Biochemische Marker des Knochenstoffwechsels bei sekundären Osteopathien

Zusammenfassung

Die Quantifizierung biochemischer Marker des Knochenstoffwechsels hat in den letzten Jahren die Möglichkeiten der Diagnose und Verlaufskontrolle metabolischer Osteopathien deutlich verbessert. Die Entwicklung von Nachweismethoden zur Bestimmung osteotroper Parameter unterschiedlicher Herkunft, biochemischer Struktur und Funktion hat unser Verständnis von Matrixzusammensetzung, physiologischen Knochenstoffwechselprozessen und den pathophysiologischen Vorgängen bei der Entwicklung primärer und sekundärer Osteopathien erweitert. Die vorliegende Arbeit gibt zunächst einen Überblick über die wichtigsten, heute zur Verfügung stehenden biochemischen Marker des Knochenstoffwechsels. Anschließend werden neueste Untersuchungsergebnisse und klinische Wertigkeit der Bestimmung dieser Substanzen bei den häufigsten sekundären Osteopathien zusammengefasst.

Biochemical Markers of Bone Turnover in Secondary Osteopathies

During recent years, diagnosis and monitoring of metabolic bone diseases have been markedly improved by the quantification of biochemical markers of bone turnover. The development of new analytical methods to detect osteotropic parameters with different skeletal origin, biochemical structure and function has increased our knowledge of bone matrix composition and the physiologic regulation of bone turnover, as well as of pathophysiologic mechanisms that may lead to the development of primary and secondary metabolic bone diseases. The present work gives an overview of the most commonly used biochemical markers of bone turnover, followed by an update of current clinical applications of these markers in secondary osteopathies with special emphasis on recent research activities.

Literatur

• 1 Bais R, Edwards J B. An optimized continous-monitoring procedure for semiautomated determination of serum acid phosphatase activity.  Clin Chem. 1976;  22 2025-2028
• 2 Beard D B, Haskell C M. Carcinoembryonic antigen in breast cancer.  Am J Med. 1986;  80 241-245
• 3 Behr W, Barnert J. Quantification of bone alkaline phosphatase in serum by precipitation with wheat-germ lectin: a simplified method and its clinical plausibility.  Clin Chem. 1986;  32 1960-1966
• 4 Bikle D D, Genant H K, Cann C, Recker R P, Halloran B P, Strewler G J. Bone disease in alcohol abuse.  Ann Intern Med. 1985;  103 42-48
• 5 Bilezikian J P, Morishima A, Bell J, Grumbach M M. Increased bone mass as a result of estrogen therapy in a man with aromatase deficiency.  N Engl J Med. 1998;  339 599-603
• 6 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;  169 197-203
• 7 Body J J, Cleeren A, Pot M, Borkowski A. Serum osteocalcin (BGP) in tumor-associated hypercalcemia.  J Bone Miner Res. 1986;  1 523-527
• 8 Boiskin I, Epstein S, Ismail F, Thomas S B, Raja R. Serum osteocalcin and bone mineral metabolism following successful renal transplantation.  Clin Nephrol. 1989;  31 316-322
• 9 Bonde M, Garnero P, Fledelius C, Quist P, Delmas P D, Christiansen C. 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 1028-1034
• 10 Bonde M, Qvist P, Fledelius C, Riis B J, Christiansen C. Evaluation of an immunoassay for quantitation of type I collagen degradation products in urine.  Clin Chem. 1994;  40 2022-2025
• 11 Boucek R J, Noble N J, Gunja-Smith Z, Butler W T. The Marfan syndrome: a deficiency in chemically stable collagen crosslinking.  New Engl J Med. 1981;  305 988-991
• 12 Bouillon R, Vanderschueren D, Van Herck E, Nielsen H K, Bex M, Heyns W, Van Baelen H. Homologous radioimmunoassay of human osteocalcin.  Clin Chem. 1992;  38 2055-2060
• 13 Bressot C, Meunier P J, Chapuy M C, Lejeune E, Edouard C, Darby A J. Histomorphometric profile, pathophysiology and reversibility of corticosteroid induced osteoporosis.  Metab Bone Dis Rel Res. 1979;  1 303-311
