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J Clin Invest. 1993 April; 91(4): 1769–1774.
PMCID: PMC288157

Serum undercarboxylated osteocalcin is a marker of the risk of hip fracture in elderly women.

Abstract

It has been previously shown that the level of circulating undercarboxylated osteocalcin (ucOC) is elevated in elderly women in comparison with young, healthy, premenopausal ones. To understand the mechanism of the increase in the ucOC in the elderly and to assess its potential consequences on bone fragility, we have measured ucOC in the sera of 195 elderly institutionalized women 70-101 yr of age. In 45 women (23%) serum ucOC was above the upper limit of the normal range for young women. The level of ucOC was negatively correlated with 25OHD (r = -0.32, P < 0.001) even after excluding the effect of age, parathyroid hormone (PTH), and creatinine by partial correlation (r = -0.24, P < 0.002). During an 18-mo follow-up, 15 women sustained a hip fracture and their baseline ucOC level was higher (P < 0.01) in women who subsequently sustained hip fracture than in the nonfracture group contrasting with no significant differences for serum calcium, phosphate, alkaline phosphatase, creatinine, PTH, 250HD, and total and carboxylated OC. The risk of hip fracture was increased in women with elevated ucOC (relative ratio 5.9, 99.9% Cl 1.5-22.7, P < 0.001). During 1 yr of calcium/vitamin D2 treatment, ucOC decreased (P < 0.05), especially in those with the initially increased values (from 2.22 +/- 0.35 to 1.41 +/- 0.29 ng/ml, P <0.005) contrasting with an increase in the placebo group (P < 0.05). In conclusion, the increase in ucOC in the elderly reflects not only some degree of vitamin K deficiency but also their poor vitamin D status, suggesting that vitamin D may be important, either directly or indirectly through its effect on bone turnover, for achieving a normal gamma-carboxylation of OC. The ucOC, but not conventional calcium metabolism parameters, predicts the subsequent risk of hip fracture, suggesting that serum ucOC reflects some changes in bone matrix associated with increased fragility.

