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Research Article| Volume 20, ISSUE 3, P503-526, September 2000

Risk Assessment for Osteoporosis II: Biochemical Markers of Bone Turnover: Bone Resorption Indices

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      This article describes the biochemical background and functional properties of molecular markers derived from osteoblasts, the collagenous, or noncollagenous bone matrix. Clinical applications and the selection, timing, and monitoring of antiosteoporotic treatment are critically discussed. Special emphasis has been put on reviewing the value of bone resorption markers in the prediction of future bone loss and the risk assessment for osteoporotic fractures. The potential of these indices as independent risk factors for future fractures alone or in combination with bone mineral density measurements has recently been demonstrated in large cohort studies. More data are needed, however, to establish biochemical markers of bone resorption as useful tools in the assessment of individual fracture risk.
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      References

        • Arden-Cordone M.
        • Siris E.S.
        • Lyles K.W.
        • et al.
        Antiresorptive effect of a single infusion of microgram quantities of zoledronate in Paget’s disease of bone.
        Calcif Tissue Int. 1997; 60: 415
        • Bais R.
        • Edwards J.B.
        An optimized continuous-monitoring procedure for semiauto-mated determination of serum acid phosphatase activity.
        Clin Chem. 1976; 22: 2025
        • Bettica P.
        • Moro L.
        • Robins S.P.
        • et al.
        Bone-resorption markers galactosyl hydroxylysine, pyridinium crosslinks, and hydroxyproline compared.
        Clin Chem. 1992; 38: 2313
        • Black D.
        • Duncan A.
        • Robins S.P.
        Quantitative analysis of the pyridinium crosslinks of collagen in urine using ion-paired reversed-phase high-performance liquid chromatography.
        Anal Biochem. 1988; 169: 197
        • Bluhmson A.
        • Eastell R.
        Prediction of bone loss in postmenopausal women.
        Eur J Clin Invest. 1992; 22: 764
        • Bonde M.
        • Garnero P.
        • Fledelius C.
        • et al.
        Measurement of bone degradation products in serum using antibodies reactive with an isomerized form of an 8 amino acid sequence of the C-telopeptide of type I collagen.
        J Bone Miner Res. 1997; 12: 1028
        • Bonde M.
        • Qvist P.
        • Fledelius C.
        • et al.
        Immunoassay for quantifying type I collagen degradation products in urine evaluated.
        Clin Chem. 1994; 40: 2022
        • Brixen K.
        • Eriksen F.L.
        Validation of local and systemic markers of bone turnover.
        in: Seibel M.J. Robins S.P. Bilezikian J.P. Dynamics of Bone and Cartilage Metabolism. Academic Press, San Diego1999: 427
        • Chen J.K.
        • Shapiro H.S.
        • Wrana J.L.
        • et al.
        Localization of bone sialoprotein (BSP) expression to sites of mineralized tissue formation in fetal rat tissues by in situ hybridization.
        Matrix. 1991; 11: 133
        • Chesnut III, C.H.
        • Bell N.H.
        • Clark G.S.
        • et al.
        Hormone replacement therapy in postmenopausal women: Urinary N-telopeptide of type I collagen monitors therapeutic effect and predicts response of bone mineral density.
        Am J Med. 1997; 102: 29
        • Cheung C.K.
        • Panesar N.S.
        • Haines C.
        • et al.
        Immunoassay of a tartrate-resistant acid phosphatase in serum.
        Clin Chem. 1995; 41: 679
        • Cheung C.K.
        • Panesar N.S.
        • Lau E.
        • et al.
        Increased bone resorption and decreased bone formation in Chinese patients with hip fracture.
        Calcif Tissue Int. 1995; 56: 347
        • Christiansen C.
        • Riis B.J.
        • Rodboro P.
        Prediction of rapid bone loss in postmenopausal women.
        Lancet. 1987; 1: 1105
        • Christiansen C.
        • Riis B.J.
        • Rodbro P.
        Screening procedure for women at risk of developing postmenopausal osteoporosis.
        Osteoporos Int. 1990; 1: 35
        • Civitelli R.
        • Gonnelli S.
        • Zacchei F.
        • et al.
        Bone turnover in postmenopausal osteoporosis. Effect of calcitonin treatment.
