Osteoprotegerin, RANKL, and Bone Turnover in Primary Hyperparathyroidism: The Effect of Parathyroidectomy and Treatment with Alendronate

Abstract

Receptor activator of nuclear factor-κB (RANK), RANK ligand (RANKL), and its decoy receptor osteoprotegerin (OPG) play key roles in regulating bone turnover. The OPG/RANKL/RANK system is regulated by many hormones and cytokines, among which parathormone (PTH) seems to be one of the most important. Primary hyperparathyroidism (PHPT) with chronic excess of PTH and enhanced bone resorption provides an opportunity to observe the relationships between PTH, OPG and RANKL. From a group of 63 patients with PHPT, 29 underwent effective parathyroidectomy (PTX) and 33 were treated with alendronate. After one year, bone mineral density (BMD) improved in both groups, but the biochemical disturbances and PTH returned to normal only after PTX. The baseline serum concentrations of OPG and RANKL were higher in PHPT patients than in healthy controls, whilst the OPG/RANKL-F ratio was lower. The mean OPG concentration did not change after PTX, and slightly increased after alendronate treatment despite the unchanged PTH. Twelve months after treatment, RANKL slightly declined in both groups and the ratio of OPG/RANKL consistently increased. Serum OPG and RANKL did not correlate with PTH before or after PTX or alendronate treatment. In conclusion, bone resorption in PHPT is accompanied by a high serum concentration of OPG and RANKL as well as a low OPG/RANKL ratio. Both parathyroidectomy and treatment with alendronate diminish bone resorption, and correct the OPG/RANKL ratio in favor of OPG, although the mechanisms of their actions are different. Serum OPG concentration does not depend directly on PTH.

