Skip to main content
Top
Published in: Osteoporosis International 5/2007

01-05-2007 | Short Communication

Assessment of osteoclast number and function: application in the development of new and improved treatment modalities for bone diseases

Authors: K. Henriksen, L. B. Tanko, P. Qvist, P. D. Delmas, C. Christiansen, M. A. Karsdal

Published in: Osteoporosis International | Issue 5/2007

Login to get access

Abstract

Numerous experimental and clinical observations suggest that overall changes in bone resorption during menopause or treatment with hormone replacement therapy (HRT) are combined effects of changes in osteoclast number and function. Moreover, due to a coupling between osteoclastic bone resorption and osteoblastic bone formation, pronounced alteration of osteoclast number will eventually lead to alteration of osteoblastic bone formation. Fragments of type I collagen, such as the C- and N-terminal telopeptides of collagen type I (CTX and NTX, respectively), are generated during bone resorption and hence can be used as surrogate markers of osteoclast function. Circulating levels of different enzymes in the serum, such as TRAP 5b and cathepsin K are proportional to the number of osteoclasts, and hence can be used as surrogate markers of osteoclast number. Since antiresorptive effects can be obtained in different ways, we felt it was timely to discuss the different scenarios, highlight differences specific to different pharmacological interventions with different mechanisms of action, and discuss how these bone markers can assist us in a deeper analysis of the pharmacodynamics and safety profile of existing and upcoming drug candidates.
Literature
1.
go back to reference Baron R (2003) Anatomy and biology of bone matrix and cellular elements. Primer on the metabolic bone diseases and disorders of mineral metabolism. American Society for Bone and Mineral Research, Washington, pp 1–8 Baron R (2003) Anatomy and biology of bone matrix and cellular elements. Primer on the metabolic bone diseases and disorders of mineral metabolism. American Society for Bone and Mineral Research, Washington, pp 1–8
2.
go back to reference Martin TJ (1993) Hormones in the coupling of bone resorption and formation. Osteoporos Int 3(Suppl 1):121–125PubMedCrossRef Martin TJ (1993) Hormones in the coupling of bone resorption and formation. Osteoporos Int 3(Suppl 1):121–125PubMedCrossRef
3.
go back to reference Vaananen HK, Harkonen PL (1996) Estrogen and bone metabolism. Maturitas 23 Suppl:S65–S69PubMed Vaananen HK, Harkonen PL (1996) Estrogen and bone metabolism. Maturitas 23 Suppl:S65–S69PubMed
4.
go back to reference Manolagas SC (2000) Birth and death of bone cells: basic regulatory mechanisms and implications for the pathogenesis and treatment of osteoporosis. Endocr Rev 21:115–137PubMedCrossRef Manolagas SC (2000) Birth and death of bone cells: basic regulatory mechanisms and implications for the pathogenesis and treatment of osteoporosis. Endocr Rev 21:115–137PubMedCrossRef
5.
6.
go back to reference Garnero P, Sornay-Rendu E, Claustrat B et al (2000) Biochemical markers of bone turnover, endogenous hormones and the risk of fractures in postmenopausal women: the OFELY study. J Bone Miner Res 15:1526–1536PubMedCrossRef Garnero P, Sornay-Rendu E, Claustrat B et al (2000) Biochemical markers of bone turnover, endogenous hormones and the risk of fractures in postmenopausal women: the OFELY study. J Bone Miner Res 15:1526–1536PubMedCrossRef
7.
go back to reference Ravn P, Hosking D, Thompson D et al (1999) Monitoring of alendronate treatment and prediction of effect on bone mass by biochemical markers in the early postmenopausal intervention cohort study. J Clin Endocrinol Metab 84:2363–2368PubMedCrossRef Ravn P, Hosking D, Thompson D et al (1999) Monitoring of alendronate treatment and prediction of effect on bone mass by biochemical markers in the early postmenopausal intervention cohort study. J Clin Endocrinol Metab 84:2363–2368PubMedCrossRef