        J Clin Invest. 1988; 82: 1268
        • Clemens J.D.
        • Herrick M.V.
        • Singer F.R.
        • et al.
        Evidence that serum NTx (collagen-type I N-telopeptides) can act as an immunochemical marker of bone resorption.
        Clin Chem. 1997; 43: 2058
        • Coleman R.E.
        • Purohit O.P.
        • Black C.
        • et al.
        Double-blind, randomised, placebo-controlled, dose-finding study of oral ibandronate in patients with metastatic bone disease.
        Ann Oncol. 1999; 10: 311
        • Colwell A.
        • Russell R.G.
        • Eastell R.
        Factors affecting the assay of urinary 3-hydroxy pyridinium crosslinks of collagen as markers of bone resorption.
        Eur J Clin Invest. 1993; 23: 341
        • Cosman F.
        • Nieves J.
        • Wilkinson C.
        • et al.
        Bone density change and biochemical indices of skeletal turnover.
        Calcif Tissue Int. 1996; 58: 236
        • Cummings S.R.
        • Black D.M.
        • Navic M.C.
        Appendicular bone density and age predict hip fracture in women.
        J Am Med Soc. 1990; 263: 665
        • Cunningham L.W.
        • Ford J.D.
        • Segrest J.P.
        The isolation of identical hydroxylysyl glycosides from hydroxy lates of soluble collagen and from human urine.
        J Biol Chem. 1967; 242: 2570
        • Deacon A.C.
        • Hulme P.
        • Hesp R.
        • et al.
        Estimation of whole body bone resorption rate: A comparison of urinary total hydroxyproline excretion with two radioisotopic tracer methods in osteoporosis.
        Clin Chim Acta. 1987; 166: 297
        • Delmas P.D.
        • Gineyts E.
        • Bertholin A.
        • et al.
        Immunoassay of pyridinoline crosslink excretion in normal adults and in Paget’s disease.
        J Bone Miner Res. 1993; 8: 643
        • Dresner-Pollak R.
        • Seibel M.J.
        • Greenspan S.
        • et al.
        Biochemical markers of bone turnover reflect femoral bone loss in elderly women.
        Calcif Tissue Int. 1996; 59: 328
        • Eastell R.
        • Robins S.
        • Colwell T.
        • et al.
        Evaluation of bone turnover in type I osteoporosis using biochemical markers specific for both bone formation and bone resorption.
        Osteoporos Int. 1993; 3: 255
        • Ebeling P.R.
        • Atley L.M.
        • Guthrie J.R.
        • et al.
        Bone turnover markers and bone density across the menopausal transition.
        J Clin Endocrinol Metab. 1996; 81: 3366
        • Ensrud K.E.
        • Palermo L.
        • Black D.M.
        • et al.
        Hip and calcaneal bone loss increase with advancing age: Longitudinal results from the study of osteoporotic fractures.
        J Bone Miner Res. 1995; 10: 1778
        • Eyre D.R.
        • Dickson I.R.
        • Van Ness K.
        Collagen cross-linking in human bone and articular cartilage. Age-related changes in the content of mature hydroxypyridinium residues.
        Biochem J. 1988; 252: 495
        • Fedarko N.S.
        • Fohr B.
        • Young M.F.
        • et al.
        Integrins and factor H mediate bone sialoprotein’s and osteopontin’s protective properties in complement attack on susceptible cancer cells.
        J Bone Miner Res. 1999; 14: S187
        • Fiore C.E.
        • Falcidia E.
        • Foti R.
        • et al.
        Postoophorectomy bone loss is associated with reduced bone Gla protein serum levels: A possible effect of osteoblastic insufficiency.
        Calcif Tissue Int. 1987; 41: 303
        • Fisher L.W.
        • Whitson S.W.
        • Avioli L.W.
        • et al.
        Matrix sialoprotein of developing bone.
        J Biol Chem. 1983; 258: 12723
        • Fledelius C.
        • Johnsen A.H.
        • Cloos P.A.C.
        • et al.
        Characterization of urinary degradation products derived from type I collagen. Identification of a beta-isomerized Asp-Gly sequence within the C-terminal telopeptide (alphal) region.
        J Biol Chem. 1997; 11: 9755
        • Fujimoto D.
        • Moriguchi T.
        • Ishida T.
        • et al.
