Skip to main content
NCBI home page
The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1993 Mar;91(3):1138–1148. doi: 10.1172/JCI116273

An evaluation of several biochemical markers for bone formation and resorption in a protocol utilizing cyclical parathyroid hormone and calcitonin therapy for osteoporosis.

A B Hodsman 1, L J Fraher 1, T Ostbye 1, J D Adachi 1, B M Steer 1
PMCID: PMC288070  PMID: 8450043

Abstract

Female patients (n = 20) with osteoporosis, aged 66 +/- 5 yr were studied during a 24-h infusion of parathyroid hormone (PTH [1-34]) at a rate of 0.5 IU equivalents/kg.h, and then during a 28-d period of subcutaneous injections, at a dose of 800 IU equivalents per day. Thereafter half the patients received subcutaneous injections of calcitonin, 75 U/d for 42 d, and all patients were followed to the end of a 90-d cycle. Biochemical markers of bone formation (serum alkaline phosphatase, osteocalcin, and the carboxy-terminal extension peptide of pro-collagen 1) and bone resorption (fasting urine calcium, hydroxyproline, and deoxypyridinoline) were compared during treatment by the intravenous and subcutaneous route of PTH administration, and subsequently during calcitonin therapy. During intravenous PTH infusion there were significant reductions in all three bone formation markers, despite expected rises in urinary calcium and hydroxyproline. By contrast, the circulating markers of bone formation increased rapidly by > 100% of baseline values during daily PTH injections (P < 0.001). Significant increases in bone resorption markers were only seen at the end of the 28 d of injections, but were < 100% over baseline values, (P < 0.05). Quantitative bone histomorphometry from biopsies obtained after 28 d of PTH treatment confirmed that bone formation at both the cellular and tissue levels were two to five times higher than similar indices measured in a control group of biopsies from untreated osteoporotic women. Subsequent treatment of these patients with calcitonin showed no significant changes in the biochemical markers of bone formation and only a modest attenuation of bone resorption. Thus, PTH infusion may inhibit bone formation, as judged by circulating biochemical markers, whereas daily injections confirm the potent anabolic actions of the hormone. Sequential calcitonin therapy does not appear to act synergistically with PTH in cyclical therapeutic protocols.