8.
go back to reference Ravn P, Clemmesen B, Christiansen C (1999) Biochemical markers can predict the response in bone mass during alendronate treatment in early postmenopausal women. Alendronate Osteoporosis Prevention Study Group. Bone 24:237–244PubMedCrossRef Ravn P, Clemmesen B, Christiansen C (1999) Biochemical markers can predict the response in bone mass during alendronate treatment in early postmenopausal women. Alendronate Osteoporosis Prevention Study Group. Bone 24:237–244PubMedCrossRef
9.
go back to reference Holzer G, Noske H, Lang T (2005) Soluble cathepsin K: a novel marker for the prediction of nontraumatic fractures? J Lab Clin Med 146:13–17PubMedCrossRef Holzer G, Noske H, Lang T (2005) Soluble cathepsin K: a novel marker for the prediction of nontraumatic fractures? J Lab Clin Med 146:13–17PubMedCrossRef
10.
go back to reference Gertz BJ, Clemens JD, Holland SD et al (1998) Application of a new serum assay for type I collagen cross-linked N-telopeptides: assessment of diurnal changes in bone turnover with and without alendronate treatment. Calcif Tissue Int 63:102–106PubMedCrossRef Gertz BJ, Clemens JD, Holland SD et al (1998) Application of a new serum assay for type I collagen cross-linked N-telopeptides: assessment of diurnal changes in bone turnover with and without alendronate treatment. Calcif Tissue Int 63:102–106PubMedCrossRef
11.
go back to reference Woitge HW, Pecherstorfer M, Li Y (1999) Novel serum markers of bone resorption: clinical assessment and comparison with established urinary indices. J Bone Miner Res 14:792–801PubMedCrossRef Woitge HW, Pecherstorfer M, Li Y (1999) Novel serum markers of bone resorption: clinical assessment and comparison with established urinary indices. J Bone Miner Res 14:792–801PubMedCrossRef
12.
go back to reference Christgau S, Bitsch-Jensen O, Hanover BN et al (2000) Serum crosslaps for monitoring the response in individuals undergoing antiresorptive therapy. Bone 26:505–511PubMedCrossRef Christgau S, Bitsch-Jensen O, Hanover BN et al (2000) Serum crosslaps for monitoring the response in individuals undergoing antiresorptive therapy. Bone 26:505–511PubMedCrossRef
13.
go back to reference Halleen JM, Alatalo SL, Suominen H et al (2000) Tartrate-resistant acid phosphatase 5b: a novel serum marker of bone resorption. J Bone Miner Res 15:1337–1345PubMedCrossRef Halleen JM, Alatalo SL, Suominen H et al (2000) Tartrate-resistant acid phosphatase 5b: a novel serum marker of bone resorption. J Bone Miner Res 15:1337–1345PubMedCrossRef
14.
go back to reference Kirstein B, Chambers TJ, Fuller K (2006) Secretion of tartrate-resistant acid phosphatase by osteoclasts correlates with resorptive behavior. J Cell Biochem 98:1085–1094PubMedCrossRef Kirstein B, Chambers TJ, Fuller K (2006) Secretion of tartrate-resistant acid phosphatase by osteoclasts correlates with resorptive behavior. J Cell Biochem 98:1085–1094PubMedCrossRef
15.
go back to reference Schaller S, Henriksen K, Sveigaard C et al (2004) The chloride channel inhibitor n53736 prevents bone resorption in ovariectomized rats without changing bone formation. J Bone Miner Res 19:1144–1153PubMedCrossRef Schaller S, Henriksen K, Sveigaard C et al (2004) The chloride channel inhibitor n53736 prevents bone resorption in ovariectomized rats without changing bone formation. J Bone Miner Res 19:1144–1153PubMedCrossRef
16.
go back to reference Karsdal MA, Henriksen K, Sorensen MG et al (2005) Acidification of the osteoclastic resorption compartment provides insight into the coupling of bone formation to bone resorption. Am J Pathol 166:467–476PubMed Karsdal MA, Henriksen K, Sorensen MG et al (2005) Acidification of the osteoclastic resorption compartment provides insight into the coupling of bone formation to bone resorption. Am J Pathol 166:467–476PubMed
17.