        The structure of pyridinoline, a collagen crosslink.
        Biochem Biophys Res Commun. 1978; 84: 52
        • Fujisawa R.
        • Butler W.T.
        • Brunn J.C.
        • et al.
        Differences in composition of cell-attachment sialoproteins between dentin and bone.
        J Dent Res. 1993; 72: 1222
        • Fujisawa R.
        • Nodasaka Y.
        • Kuboki Y.
        Further characterization of interaction between bone sialoprotein (BSP) and collagen.
        Calcif Tissue Int. 1995; 56: 140
        • Gardseil P.
        • Johnell O.
        • Nilsson B.E.
        The predictive value of bone loss for fragility fractures in women: A longitudinal study over 15 years.
        Calcif Tissue Int. 1991; 49: 90
        • Garnero P.
        • Shih W.J.
        • Gineyts E.
        • et al.
        Comparison of new biochemical markers of bone turnover in late postmenopausal osteoporotic women in response to alendronate treatment.
        J Clin Endocrinol Metab. 1994; 79: 1693
        • Garnero P.
        • Sornay-Rendu E.
        • Chapuy M.C.
        • et al.
        Increased bone turnover in late postmenopausal women is a major determinant of osteoporosis.
        J Bone Miner Res. 1996; 11: 337
        • Garnero P.
        • Sornay-Rendu E.
        • Duboeuf F.
        • et al.
        Markers of bone turnover predict postmenopausal forearm bone loss over 4 years: The OFELY study.
        J Bone Miner Res. 1999; 14: 1614
        • Gomez Jr, B.
        • Ardakani S.
        • Evans B.J.
        • et al.
        Monoclonal antibody assay for free urinary pyridinium cross-links.
        Clin Chem. 1996; 42: 1168
        • Gunja-Smith Z.
        • Boucek R.J.
        Collagen cross-linking compounds in human urine.
        Biochem J. 1981; 197: 759
        • Halleen J.M.
        • Karp M.
        • Viloma S.
        • et al.
        Two-site immunoassays for osteoclastic tartrate-resistant acid phosphatase based on characterization of six monoclonal antibodies.
        J Bone Miner Res. 1999; 14: 464
        • Hannon R.
        • Blumsohn A.
        • Naylor K.
        • et al.
        Response of biochemical markers of bone turnover to hormone replacement therapy: Impact of biological variability.
        J Bone Miner Res. 1998; 13: 1124
        • Hansen M.
        Assessment of age and risk factors on bone density and bone turnover in healthy premenopausal women.
        Osteoporos Int. 1994; 4: 123
        • Hanson D.A.
        • Weis M.A.
        • Bollen A.M.
        • et al.
        A specific immunoassay for monitoring human bone resorption: Quantitation of type I collagen cross-linked N-telopeptides in urine.
        J Bone Miner Res. 1992; 7: 1251
        • Hassager C.
        • Jensen L.T.
        • Podenphant J.
        • et al.
        The carboxy-terminal pyridinoline cross-linked telopeptide of type I collagen in serum as a marker of bone resorption: The effect of nandrolone decanoate and hormone replacement therapy.
        Calcif Tissue Int. 1994; 54: 30
        • Heinegard D.
        • Oldberg A.
        Structure and biology of cartilage and bone matrix noncolla-geneous macromolecules.
        FASEB J. 1989; 3: 2042
        • Hui S.L.
        • Slemenda C.W.
        • Johnston C.C.
        The contribution of bone loss to postmenopausal osteoporosis.
        Osteoporos Int. 1990; 1: 30
        • James I.T.
        • Perrett D.
        Automated on-line solid-phase extraction and high-performance liquid chromatographic analysis of total and free pyridinium crosslinks in serum.
        J Chromatogr A. 1998; 798: 159
        • Johansen J.S.
        • Riis B.J.
        • Delmas P.D.
        • et al.
        Plasma BGP: An indicator of spontaneous bone loss and of the effect of oestrogen treatment in postmenopausal women.
        Eur J Clin Invest. 1988; 18: 191
        • Kanis J.A.
        Assessment of fracture risk and its application to screening for postmenopausal osteoporosis: Synopsis of a WHO report.
        Osteoporos Int. 1994; 4: 368
        • Kanis J.A.
        • Melton III, L.J.
        • Christiansen C.