Full text

PDF
1138

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Beardsworth L. J., Eyre D. R., Dickson I. R. Changes with age in the urinary excretion of lysyl- and hydroxylysylpyridinoline, two new markers of bone collagen turnover. J Bone Miner Res. 1990 Jul;5(7):671–676. doi: 10.1002/jbmr.5650050702. [DOI] [PubMed] [Google Scholar]
  2. Beresford J. N., Gallagher J. A., Poser J. W., Russell R. G. Production of osteocalcin by human bone cells in vitro. Effects of 1,25(OH)2D3, 24,25(OH)2D3, parathyroid hormone, and glucocorticoids. Metab Bone Dis Relat Res. 1984;5(5):229–234. doi: 10.1016/0221-8747(84)90064-x. [DOI] [PubMed] [Google Scholar]
  3. 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 Feb 15;169(1):197–203. doi: 10.1016/0003-2697(88)90274-6. [DOI] [PubMed] [Google Scholar]
  4. Cleary J., Saunders R. A. A simplified procedure for the measurement of total hydroxyproline in urine. Clin Chim Acta. 1974 Dec 17;57(3):217–223. doi: 10.1016/0009-8981(74)90400-8. [DOI] [PubMed] [Google Scholar]
  5. Dahl E., Nordal K. P., Halse J., Attramadal A. Histomorphometric analysis of normal bone from the iliac crest of Norwegian subjects. Bone Miner. 1988 Mar;3(4):369–377. [PubMed] [Google Scholar]
  6. Dandona P., Coumar A., Gill D. S., Bell J., Thomas M. Sodium fluoride stimulates osteocalcin in normal subjects. Clin Endocrinol (Oxf) 1988 Oct;29(4):437–441. doi: 10.1111/j.1365-2265.1988.tb02893.x. [DOI] [PubMed] [Google Scholar]
  7. Duda R. J., Jr, O'Brien J. F., Katzmann J. A., Peterson J. M., Mann K. G., Riggs B. L. Concurrent assays of circulating bone Gla-protein and bone alkaline phosphatase: effects of sex, age, and metabolic bone disease. J Clin Endocrinol Metab. 1988 May;66(5):951–957. doi: 10.1210/jcem-66-5-951. [DOI] [PubMed] [Google Scholar]
  8. Eastell R., Delmas P. D., Hodgson S. F., Eriksen E. F., Mann K. G., Riggs B. L. Bone formation rate in older normal women: concurrent assessment with bone histomorphometry, calcium kinetics, and biochemical markers. J Clin Endocrinol Metab. 1988 Oct;67(4):741–748. doi: 10.1210/jcem-67-4-741. [DOI] [PubMed] [Google Scholar]
  9. Eriksen E. F., Hodgson S. F., Eastell R., Cedel S. L., O'Fallon W. M., Riggs B. L. Cancellous bone remodeling in type I (postmenopausal) osteoporosis: quantitative assessment of rates of formation, resorption, and bone loss at tissue and cellular levels. J Bone Miner Res. 1990 Apr;5(4):311–319. doi: 10.1002/jbmr.5650050402. [DOI] [PubMed] [Google Scholar]
  10. Eriksen E. F., Mosekilde L., Melsen F. Trabecular bone remodeling and balance in primary hyperparathyroidism. Bone. 1986;7(3):213–221. doi: 10.1016/8756-3282(86)90020-7. [DOI] [PubMed] [Google Scholar]
  11. 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 Jun 1;252(2):495–500. doi: 10.1042/bj2520495. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Fraher L. J., Hodsman A. B., Jonas K., Saunders D., Rose C. I., Henderson J. E., Hendy G. N., Goltzman D. A comparison of the in vivo biochemical responses to exogenous parathyroid hormone-(1-34) [PTH-(1-34)] and PTH-related peptide-(1-34) in man. J Clin Endocrinol Metab. 1992 Aug;75(2):417–423. doi: 10.1210/jcem.75.2.1322424. [DOI] [PubMed] [Google Scholar]
  13. Frost H. M. Coherence treatment of osteoporoses. Orthop Clin North Am. 1981 Jul;12(3):649–669. [PubMed] [Google Scholar]