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Selected References

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  • Gehron Robey P. The biochemistry of bone. Endocrinol Metab Clin North Am. 1989 Dec;18(4):858–902. [PubMed]
  • Delmas PD. Biochemical markers of bone turnover for the clinical assessment of metabolic bone disease. Endocrinol Metab Clin North Am. 1990 Mar;19(1):1–18. [PubMed]
  • Price PA, Williamson MK, Lothringer JW. Origin of the vitamin K-dependent bone protein found in plasma and its clearance by kidney and bone. J Biol Chem. 1981 Dec 25;256(24):12760–12766. [PubMed]
  • Price PA, Williamson MK. Effects of warfarin on bone. Studies on the vitamin K-dependent protein of rat bone. J Biol Chem. 1981 Dec 25;256(24):12754–12759. [PubMed]
  • Lian J, Stewart C, Puchacz E, Mackowiak S, Shalhoub V, Collart D, Zambetti G, Stein G. Structure of the rat osteocalcin gene and regulation of vitamin D-dependent expression. Proc Natl Acad Sci U S A. 1989 Feb;86(4):1143–1147. [PubMed]
  • Furie B, Furie BC. Molecular basis of vitamin K-dependent gamma-carboxylation. Blood. 1990 May 1;75(9):1753–1762. [PubMed]
  • Menon RK, Gill DS, Thomas M, Kernoff PB, Dandona P. Impaired carboxylation of osteocalcin in warfarin-treated patients. J Clin Endocrinol Metab. 1987 Jan;64(1):59–61. [PubMed]
  • van Haarlem LJ, Knapen MH, Hamulyák K, Vermeer C. Circulating osteocalcin during oral anticoagulant therapy. Thromb Haemost. 1988 Aug 30;60(1):79–82. [PubMed]
  • Plantalech L, Guillaumont M, Vergnaud P, Leclercq M, Delmas PD. Impairment of gamma carboxylation of circulating osteocalcin (bone gla protein) in elderly women. J Bone Miner Res. 1991 Nov;6(11):1211–1216. [PubMed]
  • Knapen MH, Hamulyák K, Vermeer C. The effect of vitamin K supplementation on circulating osteocalcin (bone Gla protein) and urinary calcium excretion. Ann Intern Med. 1989 Dec 15;111(12):1001–1005. [PubMed]
  • Hodges SJ, Pilkington MJ, Shearer MJ, Bitensky L, Chayen J. Age-related changes in the circulating levels of congeners of vitamin K2, menaquinone-7 and menaquinone-8. Clin Sci (Lond) 1990 Jan;78(1):63–66. [PubMed]
  • Hart JP, Shearer MJ, Klenerman L, Catterall A, Reeve J, Sambrook PN, Dodds RA, Bitensky L, Chayen J. Electrochemical detection of depressed circulating levels of vitamin K1 in osteoporosis. J Clin Endocrinol Metab. 1985 Jun;60(6):1268–1269. [PubMed]
  • Hodges SJ, Pilkington MJ, Stamp TC, Catterall A, Shearer MJ, Bitensky L, Chayen J. Depressed levels of circulating menaquinones in patients with osteoporotic fractures of the spine and femoral neck. Bone. 1991;12(6):387–389. [PubMed]
  • Karl PI, Friedman PA. Effects of parathyroid hormone and vitamin D on the renal vitamin K-dependent carboxylating system. J Biol Chem. 1983 Nov 10;258(21):12783–12786. [PubMed]
  • Deyl Z, Adam M. Evidence for vitamin D dependent gamma-carboxylation in osteocalcin related proteins. Biochem Biophys Res Commun. 1983 May 31;113(1):294–300. [PubMed]
  • Parfitt AM, Gallagher JC, Heaney RP, Johnston CC, Neer R, Whedon GD. Vitamin D and bone health in the elderly. Am J Clin Nutr. 1982 Nov;36(5 Suppl):1014–1031. [PubMed]
  • Chapuy MC, Arlot ME, Duboeuf F, Brun J, Crouzet B, Arnaud S, Delmas PD, Meunier PJ. Vitamin D3 and calcium to prevent hip fractures in the elderly women. N Engl J Med. 1992 Dec 3;327(23):1637–1642. [PubMed]
  • Merle B, Delmas PD. Normal carboxylation of circulating osteocalcin (bone Gla-protein) in Paget's disease of bone. Bone Miner. 1990 Nov;11(2):237–245. [PubMed]
  • Parfitt AM. Chlorothiazide-induced hypercalcemia in juvenile osteoporosis and hyperparathyroidism. N Engl J Med. 1969 Jul 10;281(2):55–59. [PubMed]
  • Kelsey JL, Hoffman S. Risk factors for hip fracture. N Engl J Med. 1987 Feb 12;316(7):404–406. [PubMed]
  • Ray WA, Griffin MR, Schaffner W, Baugh DK, Melton LJ., 3rd Psychotropic drug use and the risk of hip fracture. N Engl J Med. 1987 Feb 12;316(7):363–369. [PubMed]
  • Eastwood JB, de Wardener HE, Gray RW, Lemann JL., Jr Normal plasma-1,25-(OH)2-vitamin-D concentrations in nutritional osteomalacia. Lancet. 1979 Jun 30;1(8131):1377–1378. [PubMed]
  • Demiaux B, Arlot ME, Chapuy MC, Meunier PJ, Delmas PD. Serum osteocalcin is increased in patients with osteomalacia: correlations with biochemical and histomorphometric findings. J Clin Endocrinol Metab. 1992 May;74(5):1146–1151. [PubMed]
  • Chapuy MC, Chapuy P, Meunier PJ. Calcium and vitamin D supplements: effects on calcium metabolism in elderly people. Am J Clin Nutr. 1987 Aug;46(2):324–328. [PubMed]
  • Lips P, Wiersinga A, van Ginkel FC, Jongen MJ, Netelenbos JC, Hackeng WH, Delmas PD, van der Vijgh WJ. The effect of vitamin D supplementation on vitamin D status and parathyroid function in elderly subjects. J Clin Endocrinol Metab. 1988 Oct;67(4):644–650. [PubMed]
  • Himmelstein S, Clemens TL, Rubin A, Lindsay R. Vitamin D supplementation in elderly nursing home residents increases 25(OH)D but not 1,25(OH)2D. Am J Clin Nutr. 1990 Oct;52(4):701–706. [PubMed]
  • Lian JB, Glimcher MJ, Roufosse AH, Hauschka PV, Gallop PM, Cohen-Solal L, Reit B. Alterations of the gamma-carboxyglutamic acid and osteocalcin concentrations in vitamin D-deficient chick bone. J Biol Chem. 1982 May 10;257(9):4999–5003. [PubMed]
  • Price PA, Sloper SA. Concurrent warfarin treatment further reduces bone mineral levels in 1,25-dihydroxyvitamin D3-treated rats. J Biol Chem. 1983 May 25;258(10):6004–6007. [PubMed]
  • Lian JB, Tassinari M, Glowacki J. Resorption of implanted bone prepared from normal and warfarin-treated rats. J Clin Invest. 1984 Apr;73(4):1223–1226. [PMC free article] [PubMed]
  • Glowacki J, Lian JB. Impaired recruitment and differentiation of osteoclast progenitors by osteocalcin-deplete bone implants. Cell Differ. 1987 Sep;21(4):247–254. [PubMed]
  • DeFranco DJ, Glowacki J, Cox KA, Lian JB. Normal bone particles are preferentially resorbed in the presence of osteocalcin-deficient bone particles in vivo. Calcif Tissue Int. 1991 Jul;49(1):43–50. [PubMed]
  • Feteih R, Tassinari MS, Lian JB. Effect of sodium warfarin on vitamin K-dependent proteins and skeletal development in the rat fetus. J Bone Miner Res. 1990 Aug;5(8):885–894. [PubMed]
  • Price PA, Williamson MK, Haba T, Dell RB, Jee WS. Excessive mineralization with growth plate closure in rats on chronic warfarin treatment. Proc Natl Acad Sci U S A. 1982 Dec;79(24):7734–7738. [PubMed]
  • Fiore CE, Tamburino C, Foti R, Grimaldi D. Reduced axial bone mineral content in patients taking an oral anticoagulant. South Med J. 1990 May;83(5):538–542. [PubMed]
  • Monreal M, Olive A, Lafoz E, del Rio L. Heparins, coumarin, and bone density. Lancet. 1991 Sep 14;338(8768):706–706. [PubMed]
  • Resch H, Pietschmann P, Krexner E, Willvonseder R. Decreased peripheral bone mineral content in patients under anticoagulant therapy with phenprocoumon. Eur Heart J. 1991 Mar;12(3):439–441. [PubMed]
  • Toss G, Almqvist S, Larsson L, Zetterqvist H. Vitamin D deficiency in welfare institutions for the aged. Acta Med Scand. 1980;208(1-2):87–89. [PubMed]
  • Tsai KS, Heath H, 3rd, Kumar R, Riggs BL. Impaired vitamin D metabolism with aging in women. Possible role in pathogenesis of senile osteoporosis. J Clin Invest. 1984 Jun;73(6):1668–1672. [PMC free article] [PubMed]

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