        • et al.
        The diagnosis of osteoporosis.
        J Bone Miner Res. 1994; 9: 1137
        • Karmatschek M.
        • Maier I.
        • Seibel M.J.
        • et al.
        Improved purification of human bone sialoprotein and development of a homologous radioimmunoassay.
        Clin Chem. 1997; 43: 2076
        • Keen R.W.
        • Nguyen T.
        • Sobnack R.
        • et al.
        Can biochemical markers predict bone loss at the hip and spine? A 4-year prospective study of 141 early postmenopausal women.
        Osteoporos Int. 1996; 6: 399
        • Kivirikko K.I.
        Urinary excretion of hydroxyproline in health and disease.
        Int Rev Connect Tissue Res. 1970; 5: 93
        • Kraenzlin M.E.
        • Lau K.H.
        • Liang L.
        • et al.
        Development of an immunoassay for human serum osteoclastic tartrate-resistant acid phosphatase.
        J Clin Endocrinol Metab. 1990; 71: 442
        • Kushida K.
        • Takahashi M.
        • Kawana K.
        • et al.
        Comparison of markers for bone formation and resorption in premenopausal and postmenopausal subjects, and osteoporosis patients.
        J Clin Endocrinol Metab. 1995; 80: 2447
        • Lam K.W.
        • Lee P.
        • Li C.Y.
        • et al.
        Immunological and biochemical evidence for identity of tartrate-resistant isoenzymes of acid phosphatases from human serum and tissues.
        Clin Chem. 1980; 26: 420
        • Lam K.W.
        • Siemens M.
        • Sun T.
        • et al.
        Enzyme immunoassay for tartrate-resistant acid phosphatase.
        Clin Chem. 1982; 28: 467
        • Lau K.H.
        • Onishi T.
        • Wergedal J.E.
        • et al.
        Characterization and assay of tartrate-resistant acid phosphatase activity in serum: Potential use to assess bone resorption.
        Clin Chem. 1987; 33: 458
        • Li Y.
        • Woitge H.W.
        • Kissling C.
        • et al.
        Biological variability of serum immunoreactive bone sialoprotein.
        Clin Lab. 1998; 44: 553
        • Lo Cascio V.
        • Bertoldo F.
        • Gambaro G.
        • et al.
        Urinary galactosyl-hydroxylysine in postmenopausal osteoporotic women: A potential marker of bone fragility.
        J Bone Miner Res. 1999; 14: 1420
        • Lowry M.
        • Hall D.E.
        • Brosnan J.T.
        Hydroxyproline metabolism by the rat kidney: Distribution of renal enzymes of hydroxyproline catabolism and renal conversion of hydroxyproline to glycine and serine.
        Metabolism. 1985; 34: 955
        • Melton L.J.
        • Khosla S.
        • Atkinson E.J.
        • et al.
        Relationship of bone fractures to bone density and fractures.
        J Bone Miner Res. 1997; 12: 1083
        • Minkin C.
        Bone acid phosphatase: Tartrate-resistant acid phosphatase as a marker of osteoclast function.
        Calcif Tissue Int. 1982; 34: 285
        • Miura H.
        • Yamamoto I.
        • Yuu I.
        • et al.
        Estimation of bone mineral density and bone loss by means of bone metabolic markers in postmenopausal women.
        Endocr J. 1995; 42: 797
        • Mole P.A.
        • Walkinshaw M.H.
        • Robins S.P.
        • et al.
        Can urinary pyridinium crosslinks and urinary estrogens predict bone mass and rate of bone loss after the menopause?.
        Eur J Clin Invest. 1992; 22: 767
        • Moro L.
        • Modricky C.
        • Rovis L.
        • et al.
        Determination of galactosyl hydroxy lysine in urine as a means for the identification of osteoporotic women.
        Bone. 1988; 3: 271
        • Moro L.
        • Modricky C.
        • Stagni N.
        • et al.
        High-performance liquid chromatographic analysis of urinary hydroxylysyl glycosides as indicators of collagen turnover.
        Analyst. 1984; 109: 1621
        • Moro L.
        • Pozzi Mucelli R.S.
        • Gazzarrini C.
        • et al.
        Urinary beta-1-galactosy 1-0-hydroxy lysine (GH) as a marker of collagen turnover of bone.
