Abstract
Bone formation is influenced by the Wnt pathway through effects on osteoblast functionality, and these actions are opposed by two antagonists: sclerostin and Dickkopf-1 (DKK1). Decreased levels of serum sclerostin were found after treatment with the PTH analogue teriparatide and in patients with primary hyperparathyroidism (PHPT), while treatment with teriparatide of postmenopausal osteoporosis is associated with increases in serum DKK1. We studied mineral metabolism and Wnt pathway in 21 postmenopausal women affected by PHPT and in 42 age-matched healthy women. Mean serum calcium and PTH were significantly higher and serum phosphates significantly lower in the PHPT group compared with the control group. Serum 25-OH-vitamin D (25OHD) was lower in PHPT patients and 1,25 dihydroxy-vitamin D [1,25(OH)2D] was significantly higher. Patients with PHPT had significantly higher levels of bone alkaline phosphatase (BAP) and of serum C-terminal telopeptides of type I collagene (sCTX). Serum sclerostin in PHPT was significantly lower (−26 %) and serum DKK1 significantly higher (+57 %) than in healthy control subjects. Serum PTH was positively correlated with 1,25OH2D (p < 0.001), BAP (p = 0.036), sCTX (p = 0.003), and DKK1 (p = 0.007) and negatively with 25OHD (p = 0.002) and sclerostin (p = 0.02). In PHPT patients, serum sclerostin was negatively correlated with BAP (p = 0.038) and sCTX (p = 0.07). Patients with PHPT have significantly lower sclerostin and higher DKK1 levels compared with healthy postmenopausal control subjects. Further studies are warranted in order to verify whether the balance between these two opposite effects on Wnt function might help explain the variable bone involvement among patients with PHPT.
Similar content being viewed by others
References
Adami S, Marcocci C, Gatti D (2002) Epidemiology of primary hyperparathyroidism in Europe. J Bone Miner Res 17:N18–N23
Fraser WD (2009) Hyperparathyroidism. Lancet 374:145–158
Baron R, Rawadi G (2007) Targeting the Wnt/beta-catenin pathway to regulate bone formation in the adult skeleton. Endocrinology 148:2635–2643
Ott SM (2005) Sclerostin and Wnt signalling: the pathway to bone strength. J Clin Endocrinol Metab 90:6741–6743
Atkins GJ, Rowe PS, Lim HP, Welldon KJ, Ormsby R, Wijenayaka AR, Zelenchuk L, Evdokiou A, Findlay DM (2011) Sclerostin is a locally acting regulator of late-osteoblast/preosteocyte differentiation and regulates mineralization through a MEPE-ASARM-dependent mechanism. J Bone Miner Res 26:1425–1436
Robling AG, Niziolek PJ, Baldridge LA, Condon KW, Allen MR, Alam I, Mantila SM, Gluhak-Heinrich J, Bellido TM, Harris SE, Turner CH (2008) Mechanical stimulation of bone in vivo reduces osteocyte expression of Sost/sclerostin. J Biol Chem 283:5866–5875
Staehling-Hampton K, Proll S, Paeper BW, Zhao L, Charmley P, Brown A, Gardner JC, Galas D, Schatzman RC, Beighton P, Papapoulos S, Hamersma H, Brunkow ME (2002) A 52-kb deletion in the SOST-MEOX1 intergenic region on 17q12–q21 is associated with van Buchem disease in the Dutch population. Am J Med Genet 110:144–152
Balemans W, Patel N, Ebeling M, Van Hul E, Wuyts W, Lacza C, Dioszegi M, Dikkers FG, Hildering P, Willems PJ, Verheij JB, Lindpaintner K, Vickery B, Foernzler D, Van Hul W (2002) Identification of a 52 kb deletion downstream of the SOST gene in patients with van Buchem disease. J Med Genet 39:91–97
Li X, Ominsky MS, Niu QT, Sun N, Daugherty B, D’Agostin D, Kurahara C, Gao Y, Cao J, Gong J, Asuncion F, Barrero M, Warmington K, Dwyer D, Stolina M, Morony S, Sarosi I, Kostenuik PJ, Lacey DL, Simonet WS, Ke HZ, Paszty C (2008) Targeted deletion of the sclerostin gene in mice results in increased bone formation and bone strength. J Bone Miner Res 23:860–869
