Skip to main content
Top
Published in: Calcified Tissue International 2/2012

01-02-2012 | Original Research

Longitudinal Assessment of In Vivo Bone Dynamics in a Mouse Tail Model of Postmenopausal Osteoporosis

Authors: Floor M. Lambers, Gisela Kuhn, Friederike A. Schulte, Kathleen Koch, Ralph Müller

Published in: Calcified Tissue International | Issue 2/2012

Login to get access

Abstract

Recently, it has been shown that transient bone biology can be observed in vivo using time-lapse micro-computed tomography (μCT) in the mouse tail bone. Nevertheless, in order for the mouse tail bone to be a model for human disease, the hallmarks of any disease must be mimicked. The aim of this study was to investigate whether postmenopausal osteoporosis could be modeled in caudal vertebrae of C57Bl/6 mice, considering static and dynamic bone morphometry as well as mechanical properties, and to describe temporal changes in bone remodeling rates. Twenty C57Bl/6 mice were ovariectomized (OVX, n = 11) or sham-operated (SHM, n = 9) and monitored with in vivo μCT on the day of surgery and every 2 weeks after, up to 12 weeks. There was a significant decrease in bone volume fraction for OVX (−35%) compared to SHM (+16%) in trabecular bone (P < 0.001). For OVX, high-turnover bone loss was observed, with the bone resorption rate exceeding the bone formation rate (P < 0.001). Furthermore there was a significant decrease in whole-bone stiffness for OVX (−16%) compared to SHM (+11%, P < 0.001). From these results we conclude that the mouse tail vertebra mimics postmenopausal bone loss with respect to these parameters and therefore might be a suitable model for postmenopausal osteoporosis. When evaluating temporal changes in remodeling rates, we found that OVX caused an immediate increase in bone resorption rate (P < 0.001) and a delayed increase in bone formation rate (P < 0.001). Monitoring transient bone biology is a promising method for future research.
Literature
1.
go back to reference Ström O, Borgström F, Kanis JA, Compston J, Cooper C, McCloskey EV, Jönsson B (2011) Osteoporosis: burden, health care provision and opportunities in the EU. Arch Osteoporos. doi:10.1007/s11657-011-0060-1 Ström O, Borgström F, Kanis JA, Compston J, Cooper C, McCloskey EV, Jönsson B (2011) Osteoporosis: burden, health care provision and opportunities in the EU. Arch Osteoporos. doi:10.​1007/​s11657-011-0060-1
2.
go back to reference Reinwald S, Burr D (2008) Review of nonprimate, large animal models for osteoporosis research. J Bone Miner Res 23:1353–1368PubMedCrossRef Reinwald S, Burr D (2008) Review of nonprimate, large animal models for osteoporosis research. J Bone Miner Res 23:1353–1368PubMedCrossRef
3.
go back to reference Kimmel DB (1996) Animal models for in vivo experimentation in osteoporosis research. In: Marcus R, Feldman D, Kelsey J (eds) Osteoporosis. Academic Press, San Diego, pp 671–690 Kimmel DB (1996) Animal models for in vivo experimentation in osteoporosis research. In: Marcus R, Feldman D, Kelsey J (eds) Osteoporosis. Academic Press, San Diego, pp 671–690
4.
5.
go back to reference Brouwers JEM, Lambers FM, Gasser JA, van Rietbergen B, Huiskes R (2008) Bone degeneration and recovery after early and late bisphosphonate treatment of ovariectomized Wistar rats assessed by in vivo micro-computed tomography. Calcif Tissue Int 82:202–211PubMedCrossRef Brouwers JEM, Lambers FM, Gasser JA, van Rietbergen B, Huiskes R (2008) Bone degeneration and recovery after early and late bisphosphonate treatment of ovariectomized Wistar rats assessed by in vivo micro-computed tomography. Calcif Tissue Int 82:202–211PubMedCrossRef
6.