• 14 Brown J P, Delmas P D, Malaval L, Edouard C, Chapuy M C, Meunier P J. Serum bone Gla-protein: a specific marker for bone formation in postmenopausal osteoporosis.  Lancet. 1984;  1 1091-1093
• 15 Carlson K, Simonsson B, Ljunghall S. Acute effects of high-dose chemotherapy followed by bone marrow transplantation on serum markers of bone metabolism.  Calcif Tissue Int. 1994;  55 408-411
• 16 Chen J K, Shapiro H S, Wrana J L, Reimers S, Heersche J N, Sodek J. Localization of bone sialoprotein (BSP) expression to sites of mineralized tissue formation in fetal rat tissues by in situ hybridization.  Matrix. 1991;  11 133-143
• 17 Christiansen C, Riis B J, Rodboro P. Prediction of rapid bone loss in postmenopausal women.  Lancet. 1987;  1 1105-1108
• 18 Clarke N W, McClure J, George N JR. Disodium pamidronate identifies differential osteoclastic bone resorption in metastatic prostate cancer.  Br J Urol. 1992;  69 64-70
• 19 Clemens J D, Herrick M V, Singer F R, Eyre D R. Evidence that serum NTx (collagen-type I N-telopeptides) can act as an immunochemical marker of bone resorption.  Clin Chem. 1997;  43 2058-2063
• 20 Conti A, Sartorio A, Ferrero S, Ferrario S, Ambrosi B. Modifications of biochemical markers of bone and collagen turnover during corticosteroid therapy.  J Endocrinol Invest. 1996;  19 127-130
• 21 Curtis P H Jr, Clark W S, Herndon C H. Vertebral fractures resulting from prolonged cortisone and corticotropin therapy.  JAMA. 1954;  156 467-469
• 22 Cushing H. The basophil adenomas of the pituitary body and their clinical manifestations.  Bull John Hopkins Hosp. 1935;  50 137-195
• 23 De Marchi S, Cecchin E, Basile A, Bertotti A, Nardini R, Bartoli E. Renal tubular dysfunction in chronic alcohol abuse: effects of abstinence.  N Engl J Med. 1993;  329 1927-1934
• 24 Delmas P D, Stenner D, Wahner H W, Mann K G, Riggs B L. Increase in serum bone gamma-carboxyglutamic acid protein with aging in women. Implications for the mechanism of age-related bone loss.  J Clin Invest. 1983;  71 1316-1321
• 25 Eastell R, Dickson E R, Hodgson S F, Wiesner R H, Porayko M K, Wahner H W, Cedel S L, Riggs B L, Krom R A. Rates of vertebral bone loss before and after liver transplantion in women with primary biliary cirrhosis.  Hepatology. 1991;  14 296-300
• 26 Ebeling P R, Erbas B, Hopper J L, Wark J D, Rubinfeld A R. Bone mineral density and bone turnover in asthmatics treated with long-term inhaled or oral glucocorticoids.  J Bone Miner Res. 1998;  13 1283-1289
• 27 Ebeling P R, Peterson J M, Riggs B L. Utility of type I procollagen propeptide assays for assessing abnormalities in metabolic bone diseases.  J Bone Miner Res. 1992;  7 1243-1250
• 28 Ekenstam E, Stalenheim G, Hallgren R. The acute effect of high dose corticosteroid treatment on serum osteocalcin.  Metabolism. 1988;  37 141-144
• 29 Epstein S. Serum and urinary markers of bone remodelling: assessment of bone turnover.  Endocr Rev. 1988;  9 437-449
• 30 Eyre D R, Dickson I R, Van Ness K P. Collagen crosslinking in human bone and articular cartilage.  Biochem J. 1988;  252 495-500
• 31 Eyre D R, Koob T J, Van Ness K P. Quantitation of hydroxypyridinium crosslinks in collagen by high-performance liquid chromatography.  Anal Biochem. 1984;  137 380-388
• 32 Felson D T, Zhang Y, Hannan M T, Kannel W B, Kiel D P. Alcohol intake and bone mineral density in elderly men and women. The Framingham Study.  Am J Epidemiol. 1995;  142 485-492
• 33 Fessler L I, Morris N P, Fessler J H. Procollagen: biological scission of amino and carboxyl extension peptides.  Proc Natl Acad Sci USA. 1975;  72 4905-4909
• 34 Fisher L W, Whitson S W, Avioli L V, Termine J D. Matrix sialoprotein of developing bone.  J Biol Chem. 1983;  258 12 723-12 727