Bellido T, Ali AA, Gubrij I, Plotkin LI, Fu Q, O’Brien CA, Manolagas SC, Jilka RL (2005) Chronic elevation of parathyroid hormone in mice reduces expression of sclerostin by osteocytes: a novel mechanism for hormonal control of osteoblastogenesis. Endocrinology 146:4577–4583
Keller H, Kneissel M (2005) SOST is a target gene for PTH in bone. Bone 37:148–158
O’Brien CA, Plotkin LI, Galli C, Goellner JJ, Gortazar AR, Allen MR, Robling AG, Bouxsein M, Schipani E, Turner CH, Jilka RL, Weinstein RS, Manolagas SC, Bellido T (2008) Control of bone mass and remodeling by PTH receptor signaling in osteocytes. PLoS ONE 3:e2942
Powell WF Jr, Barry KJ, Tulum I, Kobayashi T, Harris SE, Bringhurst FR, Pajevic PD (2011) Targeted ablation of the PTH/PTHrP receptor in osteocytes impairs bone structure and homeostatic calcemic responses. J Endocrinol 209:21–32
Kramer I, Loots GG, Studer A, Keller H, Kneissel M (2010) Parathyroid hormone (PTH)-induced bone gain is blunted in SOST over expressing and deficient mice. J Bone Miner Res 25:178–189
Rhee Y, Allen MR, Condon K, Lezcano V, Ronda AC, Galli C, Olivos N, Passeri G, O’Brien CA, Bivi N, Plotkin LI, Bellido T (2011) PTH receptor signalling in osteocytes governs periosteal bone formation and intracortical remodelling. J Bone Miner Res 26:1035–1046
Yu EW, Kumbhani R, Siwila-Sackman E, Leder BZ (2011) Acute decline in serum sclerostin in response to PTH infusion in healthy men. J Clin Endocrinol Metab 96:E1848–E1851
Drake MT, Srinivasan B, Modder UI, Peterson JM, McCready LK, Riggs BL, Dwyer D, Stolina M, Kostenuik P, Khosla S (2010) Effects of parathyroid hormone treatment on circulating sclerostin levels in postmenopausal women. J Clin Endocrinol Metab 95:5056–5062
van Lierop AH, Witteveen JE, Hamdy NAT, Papapoulos SE (2010) Patients with primary hyperparathyroidism have lower circulating sclerostin levels than euparathyroid controls. Eur J Endocrinol 163:833–837
Kaji H, Imanishi Y, Sugimoto T, Seino S (2011) Comparisons of serum sclerostin levels among patients with postmenopausal osteoporosis, primary hyperparathyroidism and osteomalacia. Exp Clin Endocrinol Diabetes 119:440–444
Costa AG, Cremers S, Rubin MR, McMahon DJ, Sliney J Jr, Lazaretti-Castro M, Silverberg SJ, Bilezikian JP (2011) Circulating sclerostin in disorders of parathyroid gland function. J Clin Endocrinol Metab 96:3804–3810
Ardawi MS, Al-Sibiany AM, Bakhsh TM, Rouzi AA, Qari MH (2012) Decreased serum sclerostin levels in patients with primary hyperparathyroidism: a cross-sectional and a longitudinal study. Osteoporos Int 23:1789–1797
Morvan F, Boulukos K, Clément-Lacroix P, Roman Roman S, Suc-Royer I, Vayssière B, Ammann P, Martin P, Pinho S, Pognonec P, Mollat P, Niehrs C, Baron R, Rawadi G (2006) Deletion of a single allele of the Dkk1 gene leads to an increase in bone formation and bone mass. J Bone Miner Res 21:934–945
Li J, Sarosi I, Cattley RC, Pretorius J, Asuncion F, Grisanti M, Morony S, Adamu S, Geng Z, Qiu W, Kostenuik P, Lacey DL, Simonet WS, Bolon B, Qian X, Shalhoub V, Ominsky MS, Zhu Ke H, Li X, Richards WG (2006) DKK1-mediated inhibition of Wnt signalling in bone results in osteopenia. Bone 39:754–766
Li X, Grisanti M, Fan W, Asuncion FJ, Tan HL, Dwyer D, Han CY, Yu L, Lee J, Lee E, Barrero M, Kurimoto P, Niu QT, Geng Z, Winters A, Horan T, Steavenson S, Jacobsen F, Chen Q, Haldankar R, Lavallee J, Tipton B, Daris M, Sheng J, Lu HS, Daris K, Deshpande R, Valente EG, Salimi-Moosavi H, Kostenuik PJ, Li J, Liu M, Li C, Lacey DL, Simonet WS, Ke HZ, Babij P, Stolina M, Ominsky MS, Richards WG (2011) Dickkopf-1 regulates bone formation in young growing rodents and upon traumatic injury. J Bone Miner Res 26:2610–2621