go back to reference Boyd SK, Davison P, Müller R, Gasser JA (2006) Monitoring individual morphological changes over time in ovariectomized rats by in vivo micro-computed tomography. Bone 39:854–862PubMedCrossRef Boyd SK, Davison P, Müller R, Gasser JA (2006) Monitoring individual morphological changes over time in ovariectomized rats by in vivo micro-computed tomography. Bone 39:854–862PubMedCrossRef
7.
go back to reference Waarsing JH, Day JS, van der Linden JC, Ederveen AG, Spanjers C, De Clerck N, Sasov A, Verhaar JA, Weinans H (2004) Detecting and tracking local changes in the tibiae of individual rats: a novel method to analyse longitudinal in vivo micro-CT data. Bone 34:163–169PubMedCrossRef Waarsing JH, Day JS, van der Linden JC, Ederveen AG, Spanjers C, De Clerck N, Sasov A, Verhaar JA, Weinans H (2004) Detecting and tracking local changes in the tibiae of individual rats: a novel method to analyse longitudinal in vivo micro-CT data. Bone 34:163–169PubMedCrossRef
8.
go back to reference Wronski TJ, Dann LM, Scott KS, Cintron M (1989) Long-term effects of ovariectomy and aging on the rat skeleton. Calcif Tissue Int 45:360–366PubMedCrossRef Wronski TJ, Dann LM, Scott KS, Cintron M (1989) Long-term effects of ovariectomy and aging on the rat skeleton. Calcif Tissue Int 45:360–366PubMedCrossRef
9.
go back to reference Tian XY, Liu XQ, Chen HY, Setterberg RB, Li M, Jee WS (2008) Greater efficacy of alfacalcidol in the red than in the yellow marrow skeletal sites in adult female rats. J Musculoskelet Neuronal Interact 8:257–266PubMed Tian XY, Liu XQ, Chen HY, Setterberg RB, Li M, Jee WS (2008) Greater efficacy of alfacalcidol in the red than in the yellow marrow skeletal sites in adult female rats. J Musculoskelet Neuronal Interact 8:257–266PubMed
10.
go back to reference Wronski TJ, Dann LM, Horner SL (1989) Time course of vertebral osteopenia in ovariectomized rats. Bone 10:295–301PubMedCrossRef Wronski TJ, Dann LM, Horner SL (1989) Time course of vertebral osteopenia in ovariectomized rats. Bone 10:295–301PubMedCrossRef
11.
go back to reference Miyakoshi N, Sato K, Abe T, Tsuchida T, Tamura Y, Kudo T (1999) Histomorphometric evaluation of the effects of ovariectomy on bone turnover in rat caudal vertebrae. Calcif Tissue Int 64:318–324PubMedCrossRef Miyakoshi N, Sato K, Abe T, Tsuchida T, Tamura Y, Kudo T (1999) Histomorphometric evaluation of the effects of ovariectomy on bone turnover in rat caudal vertebrae. Calcif Tissue Int 64:318–324PubMedCrossRef
12.
go back to reference Li M, Shen Y, Qi H, Wronski TJ (1996) Comparative study of skeletal response to estrogen depletion at red and yellow marrow sites in rats. Anat Rec 245:472–480PubMedCrossRef Li M, Shen Y, Qi H, Wronski TJ (1996) Comparative study of skeletal response to estrogen depletion at red and yellow marrow sites in rats. Anat Rec 245:472–480PubMedCrossRef
13.
go back to reference Klein RF (2008) Genetics of osteoporosis—utility of mouse models. J Musculoskelet Neuronal Interact 8:287–290PubMed Klein RF (2008) Genetics of osteoporosis—utility of mouse models. J Musculoskelet Neuronal Interact 8:287–290PubMed
14.