• 35 Francini G, Montagnani M, Petrioli R, Paffetti P, Marsili S, Leone V. Comparison between CEA, TPA, CA 15/3 and hydroxyproline, alkaline phosphatase, whole body retention of ^99mTc MDP in the follow-up of bone metastases in breast cancer.  Int J Biol Markers. 1990;  5 65-72
• 36 Francis R M, Peacock M, Aaron J E, Selby P L, Taylor G A, Thompson J, Marshall D H, Horsman A. Osteoporosis in hypogonadal men: role of decreased plasma 1,25-dihydroxyvitamin D, calcium malabsorption and low bone formation.  Bone. 1986;  7 261-268
• 37 Galasko C S. Mechanisms of bone destruction in the development of skeletal metastases.  Nature. 1976;  263 507-508
• 38 Galasko C S. The significance of occult skeletal metastases, detected by skeletal scintigraphy in patients otherwise apparently ‘early’ mammary carcinoma.  Br J Surg. 1975;  62 694-696
• 39 Gennari C, Civitelli R. Glucocorticoid-induced osteoporosis.  Clin Rheum Dis. 1986;  12 637-654
• 40 Gomez B Jr, Ardakani S, Ju J, Jenkins D, Cerelli M J, Daniloff G Y, Kung V T. Monoclonal antibody assay for measuring bone-specific alkaline phosphatase activity in serum.  Clin Chem. 1995;  41 1560-1566
• 41 Gonnelli S, Rottoli P, Cepollaro C, Pondrelli C, Cappiello V, Vagliasindi M, Gennari C. Prevention of corticosteroid-induced osteoporosis with alendronate in sarcoid patients.  Calcif Tissue Int. 1997;  61 382-385
• 42 Gordon C M, Grace E, Jean Emans S, Goodman E, Crawford M H, Leboff M S. Changes in bone turnover markers and menstrual function after short-term oral DHEA in young women with anorexia nervosa.  J Bone Miner Res. 1999;  14 136-145
• 43 Gran J, Junker P, Nielsen H K, Bollerslev J. Effects of short-term treatment with prednisolone and calcitriol on bone and mineral metabolism in normal men.  Bone. 1998;  23 297-302
• 44 Gundberg C M, Hauschka P, Lian J B, Gallop P M. Osteocalcin: Isolation, characterization and detection. In: Moldave K (Hrsg) Methods in enzymology. New York; Academic Press 1984: 516-544
• 45 Gundberg C M, Weinstein R S. Multiple immunoreactive forms of osteocalcin in uremic serum.  J Clin Invest. 1986;  77 1762-1767
• 46 Haagsma E B, Thijn C J, Post J G, Slooff M J, Gips C H. Bone disease after orthotopic liver transplantation.  J Hepatol. 1988;  6 94-100
• 47 Hahn T J. Drug-induced disorders of vitamin D and mineral metabolism.  Clin Endocrinol Metab. 1980;  9 107-127
• 48 Hahn T J. Steroid and drug-induced osteopenia. In: Favus MJ (Hrsg) Primer on the metabolic bone diseases and disorders of mineral metabolism. Philadelphia, New York; Lippincott-Raven 1995: 250-255
• 49 Halleen J M, Hentunen T A, Karp M, Kakonen S M, Pettersson K, Vaananen H K. Characterization of serum tartrate-resistant acid phosphatase and development of a direct two-site immunoassay.  J Bone Miner Res. 1998;  13 683-687
• 50 Halleen J M, Karp M, Viloma S, Laaksonen P, Hellman J, Kakonen S M, Stepan J J, Holmes S, Vaananen H K, Pettersson K. Two-site immunoassays for osteoclastic tartrate resistant acid phosphatase based on characterization of six monoclonal antibodies.  J Bone Miner Res. 1999;  14 464-469
• 51 Hanson D A, Weis M A, Bollen A M, Maslan S L, Singer F R, Eyre D R. 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 1251-1258
• 52 Harris E D Jr. Rheumatoid arthritis. Pathophysiology and implications for therapy.  N Engl J Med. 1990;  322 1277-1289
• 53 Hassager C, Jensen L T, Pødenphant J, Thomsen K, Christiansen C. The carboxy-terminal pyridinoline crosslinked 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 30-33
• 54 Hawkins F G, Leon M, Lopez M B, Valero M A, Larrodera L, Garcia-Garcia I, Loinaz C, Moreno Gonzalez E. Bone loss and turnover in patients with liver transplantation.  Hepatogastroenterology. 1994;  41 158-161
• 55 Heinegard D, Oldberg Å. Structure and biology of cartilage and bone matrix noncollageneous macromolecules.  FASEB J. 1989;  3 2042-2051
