Serum Osteoprotegerin and RANKL are not Specifically Altered in Women with Postmenopausal Osteoporosis Treated with Teriparatide or Risedronate: A Randomized, Controlled Trial

Abstract

Risedronate and teriparatide have opposite actions on the osteoblast-osteoclast dipole and are expected to influence the RANK/RANKL/osteoprotegerin (OPG) system. We aimed to evaluate changes in serum OPG and RANKL after risedronate or teriparatide administration in postmenopausal osteoporotic women. Seventy-four postmenopausal Caucasian women (age 64.1±1.0 years) were studied. Women with osteopenia served as controls (group 1, n=30). Women with osteoporosis were randomly assigned to either risedronate 35 mg once weekly (group 2, n=21) or teriparatide 20 μg once daily (group 3, n=23) for six months. Blood samples for serum RANKL, OPG, N-terminal propeptide of type 1 collagen (P1NP), and C-terminal telopeptide of type 1 collagen (CTx) were obtained before treatment and three and six months after treatment. P1NP and CTx levels remained unchanged in group 1, decreased in group 2 (p<0.001), and increased in group 3 women (p<0.001) throughout the treatment. OPG levels remained unchanged while RANKL decreased gradually in all groups (p<0.001). There was no correlation between OPG or RANKL and P1NP or CTx. Our data suggest that neither antiresorptive nor osteoanabolic therapy causes specific alterations of serum OPG/RANKL levels; therefore, these cytokines cannot substitute for the established markers of bone turnover in the monitoring of response to osteoporosis treatment.