        Calcif Tissue Int. 1988; 42: 87
        • Nielsen N.M.
        • von der Recke P.
        • Hansen M.A.
        • et al.
        Estimation of the effect of salmon calcitonin in established osteoporosis by biochemical bone markers.
        Calcif Tissue Int. 1994; 55: 8
        • Ogawa T.
        • Ono T.
        • Tsuda M.
        • et al.
        A novel fluor in insoluble collagen: A crosslinking moiety in collagen molecule.
        Biochem Biophys Res Commun. 1982; 107: 1252
        • Parfitt A.M.
        Age-related structural changes in trabecular and cortical bone: Cellular mechanisms and biomechanical consequences.
        Calcif Tissue Int. 1984; 36: S123
        • Parviainen M.T.
        • Jaaskelainen K.
        • Kroger H.
        • et al.
        Urinary bone resorption markers in monitoring treatment of symptomatic osteoporosis.
        Clin Chim Acta. 1999; 279: 145
        • Pratt D.A.
        • Daniloff Y.
        • Duncan A.
        • et al.
        Automated analysis of the pyridinium crosslinks of collagen in tissue and urine using solid-phase extraction and reversed-phase high-performance liquid chromatography.
        Anal Biochem. 1992; 207: 168
        • Prockop D.J.
        • Kivirikko K.I.
        • Tuderman L.
        • et al.
        The biosynthesis of collagen and its disorders.
        N Engl J Med. 1979; 301: 13
        • Ravn P.
        • Rix M.
        • Andreassen H.
        • et al.
        High bone turnover is associated with low bone mass and spinal fracture in postmenopausal women.
        Calcif Tissue Int. 1997; 60: 255
        • Reeve J.
        • Pearson J.
        • Mitchell A.
        • et al.
        Evolution of spinal bone loss and biochemical markers of bone remodeling after menopause in normal women.
        Calcif Tissue Int. 1995; 57: 105
        • Riggs B.L.
        • Melton III, L.J.
        • O’fallon W.M.
        Drug therapy for vertebral fractures in osteoporosis: Evidence that decreases in bone turnover and increases in bone mass both determine antifracture efficacy.
        Bone. 1996; 18: 197S
        • Riis B.J.
        • Hansen M.A.
        • Jensen A.M.
        • et al.
        Low bone mass and fast rate of bone loss at menopause: Equal risk factors for future fracture: A 15-year follow-up study.
        Bone. 1996; 19: 9
        • Riis B.J.
        • Overgaard K.
        • Christiansen C.
        Biochemical markers of bone turnover to monitor the bone response to postmenopausal hormone replacement therapy.
        Osteoporos Int. 1995; 5: 276
        • Risteli J.
        • Elomaa I.
        • Niemi S.
        • et al.
        Radioimmunoassay for the pyridinoline cross-linked carboxy-terminal telopeptide of type I collagen: A new serum marker of bone collagen degradation.
        Clin Chem. 1993; 39: 635
        • Robins S.P.
        Fibrillogenesis and maturation of collagens.
        in: Seibel M.J. Robins S.P. Bilezikian J.P. Dynamics of Bone and Cartilage Metabolism. Academic Press, San Diego1999: 31
        • Robins S.P.
        Turnover of collagen and its precursors.
        in: Viidik A. Vuust J. Biology of Collagen. Academic Press, New York1980: 135
        • Robins S.P.
        • Woitge H.
        • Hesley R.
        • et al.
        Direct, enzyme-linked immunoassay for urinary deoxypyridinoline as a specific marker for measuring bone resorption.
        J Bone Miner Res. 1994; 9: 1643
        • Rosen C.
        • Chesnut III, C.H.
        • Mallinak N.J.S.
        The predictive value of biochemical markers of bone turnover for bone mineral density in early postmenopausal women treated with hormone replacement or calcium supplementation.
        J Clin Endocrinol Metab. 1997; 82: 1904
        • Ross F.P.
        • Chappel J.
        • Alvarez J.I.
        • et al.
        Interactions between the bone matrix proteins osteopontin and bone sialoprotein and the osteoclast integrin alpha v beta 3 potentiate bone resorption.
        J Biol Chem. 1993; 268: 9901
        • Ross P.D.
        • Knowlton W.