• 56 Helfrich M H, Nessbitt S A, Dorey E L, Horton M A. Rat osteoclasts adhere to a wide range of RGD (Arg-Gly-Asp) peptide-containing proteins, including the bone sialoproteins and fibronectin, via a beta 3 integrin.  J Bone Miner Res. 1992;  7 335-343
• 57 Hench P S, Kendall E C, Slocumb C H, Polley H F. The effect of a hormone of the adrenal cortex (17-hydroxy-11-dehydrocorticosterone: compound E) and of pituitary adrenocorticotropic hormone on rheumatoid arthritis: preliminary report.  Proc Staff Meet Mayo Clin. 1949;  24 181-197
• 58 Horber F F, Casez J P, Steiger U, Czerniak A, Montandon A, Jaeger P. Changes in bone mass early after kidney transplantation.  J Bone Miner Res. 1994;  9 1-9
• 59 Hosoda K, Eguchi H, Nakamoto T, Kubota T, Honda H, Jindai S, Hasegawa R, Kiyoki M, Yamaji T, Shiraki M. Sandwich immunoassay for intact human osteocalcin.  Clin Chem. 1992;  38 2233-2238
• 60 Hruska K A, Teitelbaum S L. Renal osteodystrophy.  N Engl J Med. 1995;  333 166-174
• 61 Jackson J A, Kleerekoper M, Parfitt A M, Rao D S, Villanueva A R, Frame B. Bone histomorphometry in hypogonadal and eugonadal men with spinal osteoporosis.  J Clin Endocrinol Metab. 1987;  65 53-58
• 62 Jackson J A, Riggs M W, Spiekermann A M. Testosterone deficiency as a risk factor for hip fractures in men: A case-control study.  Am J Med Sci. 1992;  304 4-8
• 63 Julian B A, Laskow D A, Dubovsky J, Dubovsky E V, Curtis J J, Quarles L D. Rapid loss of vertebral mineral density after renal transplantation.  N Engl J Med. 1991;  325 544-550
• 64 Jüppner H, Schettler T, Giebel G, Wenner S, Hesch R D. Radioimmunoassay for human osteocalcin using an antibody raised against the synthetic human (h37 - 49) sequence.  Calcif Tissue Int. 1986;  39 310-315
• 65 Karmatschek M, Maier I, Seibel M J, Woitge H W, Ziegler R, Armbruster F P. Improved purification of human bone sialoprotein and development of a homologous radioimmunoassay.  Clin Chem. 1997;  43 2076-2082
• 66 Katznelson L, Finkelstein J S, Schoenfeld D A, Rosenthal D I, Anderson E J, Klibanski A. Increase in bone density and lean body mass during testosterone administration in men with acquired hypogonadism.  J Clin Endocrinol Metab. 1996;  81 4358-4365
• 67 Kelly P J, Atkinson K, Ward R L, Sambrook P N, Biggs J C, Eisman J A. Reduced bone mineral density in men and women with allogenic bone marrow transplantation.  Transplantation. 1990;  50 881-883
• 68 Kother M, Schindler J, Oette K, Berthold F. Abnormalities in serum osteocalcin values in children receiving chemotherapy including ifosfamide.  In Vivo. 1992;  6 219-221
• 69 Krane S M, Conca W, Stephenson M L, Amento E P, Goldring M B. Mechanisms of matrix degradation in rheumatoid arthritis.  Ann NY Acad Sci. 1990;  580 340-354
• 70 Laitinen K, Lamberg-Allardt C, Tunninen R, Karonen S L, Tahtela R, Ylikahri R, Valimaki M. Transient hypoparathyroidism during acute alcohol intoxication.  N Engl J Med. 1991;  324 721-727
• 71 Laitinen K, Lamberg-Allardt C, Tunninen R, Karonen S L, Ylikahri R, Valimaki M. Effects of 3 weeks’ moderate alcohol intake on bone and mineral metabolism in normal men.  Bone Miner. 1991;  13 139-151
• 72 Lam K W, Lee P F, Li C Y, Yam L T. Immunological and biochemical evidence for identity of tartrate-resistant isoenzymes of acid phosphatases from human serum and tissue.  Clin Chem. 1980;  26 420-422
• 73 Lam K W, Siemens M, Sun T, Li C Y, Yam L T. Enzyme immunoassay for tartrate-resistant acid phosphatase.  Clin Chem. 1982;  28 467-470
• 74 Lau K H, Onishi T, Wergedal J E, Singer F R, Baylink D J. Characterization of and assay for human tartrate-resistant acid phosphatase activity in serum: potential use to assess bone resorption.  Clin Chem. 1987;  33 458-462
• 75 Laurence J R, Neville A M. The detection and evaluation of human tumor metastases.  Cancer Met Rev. 1983;  2 351-374