go back to reference Koh AJ, Demiralp B, Neiva KG et al (2005) Cells of the osteoclast lineage as mediators of the anabolic actions of parathyroid hormone in bone. Endocrinology 146:4584–4596PubMedCrossRef Koh AJ, Demiralp B, Neiva KG et al (2005) Cells of the osteoclast lineage as mediators of the anabolic actions of parathyroid hormone in bone. Endocrinology 146:4584–4596PubMedCrossRef
18.
go back to reference Martin TJ, Sims NA (2005) Osteoclast-derived activity in the coupling of bone formation to resorption. Trends Mol Med 11:76–81PubMedCrossRef Martin TJ, Sims NA (2005) Osteoclast-derived activity in the coupling of bone formation to resorption. Trends Mol Med 11:76–81PubMedCrossRef
19.
go back to reference Reszka AA, Rodan GA (2003) Mechanism of action of bisphosphonates. Curr Osteoporos Rep 1:45–52PubMed Reszka AA, Rodan GA (2003) Mechanism of action of bisphosphonates. Curr Osteoporos Rep 1:45–52PubMed
20.
go back to reference Nenonen A, Cheng S, Ivaska KK et al (2005) Serum TRACP 5b Is a useful marker for monitoring alendronate treatment: comparison with other markers of bone turnover. J Bone Miner Res 20:1804–1812CrossRef Nenonen A, Cheng S, Ivaska KK et al (2005) Serum TRACP 5b Is a useful marker for monitoring alendronate treatment: comparison with other markers of bone turnover. J Bone Miner Res 20:1804–1812CrossRef
21.
go back to reference McClung MR, Lewiecki EM, Cohen SB et al (2006) Denosumab in postmenopausal women with low bone mineral density. N Engl J Med 354:821–831PubMedCrossRef McClung MR, Lewiecki EM, Cohen SB et al (2006) Denosumab in postmenopausal women with low bone mineral density. N Engl J Med 354:821–831PubMedCrossRef
22.
go back to reference Hamdy NA (2006) Osteoprotegerin as a potential therapy for osteoporosis. Curr Rheumatol Rep 8:50–54PubMed Hamdy NA (2006) Osteoprotegerin as a potential therapy for osteoporosis. Curr Rheumatol Rep 8:50–54PubMed
23.
go back to reference Hannon RA, Clowes JA, Eagleton AC et al (2004) Clinical performance of immunoreactive tartrate-resistant acid phosphatase isoform 5b as a marker of bone resorption. Bone 34:187–194PubMedCrossRef Hannon RA, Clowes JA, Eagleton AC et al (2004) Clinical performance of immunoreactive tartrate-resistant acid phosphatase isoform 5b as a marker of bone resorption. Bone 34:187–194PubMedCrossRef
24.
go back to reference Tahtela R, Seppanen J, Laitinen K et al (2005) Serum tartrate-resistant acid phosphatase 5b in monitoring bisphosphonate treatment with clodronate: a comparison with urinary N-terminal telopeptide of type I collagen and serum type I procollagen amino-terminal propeptide. Osteoporos Int 16:1109–1116PubMedCrossRef Tahtela R, Seppanen J, Laitinen K et al (2005) Serum tartrate-resistant acid phosphatase 5b in monitoring bisphosphonate treatment with clodronate: a comparison with urinary N-terminal telopeptide of type I collagen and serum type I procollagen amino-terminal propeptide. Osteoporos Int 16:1109–1116PubMedCrossRef
25.
go back to reference Hansdottir H, Franzson L, Prestwood K et al (2004) The effect of raloxifene on markers of bone turnover in older women living in long-term care facilities. J Am Geriatr Soc 52:779–783PubMedCrossRef Hansdottir H, Franzson L, Prestwood K et al (2004) The effect of raloxifene on markers of bone turnover in older women living in long-term care facilities. J Am Geriatr Soc 52:779–783PubMedCrossRef
26.
go back to reference Hannon RA, Clack G, Gallager N et al (2005) The effect of AZ0530, a highly selective SRC inhibitor, on bone turnover in healthy males. European Calcified Tissue Society Conference 2005 [Abstract nb OC042] Hannon RA, Clack G, Gallager N et al (2005) The effect of AZ0530, a highly selective SRC inhibitor, on bone turnover in healthy males. European Calcified Tissue Society Conference 2005 [Abstract nb OC042]
27.
go back to reference Capparelli C, Morony S, Warmington KS et al (2000) Pharmacologic Effects of a Single Treatment with Osteoprotegerin (OPG) on Bone Remodeling and Bone Density in Normal Rats. J Bone Miner Res 15 [Suppl 1], abstract 1132 Capparelli C, Morony S, Warmington KS et al (2000) Pharmacologic Effects of a Single Treatment with Osteoprotegerin (OPG) on Bone Remodeling and Bone Density in Normal Rats. J Bone Miner Res 15 [Suppl 1], abstract 1132