Key words

alendronate - hyperparathyroidism - RANKL - bone mineral density

• References

• 1 Simonet WS, Lacey DL, Dunstan CR, Kelley M, Chang MS, Luthy R, Nguyen HQ, Wooden S, Bennett L, Boone T, Shimamoto G, DeRose M, Elliott R, Colombero A, Tan HL, Trail G, Sullivan J, Davey E, Bucay N, Renshaw-Gregg L, Hughes TM, Hill D, Pattison W, Campbell P, Boyle WJ. Osteoprotegerin: a novel secreted protein involved in the regulation of bone density. Cell 1997; 89: 309-319
• 2 Yasuda H, Shima N, Nakagawa N, Yamaguchi K, Kinosaki M, Mochizuki S, Tomoyasu A, Yano K, Goto M, Murakami A, Tsuda E, Morinaga T, Higashio K, Udagawa N, Takahashi N, Suda T. Osteoclast differentiation factor is a ligand for osteoprotegerin/osteoclastogenesis-inhibitory factor and is identical to TRANCE/RANKL. Proc Natl Acad Sci USA 1998; 95: 3597-3602
• 3 Bucay N, Sarosi I, Dunstan CR, Morony S, Tarpley J, Capparelli C, Scully S, Tan HL, Xu W, Lacey DL, Boyle WJ, Simonet WS. Osteoprotegerin-deficient mice develop early onset osteoporosis and arterial calcification. Genes Dev 1998; 12: 1260-1268
• 4 Bone HG, Bolognese MA, Yuen CK, Kendler DL, Wang H, Liu Y, San Martin J. Effects of denosumab on bone mineral density and bone turn­over in postmenopausal women. J Clin Endocrinol Metab 2008; 93: 2149-2157
• 5 Rogers A, Eastell R. Circulating osteoprotegerin and receptor activator for nuclear factor kappaB ligand: clinical utility in metabolic bone disease assessment. J Clin Endocrinol Metab 2005; 90: 6323-6331
• 6 Kearns AE, Khosla S, Kostenuik PJ. Receptor activator of nuclear factor kappaB ligand and osteoprotegerin regulation of bone remodeling in health and disease. Endocr Rev 2008; 29: 155-192
• 7 Findlay DM, Atkins GJ. Relationship between serum RANKL and RANKL in bone. Osteoporos Int 2011; 22: 2597-2602
• 8 Chow CC, Chan WB, Li JKY, Chan NN, Chan MH, Ko GTC, Lo KW, Cockram CS. Oral Alendronate increases bone mineral density in postmenopausal women with primary hyperparathyroidism. J Clin Endocrinol Metab 2003; 88: 581-587
• 9 Rossini M, Gatti D, Isaia G, Sartori L, Braga V, Adami S. Effects of oral alendronate in elderly patients with osteoporosis and mild primary hyperparathyroidism. J Bone Miner Res 2001; 16: 113-119
• 10 Khan AA, Bilezikian JP, Kung AWC, Ahmed MM, Dubois SJ, Ho AYY, Schussheim D, Rubin MR, Shaikh AM, Silverberg SJ, Standish TI, Syed Z, Syed ZA. Alendronate in primary hyperparathyroidism: a double-blind, randomized, placebo-controlled trial. J Clin Endocrinol Metab 2004; 89: 3319-3325
• 11 Bilezikian JP, Khan AA, Potts Jr JT. on behalf of the Third International Workshop on the Management of Asymptomatic Primary Hyperthyroidism . Guidelines for the Management of Asymptomatic Primary Hyperparathyroidism: Summary Statement from the Third International Workshop. J Clin Endocrinol Metab 2009; 94: 335-339
• 12 Huang JC, Sakata T, Pfleger LL, Bencsik M, Halloran BP, Bikle DD, Nissenson RA. PTH differentially regulates expression of RANKL and OPG. J Bone Miner Res 2004; 19: 235-244
• 13 Ma YL, Cain RL, Halladay DL, Yang X, Zeng Q, Miles RR, Chandrasekhar S, Martin TJ, Onvia JE. Catabolic effects of continuous human PTH (1–38) in vivo is associated with sustained stimulation of RANKL and inhibition of osteoprotegerin and gene associated bone formation. Endocrinology 2001; 142: 4047-4054
• 14 Anastasilakis AD, Goulis DG, Polyzos SA, Gerou S, Pavlidou V, Koukoulis G, Avramidis A. Acute changes in serum osteoprotegerin and receptor activator for nuclear factor-kappaB ligand levels in women with established osteoporosis treated with teriparatide. Eur J Endocrinol 2008; 158: 411-415
• 15 Kudlacek S, Schneider B, Woloszczuk W, Pietschmann P, Willvonseder R. Austrian Study Group on Normative Values of Bone Metabolism. Serum levels of osteoprotegerin increase with age in a healthy adult population. Bone 2003; 32: 681-686
• 16 Jacome-Galarza CE, Lee SK, Lorenzo JA, Aguila HL. Parathyroid hormone regulates the distribution and osteoclastogenic potential of hematopoetic progenitors in the bone marrow. J Bone Miner Res 2011; 26: 1207-1216
• 17 Fiore CE, Pennisi P, Ferro G, Ximenes B, Privitelli LR, Mangiafico RA, Santoro F, Parisi N, Lombardo T. Altered Osteoprotegerin/RANKL Ratio and Low Bone Mineral Density in Celiac Patients on Long-term Treatment with Gluten-free Diet. Horm Metab Res 2006; 38: 417-422
• 18 Martini G, Gennari L, Merlotti D, Salvadori S, Franci MB, Campagna S, Avanzati A, De Paola V, 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
• 19 Jabbar S, Drury J, Fordham JN, Datta HK, Francis RM, Tuck SP. Oteoprotegerin, RANKL and bone turnover in postmenopausal osteoporosis. J Clin Pathol 2011; 64: 354-357
• 20 Stilgren LS, Hegedüs LM, Beck-Nielsen H, Abrahamsen B. Osteoprotegerin levels in primary hyperparathyroidism: effect of parathyroidectomy and association with bone metabolism. Calcif Tissue Int 2003; 73: 210-216
• 21 Stilgren LS, Rettmer E, Eriksen EF, Hegedüs L, Beck-Nielsen H, Abrahamsen B. Skeletal changes in osteoprotegerin and receptor activator of nuclear factor kappab ligand mRNA levels in primary hyperparathyroidism: effect of parathyroidectomy and association with bone metabolism. Bone 2004; 35: 256-265
• 22 Nakchbandi IA, Lang R, Kinder B, Insogna KL. The role of the receptor activator of nuclear factor-κB ligand/osteoprotegerin cytokine system in primary hyperparathyroidism. J Clin Endocrinol Metab 2008; 93: 967-973
• 23 Kerschan-Schindl K, Riss P, Krestan C, Rauner M, Bieglmayer C, Gleiss A, Fialka-Moser V, Niederle V, Pietschmann P. Bone Metabolism in Patients with Primary Hyperparathyroidism Before and After Surgery. Horm Metab Res 2012; 44: 476-481
• 24 Dundar U, Kavuncu V, Ciftci IH, Evcik D, Solak O, Cakir T. The effect of risedronate treatment on serum cytokines in postmenopausal osteoporosis: a 6-month randomized and controlled study. J Bone Miner Metab 2009; 27: 464-470
• 25 Reyes-García R, Muñoz-Torres M, García DF, Mezquita-Raya P, García Salcedo JA, de Dios Luna J. Effects of alendronate treatment on serum levels of osteoprotegerin and total receptor activator of nuclear factor kappaB in women with postmenopausal osteoporosis. Menopause 2010; 17: 140-144
• 26 Eslami B, Zhou S, Van Eekeren I, LeBoff MS, Glowacki J. Reduced osteoclastogenesis and RANKL expression in marrow from women taking alendronate. Calcif Tissue Int 2011; 88: 272-280
• 27 Nakamichi Y, Udagawa N, Kobayashi Y, Nakamura M, Yamamoto Y, Tamashita T, Mizoguchi T, Sato M, Mogi M, Penninger JM, Takahashi N. Osteoprotegerin reduces the serum level of receptor activator of NF-κB ligand derived from osteoblasts. J Immunol 2007; 178: 192-200