• 76 Leblanc A D, Schneider V S, Evans H J, Engelbretson D A, Krebs J M. Bone mineral loss and recovery after 17 weeks of bed rest.  J Bone Miner Res. 1990;  5 843-850
• 77 Lian J B, Friedman P A. The vitamin K-dependent synthesis of gamma-carboxyglutamic acid by bone microsomes.  J Biol Chem. 1987;  253 6623-6626
• 78 Lindholm J, Steiniche T, Rasmussen E, Thamsborg G, Nielsen I O, Brockstedt-Rasmussen H, Storm T, Hyldstrup L, Schou C. Bone disorder in men with chronic alcoholism: a reversible disease?.  J Clin Endocrinol Metab. 1991;  73 118-124
• 79 Lindsay R, Cosman F. Skeletal effects of estrogen analogs.  Osteopor Int. 1997;  7 40-42
• 80 Loertscher R, Thiel G, Harder F, Brunner F P. Persistent elevation of alkaline phosphatase in cyclosporine-treated renal transplant recipients.  Transplantation. 1983;  36 115-116
• 81 Lukert B P, Higgins J C, Stoskopf M M. Serum osteocalcin is increased in patients with hyperparathyroidism and decreased in patients receiving glucocorticoids.  J Clin Endocrinol Metab. 1986;  62 1056-1058
• 82 Marhoffer W, Schatz H, Stracke H, Ullmann J, Schmidt K, Federlin K. Serum osteocalcin levels in rheumatoid arthritis: a marker for accelerated bone turnover in late onset rheumatoid arthritis.  J Rheumatol. 1991;  18 1158-1162
• 83 McDonald J A, Dunstan C R, Dilworth P, Sherbon K, Sheil A G, Evans R A, McCaughan G W. Bone loss after liver transplantation.  Hepatology. 1991;  14 613-619
• 84 Melkko J, Niemi S, Risteli L, Risteli J. Radioimmunoassay of the carboxyterminal propeptide of human type I procollagen.  Clin Chem. 1990;  36 1328-1332
• 85 Merry A H, Harwood R, Woolley D E, Grant M E, Jackson D S. Identification and partial characterization of the non-collagenous amino- and carboxy-terminal extension peptides of cartilage procollagen.  Biochem Biophys Res Commun. 1976;  71 83-90
• 86 Meys E, Fontanges E, Fourcade N, Thomasson A, Pouyet M, Delmas P D. Bone loss after orthotopic liver transplantation.  Am J Med. 1994;  97 445-450
• 87 Meys E, Terreaux-Duvert F, Beaume-Six T, Dureau G, Meunier P J. Bone loss after cardiac transplantation: effects of calcium, calcidiol and monofluorophosphate.  Osteoporos Int. 1993;  3 322-329
• 88 Minkin C. Bone acid phosphatase: Tartrate-resistant acid phosphatase as a marker of osteoclast function.  Calcif Tissue Int. 1982;  34 285-290
• 89 Monoghan D A, Power M J, Fottrell P F. Sandwich enzyme immunoassay of osteocalcin in serum with use of an antibody against human osteocalcin.  Clin Chem. 1993;  39 942-947
• 90 Moss D W, Whitby L G. A simplified heat-inactivation method for investigating alkaline phosphatase isoenzymes in serum.  Clin Chim Acta. 1975;  61 63-71
• 91 Moss D W. Perspectives in alkaline phosphatase research (Review).  Clin Chem. 1992;  38 2386-2392
• 92 Mundy G R. The hypercalcemia of malignancy.  Kidney Int. 1987;  31 142-155
• 93 Nakanishi M, Yoh K, Uchida K, Maruo S, Matsuoka A. Improved method for measuring tartrate-resistant acid phosphatase activity in serum.  Clin Chem. 1998;  44 221-225
• 94 Nguyen T V, Eisman J A, Kelly P J, Sambrook P N. Risk factors for osteoporotic fractures in elderly men.  Am J Epidemiol. 1996;  144 255-263
• 95 Nordin B EC, Marshall D H, Francis R M, Crilly R G. The effects of sex steroids and corticosteroid hormones on bone.  J Steroid Biochem. 1981;  15 171-174
• 96 Nyquist F, Ljunghall S, Berglund M, Obrant K. Biochemical markers of bone metabolism after short and long time ethanol withdrawal in alcoholics.  Bone. 1996;  19 51-54
• 97 Oikarinen A, Autio P, Vuori J, Vaananen K, Risteli L, Kiistala U, Risteli J. Systemic glucocorticoid treatment decreases serum concentrations of carboxyterminal propeptide of type I procollagen and aminoterminal propeptide of type III procollagen.  Br J Dermatol. 1992;  126 172-178