Key words

osteoprotegerin - RANKL - teriparatide - risedronate - bone markers

References

• 1 Sambrook P, Cooper C. Osteoporosis.  Lancet. 2006;  367 2010-2018
• 2 Wolinsky F, Fitzgerald J, Stump T. The effect of hip fracture on mortality, hospitalization, and functional status: a prospective study.  Am J Public Health. 1997;  87 398-403
• 3 Ray N, Chan J, Thamer M, Melton LR. Medical expenditures for the treatment of osteoporotic fractures in the United States in 1995: report from the National Osteoporosis Foundation.  J Bone Miner Res. 1997;  12 24-35
• 4 Fleisch H. Bisphosphonates: mechanisms of action.  Endocr Rev. 1998;  19 80-100
• 5 Nenonen A, Cheng S, Ivaska K, Alatalo S, Lehtimaki T, Schmidt-Gayk H, Uusi-Rasi K, Heinonen A, Kannus P, Sievanen H, Vuori I, Vaananen H, Halleen J. Serum TRACP 5b is a useful marker for monitoring alendronate treatment: comparison with other markers of bone turnover.  J Bone Miner Res. 2005;  20 1804-1812
• 6 Rosen H, Moses A, Garber J, Iloputaife I, Ross D, Lee S, Greenspan S. Serum CTX: a new marker of bone resorption that shows treatment effect more often than other markers because of low coefficient of variability and large changes with bisphosphonate therapy.  Calcif Tissue Int. 2000;  66 100-103
• 7 Hodsman A, Bauer D, Dempster D, Dian L, Hanley D, Harris S, Kendler D, MacClung M, Miller P, Olszynski W, Orwoll E, Yuen C. Parathyroid hormone and teriparatide for the treatment of osteoporosis: a review of the evidence and suggested guidelines for its use.  Endocr Rev. 2005;  26 688-703
• 8 Orwoll E, Scheele W, Paul S, Adami S, Syversen U, Diez-Perez A, Kaufman J, Clancy A, Gaich G. The effect of teriparatide [human parathyroid hormone (1-34)] therapy on bone density in men with osteoporosis.  J Bone Miner Res. 2003;  18 9-17
• 9 Body J, Gaich G, Scheele W, Kulkarni P, Miller P, Peretz A, Dore R, Correa-Rotter R, Papaioannou A, Cumming D, Hodsman AB. A randomized double-blind trial to compare the efficacy of teriparatide [recombinant human parathyroid hormone (1-34)] with alendronate in postmenopausal women with osteoporosis.  J Clin Endocrinol Metab. 2002;  87 4528-4535
• 10 Black D, Greenspan S, Ensrud K, Palermo L, MacGowan J, Lang T, Garnero P, Bouxsein M, Bilezikian J, Rosen C. The effects of parathyroid hormone and alendronate alone or in combination in postmenopausal osteoporosis.  N Engl J Med. 2003;  349 1207-1215
• 11 Chen P, Satterwhite J, Licata A, Lewiecki E, Sipos A, Misurski D, Wagman R. Early changes in biochemical markers of bone formation predict BMD response to teriparatide in postmenopausal women with osteoporosis.  J Bone Miner Res. 2005;  20 962-970
• 12 Eastell R, Krege J, Chen P, Glass E, Reginster J. Development of an algorithm for using PINP to monitor treatment of patients with teriparatide.  Curr Med Res Opin. 2006;  22 61-66
• 13 Gori F, Hofbauer L, Dunstan C, Spelsberg T, Khosla S, Riggs B. The expression of osteoprotegerin and RANK ligand and the support of osteoclast formation by stromal-osteoblast lineage cells is developmentally regulated.  Endocrinology. 2000;  141 4768-4776
• 14 Rogers A, Richard E. Circulating osteoprotegerin and receptor activator for nuclear factor κB ligand: clinical utility in metabolic bone disease assessment.  J Clin Endocrinol Metab. 2005;  90 6323-6331
• 15 Chen D, Sarikaya N, Gunn H, Martin S, Young J. ELISA methodology for detection of modified osteoprotegerin in clinical studies.  Clin Chem. 2001;  47 747-749
• 16 Eghbali-Fatourechi G, Khosla S, Sanyal A, Boyle W, Lacey D, Riggs B. Role of RANK ligand in mediating increased bone resorption in early postmenopausal women.  J Clin Invest. 2003;  111 1221-1230
• 17 Valleala H, Mandelin J, Laasonen L, Koivula M, Risteli J, Konttinen Y. Effect of cyclical intermittent etidronate therapy on circulating osteoprotegerin levels in patients with rheumatoid arthritis.  Eur J Endocrinol. 2003;  148 527-530
• 18 Alvarez L, Peris P, Guanabens N, Vidal S, Ros I, Pons F, Filella X, Monegal A, Munoz-Gomez J, Ballesta A. Serum osteoprotegerin and its ligand in Paget's disease of bone: relationship to disease activity and effect of treatment with bisphosphonates.  Arthritis Rheum. 2003;  48 824-828
• 19 Martini G, Gennari L, Merlotti D, Salvadori S, Franci M, Campagna S, Avanzati A, Paola V De, Valleggi F, Nuti R. Serum OPG and RANKL levels before and after intravenous bisphosphonate treatment in Paget's disease of bone.  Bone. 2007;  40 457-463
• 20 Dobnig H, Hofbauer L, Viereck V, Obermayer-Pietsch B, Fahrleitner-Pammer A. Changes in the RANK ligand/osteoprotegerin system are correlated to changes in bone mineral density in bisphosphonate-treated osteoporotic patients.  Osteoporos Int. 2006;  17 693-703
• 21 Buxton E, Yao W, Lane N. Changes in serum receptor activator of nuclear factor-κB ligand, osteoprotegerin, and interleukin-6 levels in patients with glucocorticoid-induced osteoporosis treated with human parathyroid hormone (1-34).  J Clin Endocrinol Metab. 2004;  89 3332-3336
• 22 Sasaki N, Kusano E, Ando Y, Yano K, Tsuda E, Asano Y. Glucocorticoid decreases circulating osteoprotegerin (OPG): possible mechanism for glucocorticoid induced osteoporosis.  Nephrol Dial Transplant. 2001;  16 479-482
• 23 Schett G, Kiechl S, Redlich K, Oberhollenzer F, Weger S, Egger G, Mayr A, Jocher J, Xu Q, Pietschmann P, Teitelbaum S, Smolen J, Willeit J. Soluble RANKL and risk of nontraumatic fracture.  JAMA. 2004;  291 1108-1113
• 24 Mezquita-Raya P, Higuera M de la, Garcia D, Alonso G, Ruiz-Requena M, Dios Luna J de, Escobar-Jimenez F, Munoz-Torres M. The contribution of serum osteoprotegerin to bone mass and vertebral fractures in postmenopausal women.  Osteoporos Int. 2005;  16 1368-1374
• 25 Khosla S, Arrighi H, Melton IL, Atkinson E, O’Fallon W, Dunstan C, Riggs B. Correlates of osteoprotegerin levels in women and men.  Osteoporos Int. 2002;  13 394-399
• 26 Szulc P, Hofbauer L, Heufelder A, Roth S, Delmas P. Osteoprotegerin serum levels in men: correlation with age, estrogen, and testosterone status.  J Clin Endocrinol Metab. 2001;  86 3162-3165
• 27 Rogers A, Saleh G, Hannon R, Greenfield D, Eastell R. Circulating estradiol and osteoprotegerin as determinants of bone turnover and bone density in postmenopausal women.  J Clin Endocrinol Metab. 2002;  87 4470-4475
• 28 Fahrleitner-Pammer A, Dobnig H, Piswanger-Soelkner C, Bonelli C, Dimai H, Leb G, Obermayer-Pietsch B. Osteoprotegerin serum levels in women: correlation with age, bone mass, bone turnover and fracture status.  Wien Klin Wochenschr. 2003;  115 291-297
• 29 Indridason O, Franzson L, Sigurdsson G. Serum osteoprotegerin and its relationship with bone mineral density and markers of bone turnover.  Osteoporos Int. 2005;  16 417-423
• 30 Liu J, Zhao H, Ning G, Zhao Y, Chen Y, Zhang Z, Sun L, Xu M, Chen J. Relationships between the changes of serum levels of OPG and RANKL with age, menopause, bone biochemical markers and bone mineral density in Chinese women aged 20-75.  Calcif Tissue Int. 2005;  76 1-6
• 31 Yano K, Tsuda E, Washida N, Kobayashi F, Goto M, Harada A, Ikeda K, Higashio K, Yamada Y. Immunological characterization of circulating osteoprotegerin/osteoclastogenesis inhibitory factor: increased serum concentrations in postmenopausal women with osteoporosis.  J Bone Miner Res. 1999;  14 518-527
• 32 Kudlacek S, Schneider B, Woloszczuk W, Pietschmann P, Willvonseder R. Serum levels of osteoprotegerin increase with age in a healthy adult population.  Bone. 2003;  32 681-686
• 33 Gannage-Yared M, Fares F, Semaan M, Khalife S, Jambart S. Circulating osteoprotegerin is correlated with lipid profile, insulin sensitivity, adiponectin and sex steroids in an ageing male population.  Clin Endocrinol (Oxf). 2006;  64 652-658
• 34 Oh E, Rhee E, Oh K, Lee W, Baek K, Yoon K, Kang M, Yun E, Park C, Choi M, Yoo H, Park S. Circulating osteoprotegerin levels are associated with age, waist-to-hip ratio, serum total cholesterol, and low-density lipoprotein cholesterol levels in healthy Korean women.  Metabolism. 2005;  54 49-54

Correspondence