  14. Glüer C. C., Steiger P., Selvidge R., Elliesen-Kliefoth K., Hayashi C., Genant H. K. Comparative assessment of dual-photon absorptiometry and dual-energy radiography. Radiology. 1990 Jan;174(1):223–228. doi: 10.1148/radiology.174.1.2294552. [DOI] [PubMed] [Google Scholar]
  15. Hasling C., Eriksen E. F., Melkko J., Risteli L., Charles P., Mosekilde L., Risteli J. Effects of a combined estrogen-gestagen regimen on serum levels of the carboxy-terminal propeptide of human type I procollagen in osteoporosis. J Bone Miner Res. 1991 Dec;6(12):1295–1300. doi: 10.1002/jbmr.5650061205. [DOI] [PubMed] [Google Scholar]
  16. Hassager C., Jensen L. T., Johansen J. S., Riis B. J., Melkko J., Pødenphant J., Risteli L., Christiansen C., Risteli J. The carboxy-terminal propeptide of type I procollagen in serum as a marker of bone formation: the effect of nandrolone decanoate and female sex hormones. Metabolism. 1991 Feb;40(2):205–208. doi: 10.1016/0026-0495(91)90176-w. [DOI] [PubMed] [Google Scholar]
  17. Hauschka P. V., Lian J. B., Cole D. E., Gundberg C. M. Osteocalcin and matrix Gla protein: vitamin K-dependent proteins in bone. Physiol Rev. 1989 Jul;69(3):990–1047. doi: 10.1152/physrev.1989.69.3.990. [DOI] [PubMed] [Google Scholar]
  18. Hesch R. D., Busch U., Prokop M., Delling G., Rittinghaus E. F. Increase of vertebral density by combination therapy with pulsatile 1-38hPTH and sequential addition of calcitonin nasal spray in osteoporotic patients. Calcif Tissue Int. 1989 Mar;44(3):176–180. doi: 10.1007/BF02556561. [DOI] [PubMed] [Google Scholar]
  19. Hock J. M., Fonseca J., Gunness-Hey M., Kemp B. E., Martin T. J. Comparison of the anabolic effects of synthetic parathyroid hormone-related protein (PTHrP) 1-34 and PTH 1-34 on bone in rats. Endocrinology. 1989 Oct;125(4):2022–2027. doi: 10.1210/endo-125-4-2022. [DOI] [PubMed] [Google Scholar]
  20. Hock J. M., Hummert J. R., Boyce R., Fonseca J., Raisz L. G. Resorption is not essential for the stimulation of bone growth by hPTH-(1-34) in rats in vivo. J Bone Miner Res. 1989 Jun;4(3):449–458. doi: 10.1002/jbmr.5650040321. [DOI] [PubMed] [Google Scholar]
  21. Hodgkinson A., Thompson T. Measurement of the fasting urinary hydroxyproline: creatinine ratio in normal adults and its variation with age and sex. J Clin Pathol. 1982 Aug;35(8):807–811. doi: 10.1136/jcp.35.8.807. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Hodsman A. B., Fraher L. J. Biochemical responses to sequential human parathyroid hormone (1-38) and calcitonin in osteoporotic patients. Bone Miner. 1990 May;9(2):137–152. doi: 10.1016/0169-6009(90)90080-y. [DOI] [PubMed] [Google Scholar]
  23. Hodsman A. B., Steer B. M., Fraher L. J., Drost D. J. Bone densitometric and histomorphometric responses to sequential human parathyroid hormone (1-38) and salmon calcitonin in osteoporotic patients. Bone Miner. 1991 Jul;14(1):67–83. doi: 10.1016/0169-6009(91)90103-7. [DOI] [PubMed] [Google Scholar]
  24. Hodsman A. B., Toogood J. H., Jennings B., Fraher L. J., Baskerville J. C. Differential effects of inhaled budesonide and oral prednisolone on serum osteocalcin. J Clin Endocrinol Metab. 1991 Mar;72(3):530–540. doi: 10.1210/jcem-72-3-530. [DOI] [PubMed] [Google Scholar]
  25. Hori M., Uzawa T., Morita K., Noda T., Takahashi H., Inoue J. Effect of human parathyroid hormone (PTH(1-34)) on experimental osteopenia of rats induced by ovariectomy. Bone Miner. 1988 Jan;3(3):193–199. [PubMed] [Google Scholar]