Gatti D, Viapiana O, Idolazzi L, Fracassi E, Rossini M, Adami S (2011) The waning of teriparatide effect on bone formation markers in postmenopausal osteoporosis is associated with increasing serum levels of DKK1. J Clin Endocrinol Metab 96:1555–1559
Mirza FS, Padhi ID, Raisz LG, Lorenzo JA (2010) Serum sclerostin levels negatively correlate with parathyroid hormone levels and free estrogen index in postmenopausal women. J Clin Endocrinol Metab 95:1991–1997
Pederson L, Ruan M, Westendorf JJ, Khosla S, Oursler MJ (2008) Regulation of bone formation by osteoclasts involves Wnt/BMP signalling and the chemokine sphingosine-1-phosphate. Proc Natl Acad Sci USA 105:20764–20769
Thambias S, Roplekar R, Manghat P, Fogelman I, Fraser WD, Goldsmith D, Hampson G (2012) Circulating sclerostin and dickkopf-1 (DKK1) in predialysis chronic kidney disease (CKD): relationship with bone density and arterial stiffness. Calcif Tissue Int 90:473–480
Silverberg SJ (2007) Vitamin D deficiency and primary hyperparathyroidism. J Bone Miner Res 22:V100–V104
Weaver S, Doherty DB, Jimenez C, Perrier ND (2009) Peer-reviewed, evidence-based analysis of vitamin D and primary hyperparathyroidism. World J Surg 33:2292–2302
Norman J, Goodman A, Politz D (2011) Calcium, parathyroid hormone, and vitamin D in patients with primary hyperparathyroidism: normograms developed from 10,000 cases. Endocr Pract 17:384–394
Souberbielle JC, Maury E, Friedlander G, Cormier C (2010) Vitamin D and primary hyperparathyroidism (PHPT). J Steroid Biochem Mol Biol 121:199–203
Mosekilde L (2008) Primary hyperparathyroidism and the skeleton. Clin Endocrinol 69:1–19
Eriksen EF, Mosekilde L, Melsen F (1986) Bone remodeling and balance in primary hyperparathyroidism. Bone 7:213–221
Charon SA, Eduard CM, Arlot M, Meunier PJ (1982) Effects of parathyroid hormone on remodeling of iliac trabecular bone packets in patients with primary hyperparathyroidism. Clin Orthop Relat Res 162:255–263
van Doorn L, Lips P, Netelenbos JC, Hackeng WH (1993) Bone histomorphometry and serum concentrations of intact parathyroid hormone (PTH(1–84)) in patients with primary hyperparathyroidism. Bone Miner 23:233–242
Christiansen P, Steiniche T, Vesterby A, Mosekilde L, Hessov I, Melsen F (1992) Primary hyperparathyroidism: iliac crest trabecular bone volume, remodeling and balance evaluated by histomorphometric methods. Bone 13:41–49
Steiniche T, Christiansen P, Vesterby A, Ullerup R, Hessov I, Mosekilde L, Melsen F (2000) Primary hyperparathyroidism: bone structure, balance, and remodeling before and 3 years after surgical treatment. Bone 26:535–543
Parisien M, Silverberg SJ, Shane E, de la Cruz L, Lindsay R, Bilezikian JP, Dempster DW (1990) The histomorphometry of bone in primary hyperparathyroidism: preservation of cancellous bone structure. J Clin Endocrinol Metab 70:930–938
Acknowledgments
We would like to thank Caterina Fraccarollo, Cristina Bosco, and Fabio Poli for the ELISA assays.
Author information
Authors and Affiliations
Corresponding author
Additional information
The authors have stated that they have no conflict of interest.
Rights and permissions
About this article
Cite this article
Viapiana, O., Fracassi, E., Troplini, S. et al. Sclerostin and DKK1 in Primary Hyperparathyroidism. Calcif Tissue Int 92, 324–329 (2013). https://doi.org/10.1007/s00223-012-9665-7
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00223-012-9665-7