28.
go back to reference Kostenuik P, Warmington KS, Grisanti M et al (2005) RANKL Inhibition with AMG 162, a Fully Human MAb, Causes Sustained Suppression of Bone Resorption and Increased BMD in Knockin Mice Expressing Humanized RANKL. J Bone Miner Res 20[Suppl 1], abstract SU304 Kostenuik P, Warmington KS, Grisanti M et al (2005) RANKL Inhibition with AMG 162, a Fully Human MAb, Causes Sustained Suppression of Bone Resorption and Increased BMD in Knockin Mice Expressing Humanized RANKL. J Bone Miner Res 20[Suppl 1], abstract SU304
29.
go back to reference Karsdal MA, Hjorth P, Henriksen K et al (2003) Transforming growth factor-beta controls human osteoclastogenesis through the p38 MAPK and regulation of RANK expression. J Biol Chem 278:44975–44987PubMedCrossRef Karsdal MA, Hjorth P, Henriksen K et al (2003) Transforming growth factor-beta controls human osteoclastogenesis through the p38 MAPK and regulation of RANK expression. J Biol Chem 278:44975–44987PubMedCrossRef
30.
go back to reference Henriksen K, Gram J, Schaller S et al (2004) Characterization of osteoclasts from patients harboring a G215R mutation in ClC-7 causing Autosomal Dominant Osteopetrosis type II (ADOII). Am J Pathol 164:1537–1545PubMed Henriksen K, Gram J, Schaller S et al (2004) Characterization of osteoclasts from patients harboring a G215R mutation in ClC-7 causing Autosomal Dominant Osteopetrosis type II (ADOII). Am J Pathol 164:1537–1545PubMed
31.
go back to reference Bollerslev J, Marks SC Jr, Pockwinse S et al (1993) Ultrastructural investigations of bone resorptive cells in two types of autosomal dominant osteopetrosis. Bone 14:865–869PubMedCrossRef Bollerslev J, Marks SC Jr, Pockwinse S et al (1993) Ultrastructural investigations of bone resorptive cells in two types of autosomal dominant osteopetrosis. Bone 14:865–869PubMedCrossRef
32.
go back to reference Alatalo SL, Ivaska KK, Waguespack SG et al (2004) Osteoclast-derived serum tartrate-resistant acid phosphatase 5b in Albers-Schonberg disease (type II autosomal dominant osteopetrosis). Clin Chem 50:883–890PubMedCrossRef Alatalo SL, Ivaska KK, Waguespack SG et al (2004) Osteoclast-derived serum tartrate-resistant acid phosphatase 5b in Albers-Schonberg disease (type II autosomal dominant osteopetrosis). Clin Chem 50:883–890PubMedCrossRef
33.
go back to reference Del Fattore A, Peruzzi B, Rucci N et al (2005) Clinical, genetic and cellular analysis of forty-nine osteopetrotic patients: implications for diagnosis and treatment. J Med Genet 43:315–325PubMedCrossRef Del Fattore A, Peruzzi B, Rucci N et al (2005) Clinical, genetic and cellular analysis of forty-nine osteopetrotic patients: implications for diagnosis and treatment. J Med Genet 43:315–325PubMedCrossRef
34.
go back to reference Schlemmer A, Hassager C, Jensen SB et al (1992) Marked diurnal variation in urinary excretion of pyridinium cross-links in premenopausal women. J Clin Endocrinol Metab 74:476–480PubMedCrossRef Schlemmer A, Hassager C, Jensen SB et al (1992) Marked diurnal variation in urinary excretion of pyridinium cross-links in premenopausal women. J Clin Endocrinol Metab 74:476–480PubMedCrossRef
35.
go back to reference Qvist P, Christgau S, Pedersen BJ et al (2002) Circadian variation in the serum concentration of C-terminal telopeptide of type I collagen (serum CTx): effects of gender, age, menopausal status, posture, daylight, serum cortisol, and fasting. Bone 31:57–61PubMedCrossRef Qvist P, Christgau S, Pedersen BJ et al (2002) Circadian variation in the serum concentration of C-terminal telopeptide of type I collagen (serum CTx): effects of gender, age, menopausal status, posture, daylight, serum cortisol, and fasting. Bone 31:57–61PubMedCrossRef
36.