• 98 Oldberg A, Franzen A, Heinegard D, Pierschbacher M, Ruoslathi E. Identification of a bone sialoprotein receptor in osteosarcoma cells.  J Biol Chem. 1988;  263 19 433-19 436
• 99 Pecherstorfer M, Seibel M J, Woitge H W, Horn E, Schuster J, Neuda J, Sagaster P, Kohn H, Bayer P, Thiebaud D, Ludwig H. Bone resorption in multiple myeloma and in monoclonal gammopathy of undetermined significance: quantification by urinary pyridinium cross-links of collagen.  Blood. 1997;  90 3743-3750
• 100 Pecherstorfer M, Zimmer-Roth I, Schilling T, Woitge H W, Schmidt H, Baumgartner G, Thiebaud D, Ludwig H, Seibel M J. The diagnostic value of urinary pyridinium cross-links of collagen, serum total alkaline phosphatase, and urinary calcium excretion in neoplastic bone disease.  J Clin Endocrinol Metab. 1995;  80 97-103
• 101 Peel N F, Eastell R, Russell R G. Osteoporosis in rheumatoid arthritis - the laboratory perspective.  Br J Rheum. 1991;  30 84-85
• 102 Pepersack T, Fuss M, Otero J, Bergmann P, Valsamis J, Corvilain J. Longitudinal study of bone metabolism after ethanol withdrawal in alcohlic patients.  J Bone Miner Res. 1992;  7 383-387
• 103 Peretz A, Praet J P, Bosson D, Rozenberg S, Bourdoux P. Serum osteocalcin in the assessment of corticosteroid induced osteoporosis. Effect of long and short term corticosteroid treatment.  J Rheumatol. 1989;  16 363-367
• 104 Peretz A, Praet J P, Rozenberg S, Bosson D, Famaey J P, Bourdoux P. Osteocalcin and bone mineral content in rheumatoid arthritis.  Clin Rheumatol. 1989;  8 42-48
• 105 Pietschmann P, Machold K P, Wolosczuk W, Smolen J S. Serum osteocalcin concentrations in patients with rheumatoid arthritis.  Ann Rheum Diseases. 1989;  48 654-657
• 106 Porayko M K, Wiesner R H, Hay J E, Krom R A, Dickson E R, Beaver S, Schwerman L. Bone disease in liver transplant recipients: incidence, timing, and risk factors.  Transplant Proc. 1991;  23 1462-1465
• 107 Price P A, Nishimito S K. Radioimmunoassay for the vitamin K-dependent protein of bone and its discovery in plasma.  Proc Natl Acad Sci USA. 1980;  77 2234-2238
• 108 Prior J C, Vigna Y M, Wark J D, Eyre D R, Lentle B C, Li D K, Ebeling P R, Atley L. Premenopausal ovariectomy-related bone loss: a randomized, double-blind, one-year trial of conjugated estrogen or medroxyprogesterone acetate.  J Bone Miner Res. 1997;  12 1851-1863
• 109 Prummel M F, Wiersinga W M, Lips P, Sanders G T, Sauerwein H P. The course of biochemical parameters of bone turnover during treatment with corticosteroids.  J Clin Endocrinol Metab. 1991;  72 382-386
• 110 Raisz L G, Prestwood K M. Estrogen and the risk of fracture - new data, new questions.  N Engl J Med. 1998;  339 767-768
• 111 Reid I R, Chapman G E, Fraser T RC, Davies A D, Surus A S, Meyer J, Huq N L, Ibbertson H K. Low serum osteocalcin levels in glucocorticoid-treated asthmatics.  J Clin Endocrinol Metab. 1986;  62 379-383
• 112 Reid I R, Heap S W. Determinants of vertebral mineral density in patients receiving long-term glucocorticoid therapy.  Arch Int Med. 1990;  150 2545-2548
• 113 Reid I R. Pathogenesis and treatment of steroid osteoporosis.  Clin Endocrinol. 1989;  30 83-103
• 114 Rencken M L, Chesnut C H 3rd , Drinkwater B L. Bone density at multiple skeletal sites in amenorrheic athletes.  JAMA. 1996;  276 238-240
• 115 Riggs B L, Khosla S, Melton L J 3rd . A unitary model for involutional osteoporosis: estrogen deficiency causes both type I and type II osteoporosis in postmenopausal women and contributes to bone loss in aging men.  J Bone Miner Res. 1998;  13 763-773
• 116 Risteli J, Elonaa I, Niemi S, Novamo A, Risteli L. Radioimmunoassay for the pyridinoline cross-linked carboxy-terminal telopeptide of type I collagen: a new serum marker of bone collagen degradation.  Clin Chem. 1993;  39 635-640