  26. Liu C. C., Kalu D. N. Human parathyroid hormone-(1-34) prevents bone loss and augments bone formation in sexually mature ovariectomized rats. J Bone Miner Res. 1990 Sep;5(9):973–982. doi: 10.1002/jbmr.5650050911. [DOI] [PubMed] [Google Scholar]
  27. Ljunghall S., Gärdsell P., Johnell O., Larsson K., Lindh E., Obrant K., Sernbo I. Synthetic human calcitonin in postmenopausal osteoporosis: a placebo-controlled, double-blind study. Calcif Tissue Int. 1991 Jul;49(1):17–19. doi: 10.1007/BF02555897. [DOI] [PubMed] [Google Scholar]
  28. Majeska R. J., Rodan G. A. Alkaline phosphatase inhibition by parathyroid hormone and isoproterenol in a clonal rat osteosarcoma cell line. Possible mediation by cyclic AMP. Calcif Tissue Int. 1982 Jan;34(1):59–66. doi: 10.1007/BF02411210. [DOI] [PubMed] [Google Scholar]
  29. Majeska R. J., Rodan S. B., Rodan G. A. Parathyroid hormone-responsive clonal cell lines from rat osteosarcoma. Endocrinology. 1980 Nov;107(5):1494–1503. doi: 10.1210/endo-107-5-1494. [DOI] [PubMed] [Google Scholar]
  30. Malluche H. H., Sherman D., Meyer W., Ritz E., Norman A. W., Massry S. G. Effects of long-term infusion of physiologic doses of 1-34 PTH on bone. Am J Physiol. 1982 Feb;242(2):F197–F201. doi: 10.1152/ajprenal.1982.242.2.F197. [DOI] [PubMed] [Google Scholar]
  31. Parfitt A. M., Drezner M. K., Glorieux F. H., Kanis J. A., Malluche H., Meunier P. J., Ott S. M., Recker R. R. Bone histomorphometry: standardization of nomenclature, symbols, and units. Report of the ASBMR Histomorphometry Nomenclature Committee. J Bone Miner Res. 1987 Dec;2(6):595–610. doi: 10.1002/jbmr.5650020617. [DOI] [PubMed] [Google Scholar]
  32. Parisien M., Silverberg S. J., Shane E., de la Cruz L., Lindsay R., Bilezikian J. P., Dempster D. W. The histomorphometry of bone in primary hyperparathyroidism: preservation of cancellous bone structure. J Clin Endocrinol Metab. 1990 Apr;70(4):930–938. doi: 10.1210/jcem-70-4-930. [DOI] [PubMed] [Google Scholar]
  33. Podbesek R., Edouard C., Meunier P. J., Parsons J. A., Reeve J., Stevenson R. W., Zanelli J. M. Effects of two treatment regimes with synthetic human parathyroid hormone fragment on bone formation and the tissue balance of trabecular bone in greyhounds. Endocrinology. 1983 Mar;112(3):1000–1006. doi: 10.1210/endo-112-3-1000. [DOI] [PubMed] [Google Scholar]
  34. Podbesek R., Edouard C., Meunier P. J., Parsons J. A., Reeve J., Stevenson R. W., Zanelli J. M. Effects of two treatment regimes with synthetic human parathyroid hormone fragment on bone formation and the tissue balance of trabecular bone in greyhounds. Endocrinology. 1983 Mar;112(3):1000–1006. doi: 10.1210/endo-112-3-1000. [DOI] [PubMed] [Google Scholar]
  35. Price P. A., Parthemore J. G., Deftos L. J. New biochemical marker for bone metabolism. Measurement by radioimmunoassay of bone GLA protein in the plasma of normal subjects and patients with bone disease. J Clin Invest. 1980 Nov;66(5):878–883. doi: 10.1172/JCI109954. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Reeve J., Arlot M., Price T. R., Edouard C., Hesp R., Hulme P., Ashby J. P., Zanelli J. M., Green J. R., Tellez M. Periodic courses of human 1-34 parathyroid peptide alternating with calcitriol paradoxically reduce bone remodelling in spinal osteoporosis. Eur J Clin Invest. 1987 Oct;17(5):421–428. doi: 10.1111/j.1365-2362.1987.tb01137.x. [DOI] [PubMed] [Google Scholar]