go back to reference Alexander JM, Bab I, Fish S, Müller R, Uchiyama T, Gronowicz G, Nahounou M, Zhao Q, White DW, Chorev M, Gazit D, Rosenblatt M (2001) Human parathyroid hormone 1–34 reverses bone loss in ovariectomized mice. J Bone Miner Res 16:1665–1673PubMedCrossRef Alexander JM, Bab I, Fish S, Müller R, Uchiyama T, Gronowicz G, Nahounou M, Zhao Q, White DW, Chorev M, Gazit D, Rosenblatt M (2001) Human parathyroid hormone 1–34 reverses bone loss in ovariectomized mice. J Bone Miner Res 16:1665–1673PubMedCrossRef
15.
go back to reference Cano A, Dapia S, Noguera I, Pineda B, Hermenegildo C, del Val R, Caeiro JR, Garcia-Perez MA (2008) Comparative effects of 17beta-estradiol, raloxifene and genistein on bone 3D microarchitecture and volumetric bone mineral density in the ovariectomized mice. Osteoporos Int 19:793–800PubMedCrossRef Cano A, Dapia S, Noguera I, Pineda B, Hermenegildo C, del Val R, Caeiro JR, Garcia-Perez MA (2008) Comparative effects of 17beta-estradiol, raloxifene and genistein on bone 3D microarchitecture and volumetric bone mineral density in the ovariectomized mice. Osteoporos Int 19:793–800PubMedCrossRef
16.
go back to reference Bouxsein ML, Myers KS, Shultz KL, Donahue LR, Rosen CJ, Beamer WG (2005) Ovariectomy-induced bone loss varies among inbred strains of mice. J Bone Miner Res 20:1085–1092PubMedCrossRef Bouxsein ML, Myers KS, Shultz KL, Donahue LR, Rosen CJ, Beamer WG (2005) Ovariectomy-induced bone loss varies among inbred strains of mice. J Bone Miner Res 20:1085–1092PubMedCrossRef
17.
go back to reference Li CY, Schaffler MB, Wolde-Semait HT, Hernandez CJ, Jepsen KJ (2005) Genetic background influences cortical bone response to ovariectomy. J Bone Miner Res 20:2150–2158PubMedCrossRef Li CY, Schaffler MB, Wolde-Semait HT, Hernandez CJ, Jepsen KJ (2005) Genetic background influences cortical bone response to ovariectomy. J Bone Miner Res 20:2150–2158PubMedCrossRef
18.
go back to reference Iwaniec UT, Yuan D, Power RA, Wronski TJ (2006) Strain-dependent variations in the response of cancellous bone to ovariectomy in mice. J Bone Miner Res 21:1068–1074PubMedCrossRef Iwaniec UT, Yuan D, Power RA, Wronski TJ (2006) Strain-dependent variations in the response of cancellous bone to ovariectomy in mice. J Bone Miner Res 21:1068–1074PubMedCrossRef
19.
go back to reference Klinck J, Boyd SK (2008) The magnitude and rate of bone loss in ovariectomized mice differs among inbred strains as determined by longitudinal in vivo micro-computed tomography. Calcif Tissue Int 83:70–79PubMedCrossRef Klinck J, Boyd SK (2008) The magnitude and rate of bone loss in ovariectomized mice differs among inbred strains as determined by longitudinal in vivo micro-computed tomography. Calcif Tissue Int 83:70–79PubMedCrossRef
20.
go back to reference Webster D, Wasserman E, Ehrbar M, Weber F, Bab I, Müller R (2010) Mechanical loading of mouse caudal vertebrae increases trabecular and cortical bone mass-dependence on dose and genotype. Biomech Model Mechanobiol 9:737–747PubMedCrossRef Webster D, Wasserman E, Ehrbar M, Weber F, Bab I, Müller R (2010) Mechanical loading of mouse caudal vertebrae increases trabecular and cortical bone mass-dependence on dose and genotype. Biomech Model Mechanobiol 9:737–747PubMedCrossRef
21.