        Rapid bone loss is associated with increased levels of biochemical markers.
        J Bone Miner Res. 1998; 13: 297
        • Saxne T.
        • Zunino L.
        • Heinegard D.
        Increased release of bone sialoprotein into synovial fluid reflects tissue destruction in rheumatoid arthritis.
        Arthritis Rheum. 1995; 38: 82
        • Schlemmer A.
        • Hassager C.
        • Jensen S.B.
        • et al.
        Marked diurnal variation in urinary excretion of pyridinium cross-links in premenopausal women.
        J Clin Endocrinol Metab. 1992; 74: 476
        • Schneider D.L.
        • Barrett-Connor E.L.
        Urinary N-telopeptide levels discriminate normal, osteopenic, and osteoporotic bone mineral density.
        Arch Intern Med. 1997; 157: 1241
        • Seeley D.G.
        • Browner W.S.
        • Nevitt M.C.
        • et al.
        Which fractures are associated with low appendicular bone mass in elderly women?.
        Ann Intern Med. 1991; 115: 837
        • Segrest J.P.
        • Cunningham L.W.
        Variations in human urinary O-hydroxylysyl glycoside levels and their relationship to collagen metabolism.
        J Clin Invest. 1970; 49: 1497
        • Seibel M.J.
        • Cosman F.
        • Shen V.
        • et al.
        Urinary hydroxy-pyridinium crosslinks of collagen as markers of bone resorption and estrogen efficacy in postmenopausal osteoporosis.
        J Bone Miner Res. 1993; 8: 881
        • Seibel M.J.
        • Woitge H.W.
        • Pecherstorfer M.
        • et al.
        Serum immunoreactive bone sialoprotein as a new marker of bone turnover in metabolic and malignant bone disease.
        J Clin Endocrinol Metab. 1996; 81: 3289
        • Seibel M.J.
        • Woitge H.
        • Scheidt-Nave C.
        • et al.
        Urinary hydroxypyridinium crosslinks of collagen in population-based screening for overt vertebral osteoporosis: Results of a pilot study.
        J Bone Miner Res. 1994; 9: 1433
        • Seyedin S.M.
        • Kung V.T.
        • Daniloff Y.N.
        • et al.
        Immunoassay for urinary pyridinoline: The new marker of bone resorption.
        J Bone Miner Res. 1993; 8: 635
        • Shapiro H.S.
        • Chen J.
        • Wrana J.L.
        • et al.
        Characterization of porcine bone sialoprotein: Primary structure and cellular expression.
        Matrix. 1993; 13: 431
        • Sherman S.S.
        • Tobin J.D.
        • Hollis B.W.
        • et al.
        Biochemical parameters associated with low bone density in healthy men and women.
        J Bone Miner Res. 1992; 7: 1123
        • Smith R.
        Collagen and disorders of bone.
        Clin Sci. 1980; 59: 215
        • Szulc P.
        • Arlot M.
        • Chapuy M.C.
        • et al.
        Serum undercarboxylated osteocalcin correlates with hip bone mineral density in elderly women.
        J Bone Miner Res. 1994; 9: 1591
        • Uebelhart D.
        • Schlemmer A.
        • Johansen J.S.
        • et al.
        Effect of menopause and hormone replacement therapy on the urinary excretion of pyridinium crosslinks.
        J Clin Endocrinol Metab. 1991; 72: 367
        • Van Daele P.L.
        • Seibel M.J.
        • Burger H.
        • et al.
        Case-control analysis of bone resorption markers, disability, and hip fracture risk: The Rotterdam study.
        BMJ. 1996; 24: 482
        • Weel A.E.A.M.
        • Seibel M.J.
        • Hofman A.
        • et al.
        Which fractures are associated with high bone resorption in elderly women: The Rotterdam study.
        J Bone Miner Res. 1999; 14: S160
        • Woitge H.W.
        • Pecherstorfer M.
        • Li Y.
        • et al.
        Novel serum markers of bone resorption: Clinical assessment and comparison with established urinary indices.
        J Bone Miner Res. 1999; 14: 792
        • Woitge H.W.
        • Scheidt-Nave C.
        • Kissling C.
        • et al.
        Seasonal variation of biochemical indexes of bone turnover: Results of a population-based study.
        J Clin Endocrinol Metab. 1998; 83: 68