• 117 Rizzoli R, Bonjour J P. Hormones and bones.  Lancet. 1997;  349 20-23
• 118 Robins S P, Duncan A. Pyridinium crosslinks of bone collagen and their location in peptides isolated from rat femur.  Biochim Biophys Acta. 1987;  914 233-239
• 119 Robins S P, Seibel M J, McLaren A M. Collagen markers in urine in human arthritis. In: Maroudas A, Kuettner K (Hrsg) Methods in Cartilage Research. London; Academic Press 1991: 348-352
• 120 Robins S P, Woitge H W, Hesley R, Ju J, Seyedin S, Seibel M J. Direct enzyme-linked immunoassay for urinary deoxypyridinoline as a specific marker for measuring bone resorption.  J Bone Miner Res. 1994;  9 1643-1649
• 121 Rosalki S B, Foo A Y, Burlina A, Prellwitz W, Stieber P, Neumeier D, Klein G, Poppe W A, Bodenmuller H. Multicenter evaluation of iso-ALP test kit for measurement of bone alkaline phosphatase activity in serum and plasma.  Clin Chem. 1993;  39 648-652
• 122 Ross F P, Chappel J, Alvarez J I, Sander D, Butler W T, Farach-Carson M C, Mintz K A, Robey P G, Teitelbaum S L, Cheresh D A. 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 9901-9907
• 123 Sambrook P N, Kelly P J, Fontana D, Nguyen T, Keogh A, Macdonald P, Spratt P, Freund J, Eisman J A. Mechanisms of rapid bone loss following cardiac transplantation.  Osteoporos Int. 1994;  4 273-276
• 124 Sambrook P N, Kelly P J, Koegh A, MacDonald P, Spratt P, Freund J, Eisman J A. Bone loss after cardiac transplantation: a prospective study.  J Heart Lung Transpl. 1994;  13 116-121
• 125 Schmidt H, Stracke H, Schatz H, Scheuermann E H, Fassbinder W, Schoeppe W. Osteocalcin serum levels in patients following renal transplantation.  Klin Wochenschr. 1989;  67 297-303
• 126 Seibel M J, Cosman F, Shen V, Gordon S, Dempster D W, Ratcliffe A, Lindsay R. Urinary hydroxypyridinium crosslinks of collagen as markers of bone resorption and estrogen efficacy in postmenopausal osteoporosis.  J Bone Miner Res. 1993;  8 881-889
• 127 Seibel M J, Duncan A, Robins S P. Urinary hydroxypyridinium crosslinks provide indices of cartilage and bone involvement in arthritic diseases.  J Rheumatol. 1989;  16 964-970
• 128 Seibel M J, Robins S P, Bilezikian J P. Urinary pyridinium crosslinks of collagen. Specific markers of bone resorption in metabolic bone disease.  Trends Endocrinol Metab. 1992;  3 263-270
• 129 Seibel M J, Woitge H, Scheidt-Nave C, Leidig-Bruckner G, Duncan A, Nicol P, Ziegler R, Robins S P. Urinary hydroxypyridinium crosslinks of collagen in population-based screening for overt vertebral osteoporosis: Results of a pilot study.  J Bone Miner Res. 1994;  9 1433-1440
• 130 Seibel M J, Woitge H W, Pecherstorfer M, Karmatschek M, Horn E, Ludwig H, Armbruster F P, Ziegler R. Serum immunoreactive bone sialoprotein as a new marker of bone turnover in metabolic and malignant bone disease.  J Clin Endocrinol Metab. 1996;  81 3289-3294
• 131 Shane E, Mancini D, Aaronson K, Silverberg S J, Seibel M J, Addesso V, McMahon D J. Bone mass, vitamin D deficiency, and hyperparathyroidism in congestive heart failure.  Am J Med. 1997;  103 197-207
• 132 Shane E, Rivas M, Staron R B, Silverberg S J, Seibel M J, Kuiper J, Mancini D, Addesso V, Michler R E, Factor-Litvak P. Fracture after cardiac transplantation: a prospective longitudinal study.  J Clin Endocrinol Metab. 1996;  81 1740-1746
• 133 Shane E, Rivas M C, Silverberg S J, Kim T S, Staron R B, Bilezikian J P. Osteoporosis after cardiac transplantation.  Am J Med. 1993;  94 257-264
• 134 Shapiro H S, Chen J, Wrana J L, Zhang Q, Blum M, Sodek J. Characterization of porcine bone sialoprotein: primary structure and cellular expression.  Matrix. 1993;  13 431-440
• 135 Slovik D M, Gundberg C M, Neer R M, Lian J B. Clinical evaluation of bone turnover by serum osteocalcin measurements in a hospital setting.  J Clin Endocrinol Metab. 1984;  59 228-230