go back to reference Lambers FM, Schulte FA, Kuhn G, Webster DJ, Muller R (2011) Mouse tail vertebrae adapt to cyclic mechanical loading by increasing bone formation rate and decreasing bone resorption rate as shown by time-lapsed in vivo imaging of dynamic bone morphometry. Bone. doi:10.1016/j.bone.2011.08.035 Lambers FM, Schulte FA, Kuhn G, Webster DJ, Muller R (2011) Mouse tail vertebrae adapt to cyclic mechanical loading by increasing bone formation rate and decreasing bone resorption rate as shown by time-lapsed in vivo imaging of dynamic bone morphometry. Bone. doi:10.​1016/​j.​bone.​2011.​08.​035
22.
go back to reference Reginster JY, Sarlet N, Lecart MP (2005) Fractures in osteoporosis: the challenge for the new millennium. Osteoporos Int 16(Suppl 1):S1–S3PubMedCrossRef Reginster JY, Sarlet N, Lecart MP (2005) Fractures in osteoporosis: the challenge for the new millennium. Osteoporos Int 16(Suppl 1):S1–S3PubMedCrossRef
23.
go back to reference Bilezikian JP, Matsumoto T, Bellido T, Khosla S, Martin J, Recker RR, Heaney R, Seeman E, Papapoulos S, Goldring SR (2009) Targeting bone remodeling for the treatment of osteoporosis: summary of the proceedings of an ASBMR workshop. J Bone Miner Res 24:373–385PubMedCrossRef Bilezikian JP, Matsumoto T, Bellido T, Khosla S, Martin J, Recker RR, Heaney R, Seeman E, Papapoulos S, Goldring SR (2009) Targeting bone remodeling for the treatment of osteoporosis: summary of the proceedings of an ASBMR workshop. J Bone Miner Res 24:373–385PubMedCrossRef
24.
go back to reference Egermann M, Goldhahn J, Schneider E (2005) Animal models for fracture treatment in osteoporosis. Osteoporos Int 16(Suppl 2):S129–S138PubMedCrossRef Egermann M, Goldhahn J, Schneider E (2005) Animal models for fracture treatment in osteoporosis. Osteoporos Int 16(Suppl 2):S129–S138PubMedCrossRef
25.
go back to reference Mosekilde L, Danielsen CC, Knudsen UB (1993) The effect of aging and ovariectomy on the vertebral bone mass and biomechanical properties of mature rats. Bone 14:1–6PubMedCrossRef Mosekilde L, Danielsen CC, Knudsen UB (1993) The effect of aging and ovariectomy on the vertebral bone mass and biomechanical properties of mature rats. Bone 14:1–6PubMedCrossRef
26.
go back to reference Fonseca D, Ward WE (2004) Daidzein together with high calcium preserve bone mass and biomechanical strength at multiple sites in ovariectomized mice. Bone 35:489–497PubMedCrossRef Fonseca D, Ward WE (2004) Daidzein together with high calcium preserve bone mass and biomechanical strength at multiple sites in ovariectomized mice. Bone 35:489–497PubMedCrossRef
27.
go back to reference Brouwers JEM, Lambers FM, van Rietbergen B, Ito K, Huiskes R (2009) Comparison of bone loss induced by ovariectomy and neurectomy in rats analyzed by in vivo micro-CT. J Orthop Res 27:1521–1527PubMedCrossRef Brouwers JEM, Lambers FM, van Rietbergen B, Ito K, Huiskes R (2009) Comparison of bone loss induced by ovariectomy and neurectomy in rats analyzed by in vivo micro-CT. J Orthop Res 27:1521–1527PubMedCrossRef
28.
go back to reference Silva MJ, Brodt MD, Uthgenannt BA (2004) Morphological and mechanical properties of caudal vertebrae in the SAMP6 mouse model of senile osteoporosis. Bone 35:425–431PubMedCrossRef Silva MJ, Brodt MD, Uthgenannt BA (2004) Morphological and mechanical properties of caudal vertebrae in the SAMP6 mouse model of senile osteoporosis. Bone 35:425–431PubMedCrossRef
29.
