two groups of 0.24 (0.05) pmol/L (3.7%, p b 0.001) was observed. The levels of OPG observed in this study remained within normal ranges. In conclusion, these results, showing a significant and persistent increase in OPG serum concentrations, in osteoporotic post-menopausal 8756-3282/$ – see front matter © 2012 Elsevier Inc. All rights reserved. doi:10.1016/j.bone.2011.12.024
Jean-Yves Reginster Consulting fees or paid advisory boards: Servier, Novartis, Negma, Lilly, Wyeth, Amgen, GlaxoSmithKline, Roche, Merckle, Nycomed, NPS, Theramex, UCB. Lecture fees when speaking at the invitation of a commercial sponsor: Merck Sharp and Dohme, Lilly, Rottapharm, IBSA, Genevrier, Novartis, Servier, Roche, GlaxoSmithKline, Teijin, Teva, EbeweePharma, Zodiac, Analis, Theramex, Nycomed, Novo-Nordisk. Grant support from industry: Bristol Myers Squibb, Merck Sharp & Dohme, Rottapharm, Teva, Lilly, Novartis, Roche, GlaxoSmithKline, Amgen, Servier. Olivier Bruyere Grant research: GlaxoSmithKline, IBSA, Merck Sharp & Dohme, Theramex, Novartis, Pfizer, Rottapharm, Servier. Consulting or lecture fees: IBSA, Rottapharm, Servier. Reimbursement for attending meetings: IBSA, Merck Sharp & Dohme, Novartis, Pfizer, Rottapharm, Theramex, Servier. Julien Collette has no conflict of interest. References [1] Peng S, Liu XS, Huang S, Li Z, Pan H, Zhen W, Luk KD, Guo XE, Lu WW. The cross-talk between osteoclasts and osteoblasts in response to strontium treatment: involvement of osteoprotegerin. Bone 2011;49:1290–8. [2] Peng S, Liu XS, Zhou G, Li Z, Luk KD, Guo XE, Lu WW. Osteoprotegerin deficiency attenuates strontium-mediated inhibition of osteoclastogenesis and bone resorption. J Bone Miner Res 2011;26:1272–82. [3] Meunier PJ, Roux C, Seeman E, Ortolani S, Badurski JE, Spector TD, Cannata J, Balogh A, Lemmel EM, Pors-Nielsen S, Rizzoli R, Genant HK, Reginster JY. The effects of strontium ranelate on the risk of vertebral fracture in women with postmenopausal osteoporosis. N Engl J Med 2004;350:459–68. [4] Reginster JY, Seeman E, De Vernejoul MC, Adami S, Compston J, Phenekos C, Devogelaer JP, Curiel MD, Sawicki A, Goemaere S, Sorensen OH, Felsenberg D, Meunier PJ. 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. [5] Marie PJ, Felsenberg D, Brandi ML. How strontium ranelate, via opposite effects on bone resorption and formation, prevents osteoporosis. Osteoporos Int 2011;22: 1659–67. [6] Bruyere O, Collette J, Reginster JY. The effects of strontium ranelate on biochemical markers of bone turnover and their relationship with bone mineral density. Osteoporos Int 2010;21:1039–40.
J.Y. Reginster Bone and Cartilage Metabolism Research Unit and Department of Public Health Sciences, CHU Centre-Ville, Policliniques L. Brull, University of Liège, Liège, Belgium Corresponding author at: Bone and Cartilage Metabolism Research Unit, CHU Centre-Ville, Policliniques L. Brull, Quai Godefroid Kurth 45 (9ème étage), 4020 Liege, Belgium. Fax: +32 4 270 32 53. E-mail address: [email protected].
1202
Letter to the Editor
O. Bruyere Department of Public Health Sciences, CHU Sart Tilman, University of Liège, Liège, Belgium Fax: +32 4 366 28 12. E-mail address: [email protected].
J. Collette Bone and Cartilage Markers Laboratory, Unilab Lg, CHU Sart Tilman, University of Liège, Liège, Belgium Fax: +32 4 270 32 53. E-mail address: [email protected].