• 136 Smith E P, Boyd J, Frank G R, Takahashi H, Cohen R M, Specker B, Williams T C, Lubahn D B, Korach K S. Estrogen resistance caused by a mutation in the estrogen-receptor gene in a man.  N Engl J Med. 1994;  331 1056-1061
• 137 Stempfle H U, Werner C, Echtler S, Assum T, Meister B, Angermann C E, Theisen K, Gartner R. Rapid trabecular bone loss after cardiac transplantation using FK506 (tacrolimus)-based immunosuppression.  Transplant Proc. 1998;  30 1132-1133
• 138 Stepan J J, Lachman M, Zverina J, Pacovsky V, Baylink D J. Castrated men exhibit bone loss: Effect of calcitonin treatment on biochemical indices of bone remodeling.  J Clin Endocrinol Metab. 1989;  69 523-527
• 139 Tavassoli M, Rizo M, Yam L T. Elevation of serum acid phosphatase in cancers with bone metastasis.  Cancer. 1980;  45 2400-2403
• 140 Taxel P, Raisz L GR. The effect of an aromatase inhibitor on bone turnover in older men.  Bone. 1998;  23 178
• 141 Uebelhart D, Gineyts E C, Chapuy M C, Delmas P D. Urinary excretion of pyridinium crosslinks: a new marker of bone resorption in metabolic bone disease.  Bone Miner. 1990;  8 87-96
• 142 Urena P, Ferreira A, Kung V T, Morieux C, Simon P, Ang K S, Souberbielle J C, Segre G V, Drueke T B, De Vernejoul M C. Serum pyridinoline as a specific marker of collagen breakdown and bone metabolism in hemodialysis patients.  J Bone Miner Res. 1995;  10 932-939
• 143 Van Hoof V O, Lepoutre L G, Hoylaerts M F, Chevigne R, DeBroe M E. Improved agarose electrophoretic method for separating alkaline phosphatase isoenzymes in serum.  Clin Chem. 1988;  34 1857-1862
• 144 Van Straalen J P, Sanders E, Prummel M F, Santers G TB. Bone alkaline phosphatase as indicator of bone formation.  Clin Chim Acta. 1991;  201 27-34
• 145 Vanderscheuren D, Bouillon R. Androgens and bone.  Calcif Tissue Int. 1995 ;  56 341-346
• 146 Wang C, Eyre D R, Clark R, Kleinberg D, Newman C, Iranmanesh A, Veldhuis J, Dudley R E, Berman N, Davidson T, Barstow T J, Sinow R, Alexander G, Swerdloff R S. Sublingual testosterone replacement improves muscle mass and strength, decreases bone resorption, and increases bone formation markers in hypogonadal men - a clinical research center study.  J Clin Endocrinol Metab. 1996;  81 3654-3662
• 147 Wells S A, Cooper C W, Ontjes D A. Stimulation of thyrocalcitonin secretion by ethanol in patients with medullary thyroid carcinoma - an effect apparently not mediated by gastrin.  Metabolism. 1975;  24 1215-1219
• 148 Wilmink J M, Bras J, Surachno S, van Heyst J L, van der Horst J M. Bone repair in cyclosporin treated renal transplant patients.  Transplant Proc. 1989;  21 1492-1494
• 149 Withold W, Degenhardt S, Grabensee B, Reinauer H. Comparison between serum levels of bone alkaline phosphatase and the carboxy-terminal propeptide of type I procollagen as markers of bone formation in patients following renal transplantation.  Clin Chim Acta. 1995;  239 143-151
• 150 Withold W, Degenhardt S, Heins M, Grabensee B, Reinauer H. Monitoring of bone resorption after renal transplantation by measuring the urinary excretion of pyridinium cross-links.  Eur J Clin Chem Clin Biochem. 1995;  33 15-21
• 151 Woitge H W, Pecherstorfer M, Li Y, Keck A V, Horn E, Ziegler R, Seibel M J. Novel serum markers of bone resorption: Clinical assessment and comparison with established urinary indices.  J Bone Miner Res. 1999;  14 792-801
• 152 Woitge H W, Scheidt-Nave C, Kissling C, Leidig-Bruckner G, Meyer K, Grauer A, Scharla S H, Ziegler R, Seibel M J. Seasonal variation of biochemical indexes of bone turnover: results of a population-based study.  J Clin Endocrinol Metab. 1998;  83 68-75
• 153 Woitge H W, Seibel M J, Ziegler R. Comparison of total and bone-specific alkaline phosphatase in patients with nonskeletal disorder or metabolic bone diseases.  Clin Chem. 1996;  42 1796-1804