go back to reference Schulte FA, Lambers FM, Kuhn G, Müller R (2011) In vivo micro-computed tomography allows direct three-dimensional quantification of both bone formation and bone resorption parameters using time-lapsed imaging. Bone 48:433–442PubMedCrossRef Schulte FA, Lambers FM, Kuhn G, Müller R (2011) In vivo micro-computed tomography allows direct three-dimensional quantification of both bone formation and bone resorption parameters using time-lapsed imaging. Bone 48:433–442PubMedCrossRef
30.
go back to reference Buie HR, Moore CP, Boyd SK (2008) Postpubertal architectural developmental patterns differ between the L3 vertebra and proximal tibia in three inbred strains of mice. J Bone Miner Res 23:2048–2059PubMedCrossRef Buie HR, Moore CP, Boyd SK (2008) Postpubertal architectural developmental patterns differ between the L3 vertebra and proximal tibia in three inbred strains of mice. J Bone Miner Res 23:2048–2059PubMedCrossRef
31.
go back to reference Bouxsein ML, Boyd SK, Christiansen BA, Guldberg RE, Jepsen KJ, Müller R (2010) Guidelines for assessment of bone microstructure in rodents using micro-computed tomography. J Bone Miner Res 25:1468–1486PubMedCrossRef Bouxsein ML, Boyd SK, Christiansen BA, Guldberg RE, Jepsen KJ, Müller R (2010) Guidelines for assessment of bone microstructure in rodents using micro-computed tomography. J Bone Miner Res 25:1468–1486PubMedCrossRef
32.
go back to reference Thevenaz P, Ruttimann UE, Unser M (1998) A pyramid approach to subpixel registration based on intensity. IEEE Trans Image Process 7:27–41PubMedCrossRef Thevenaz P, Ruttimann UE, Unser M (1998) A pyramid approach to subpixel registration based on intensity. IEEE Trans Image Process 7:27–41PubMedCrossRef
33.
go back to reference Webster DJ, Morley PL, van Lenthe GH, Müller R (2008) A novel in vivo mouse model for mechanically stimulated bone adaptation—a combined experimental and computational validation study. Comput Methods Biomech Biomed Eng 11:435–441CrossRef Webster DJ, Morley PL, van Lenthe GH, Müller R (2008) A novel in vivo mouse model for mechanically stimulated bone adaptation—a combined experimental and computational validation study. Comput Methods Biomech Biomed Eng 11:435–441CrossRef
34.
go back to reference Christen P, van Rietbergen B, Lambers FM, Müller R, Ito K (2011) Bone morphology allows estimation of loading history in a murine model of bone adaptation. Biomech Model Mechanobiol. doi:10.1007/s10237-011-0327-x Christen P, van Rietbergen B, Lambers FM, Müller R, Ito K (2011) Bone morphology allows estimation of loading history in a murine model of bone adaptation. Biomech Model Mechanobiol. doi:10.​1007/​s10237-011-0327-x
35.
go back to reference Melton LJ 3rd, Christen D, Riggs BL, Achenbach SJ, Müller R, van Lenthe GH, Amin S, Atkinson EJ, Khosla S (2010) Assessing forearm fracture risk in postmenopausal women. Osteoporos Int 21:1161–1169PubMedCrossRef Melton LJ 3rd, Christen D, Riggs BL, Achenbach SJ, Müller R, van Lenthe GH, Amin S, Atkinson EJ, Khosla S (2010) Assessing forearm fracture risk in postmenopausal women. Osteoporos Int 21:1161–1169PubMedCrossRef
36.
go back to reference Bain SD, Bailey MC, Celino DL, Lantry MM, Edwards MW (1993) High-dose estrogen inhibits bone resorption and stimulates bone formation in the ovariectomized mouse. J Bone Miner Res 8:435–442PubMedCrossRef Bain SD, Bailey MC, Celino DL, Lantry MM, Edwards MW (1993) High-dose estrogen inhibits bone resorption and stimulates bone formation in the ovariectomized mouse. J Bone Miner Res 8:435–442PubMedCrossRef
37.