go back to reference Hart SM, Eastell R (1999) Biochemical markers of bone turnover. Curr Opin Nephrol Hypertens 8:421–427PubMedCrossRef Hart SM, Eastell R (1999) Biochemical markers of bone turnover. Curr Opin Nephrol Hypertens 8:421–427PubMedCrossRef
37.
go back to reference Simmons DJ, Menton DN, Russell JE et al (1988) Bone cell populations and histomorphometric correlates to function. Anat Rec 222:228–236PubMedCrossRef Simmons DJ, Menton DN, Russell JE et al (1988) Bone cell populations and histomorphometric correlates to function. Anat Rec 222:228–236PubMedCrossRef
38.
go back to reference Halleen JM (2003) Tartrate-resistant acid phosphatase 5B is a specific and sensitive marker of bone resorption. Anticancer Res 23:1027–1029PubMed Halleen JM (2003) Tartrate-resistant acid phosphatase 5B is a specific and sensitive marker of bone resorption. Anticancer Res 23:1027–1029PubMed
39.
go back to reference Ple PA, Green TP, Hennequin LF et al (2004) Discovery of a new class of anilinoquinazoline inhibitors with high affinity and specificity for the tyrosine kinase domain of c-Src. J Med Chem 47:871–887PubMedCrossRef Ple PA, Green TP, Hennequin LF et al (2004) Discovery of a new class of anilinoquinazoline inhibitors with high affinity and specificity for the tyrosine kinase domain of c-Src. J Med Chem 47:871–887PubMedCrossRef
40.
go back to reference Meier C, Meinhardt U, Greenfield JR et al (2006) Serum cathepsin K concentrations reflect osteoclastic activity in women with postmenopausal osteoporosis and patients with Paget’s disease. Clin Lab 52:1–10PubMed Meier C, Meinhardt U, Greenfield JR et al (2006) Serum cathepsin K concentrations reflect osteoclastic activity in women with postmenopausal osteoporosis and patients with Paget’s disease. Clin Lab 52:1–10PubMed
41.
go back to reference Ljusberg J, Wang Y, Lang P et al (2005) Proteolytic excision of a repressive loop domain in tartrate-resistant acid phosphatase by cathepsin K in osteoclasts. J Biol Chem 280:28370–28381PubMedCrossRef Ljusberg J, Wang Y, Lang P et al (2005) Proteolytic excision of a repressive loop domain in tartrate-resistant acid phosphatase by cathepsin K in osteoclasts. J Biol Chem 280:28370–28381PubMedCrossRef
42.
go back to reference Rissanen J, Suutari S, Ylonen S et al (2005) The Ratio of Osteoclast Activity/Osteoclast Number (CTX/TRACP 5b) Improves the Interpretation of the Effects of Anti-Resorptive Treatments in Human Osteclast Cultures. J Bone Miner Res 20[Suppl 1], abstract SU290 Rissanen J, Suutari S, Ylonen S et al (2005) The Ratio of Osteoclast Activity/Osteoclast Number (CTX/TRACP 5b) Improves the Interpretation of the Effects of Anti-Resorptive Treatments in Human Osteclast Cultures. J Bone Miner Res 20[Suppl 1], abstract SU290
43.
go back to reference Finkelstein JS, Hayes A, Hunzelman JL et al (2003) The effects of parathyroid hormone, alendronate, or both in men with osteoporosis. N Engl J Med 349:1216–1226PubMedCrossRef Finkelstein JS, Hayes A, Hunzelman JL et al (2003) The effects of parathyroid hormone, alendronate, or both in men with osteoporosis. N Engl J Med 349:1216–1226PubMedCrossRef
44.
go back to reference Black DM, Greenspan SL, Ensrud KE et al (2003) The effects of parathyroid hormone and alendronate alone or in combination in postmenopausal osteoporosis. N Engl J Med 349:1207–1215PubMedCrossRef Black DM, Greenspan SL, Ensrud KE et al (2003) The effects of parathyroid hormone and alendronate alone or in combination in postmenopausal osteoporosis. N Engl J Med 349:1207–1215PubMedCrossRef
Metadata
Title
Assessment of osteoclast number and function: application in the development of new and improved treatment modalities for bone diseases
Authors
K. Henriksen
L. B. Tanko
P. Qvist
P. D. Delmas
C. Christiansen
M. A. Karsdal
Publication date
01-05-2007
Publisher
Springer-Verlag
Published in
Osteoporosis International / Issue 5/2007
Print ISSN: 0937-941X
Electronic ISSN: 1433-2965
DOI
https://doi.org/10.1007/s00198-006-0286-8

Other articles of this Issue 5/2007

Osteoporosis International 5/2007 Go to the issue