  37. Reeve J., Davies U. M., Hesp R., McNally E., Katz D. Treatment of osteoporosis with human parathyroid peptide and observations on effect of sodium fluoride. BMJ. 1990 Aug 11;301(6747):314–318. doi: 10.1136/bmj.301.6747.314. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Reeve J., Hesp R., Williams D., Hulme P., Klenerman L., Zanelli J. M., Darby A. J., Tregear G. W., Parsons J. A. Anabolic effect of low doses of a fragment of human parathyroid hormone on the skeleton in postmenopausal osteoporosis. Lancet. 1976 May 15;1(7968):1035–1038. doi: 10.1016/s0140-6736(76)92216-9. [DOI] [PubMed] [Google Scholar]
  39. Reeve J., Meunier P. J., Parsons J. A., Bernat M., Bijvoet O. L., Courpron P., Edouard C., Klenerman L., Neer R. M., Renier J. C. Anabolic effect of human parathyroid hormone fragment on trabecular bone in involutional osteoporosis: a multicentre trial. Br Med J. 1980 Jun 7;280(6228):1340–1344. doi: 10.1136/bmj.280.6228.1340. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Riggs B. L., Melton L. J., 3rd Evidence for two distinct syndromes of involutional osteoporosis. Am J Med. 1983 Dec;75(6):899–901. doi: 10.1016/0002-9343(83)90860-4. [DOI] [PubMed] [Google Scholar]
  41. Riis B. J. Biochemical markers of bone turnover in diagnosis and assessment of therapy. Am J Med. 1991 Nov 25;91(5B):64S–68S. doi: 10.1016/0002-9343(91)90251-r. [DOI] [PubMed] [Google Scholar]
  42. Robins S. P., Black D., Paterson C. R., Reid D. M., Duncan A., Seibel M. J. Evaluation of urinary hydroxypyridinium crosslink measurements as resorption markers in metabolic bone diseases. Eur J Clin Invest. 1991 Jun;21(3):310–315. doi: 10.1111/j.1365-2362.1991.tb01375.x. [DOI] [PubMed] [Google Scholar]
  43. Simon L. S., Krane S. M., Wortman P. D., Krane I. M., Kovitz K. L. Serum levels of type I and III procollagen fragments in Paget's disease of bone. J Clin Endocrinol Metab. 1984 Jan;58(1):110–120. doi: 10.1210/jcem-58-1-110. [DOI] [PubMed] [Google Scholar]
  44. Slovik D. M., Rosenthal D. I., Doppelt S. H., Potts J. T., Jr, Daly M. A., Campbell J. A., Neer R. M. Restoration of spinal bone in osteoporotic men by treatment with human parathyroid hormone (1-34) and 1,25-dihydroxyvitamin D. J Bone Miner Res. 1986 Aug;1(4):377–381. doi: 10.1002/jbmr.5650010411. [DOI] [PubMed] [Google Scholar]
  45. Tada K., Yamamuro T., Okumura H., Kasai R., Takahashi H. Restoration of axial and appendicular bone volumes by h-PTH(1-34) in parathyroidectomized and osteopenic rats. Bone. 1990;11(3):163–169. doi: 10.1016/8756-3282(90)90210-p. [DOI] [PubMed] [Google Scholar]
  46. Tam C. S., Heersche J. N., Murray T. M., Parsons J. A. Parathyroid hormone stimulates the bone apposition rate independently of its resorptive action: differential effects of intermittent and continuous administration. Endocrinology. 1982 Feb;110(2):506–512. doi: 10.1210/endo-110-2-506. [DOI] [PubMed] [Google Scholar]
  47. Uebelhart D., Gineyts E., Chapuy M. C., Delmas P. D. Urinary excretion of pyridinium crosslinks: a new marker of bone resorption in metabolic bone disease. Bone Miner. 1990 Jan;8(1):87–96. doi: 10.1016/0169-6009(91)90143-n. [DOI] [PubMed] [Google Scholar]
  48. Uebelhart D., Schlemmer A., Johansen J. S., Gineyts E., Christiansen C., Delmas P. D. Effect of menopause and hormone replacement therapy on the urinary excretion of pyridinium cross-links. J Clin Endocrinol Metab. 1991 Feb;72(2):367–373. doi: 10.1210/jcem-72-2-367. [DOI] [PubMed] [Google Scholar]

Articles from Journal of Clinical Investigation are provided here courtesy of American Society for Clinical Investigation

RESOURCES