go back to reference Kimble RB, Bain S, Pacifici R (1997) The functional block of TNF but not of IL-6 prevents bone loss in ovariectomized mice. J Bone Miner Res 12:935–941PubMedCrossRef Kimble RB, Bain S, Pacifici R (1997) The functional block of TNF but not of IL-6 prevents bone loss in ovariectomized mice. J Bone Miner Res 12:935–941PubMedCrossRef
38.
go back to reference Parfitt AM (1994) Osteonal and hemi-osteonal remodeling: the spatial and temporal framework for signal traffic in adult human bone. J Cell Biochem 55:273–286PubMedCrossRef Parfitt AM (1994) Osteonal and hemi-osteonal remodeling: the spatial and temporal framework for signal traffic in adult human bone. J Cell Biochem 55:273–286PubMedCrossRef
39.
go back to reference Vande Berg BC, Malghem J, Lecouvet FE, Maldague B (2001) Normal bone marrow: dynamic aspects in magnetic resonance imaging. J Radiol 82:127–135 Vande Berg BC, Malghem J, Lecouvet FE, Maldague B (2001) Normal bone marrow: dynamic aspects in magnetic resonance imaging. J Radiol 82:127–135
40.
go back to reference Donnelly EH, Nemhauser JB, Smith JM, Kazzi ZN, Farfan EB, Chang AS, Naeem SF (2010) Acute radiation syndrome: assessment and management. South Med J 103:541–546PubMedCrossRef Donnelly EH, Nemhauser JB, Smith JM, Kazzi ZN, Farfan EB, Chang AS, Naeem SF (2010) Acute radiation syndrome: assessment and management. South Med J 103:541–546PubMedCrossRef
41.
go back to reference Willinghamm MD, Brodt MD, Lee KL, Stephens AL, Ye J, Silva MJ (2010) Age-related changes in bone structure and strength in female and male BALB/c mice. Calcif Tissue Int 86:470–483PubMedCrossRef Willinghamm MD, Brodt MD, Lee KL, Stephens AL, Ye J, Silva MJ (2010) Age-related changes in bone structure and strength in female and male BALB/c mice. Calcif Tissue Int 86:470–483PubMedCrossRef
42.
go back to reference Glatt V, Canalis E, Stadmeyer L, Bouxsein ML (2007) Age-related changes in trabecular architecture differ in female and male C57Bl/6 J mice. J Bone Miner Res 22:1197–1207PubMedCrossRef Glatt V, Canalis E, Stadmeyer L, Bouxsein ML (2007) Age-related changes in trabecular architecture differ in female and male C57Bl/6 J mice. J Bone Miner Res 22:1197–1207PubMedCrossRef
43.
go back to reference Halloran BP, Ferguson VL, Simske SJ, Burghardt A, Venton LL, Majumdar S (2002) Changes in bone structure and mass with advancing age in the male C57Bl/6 J mouse. J Bone Miner Res 17:1044–1050PubMedCrossRef Halloran BP, Ferguson VL, Simske SJ, Burghardt A, Venton LL, Majumdar S (2002) Changes in bone structure and mass with advancing age in the male C57Bl/6 J mouse. J Bone Miner Res 17:1044–1050PubMedCrossRef
44.
go back to reference Brodt MD, Silva MJ (2010) Aged mice have enhanced endocortical response and normal periosteal response compared with young-adult mice following 1 week of axial tibial compression. J Bone Miner Res 25:2006–2015PubMedCrossRef Brodt MD, Silva MJ (2010) Aged mice have enhanced endocortical response and normal periosteal response compared with young-adult mice following 1 week of axial tibial compression. J Bone Miner Res 25:2006–2015PubMedCrossRef
45.
go back to reference Okada Y, Morimoto I, Ura K, Nakano Y, Tanaka Y, Nishida S, Nakamura T, Eto S (1998) Short-term treatment of recombinant murine interleukin-4 rapidly inhibits bone formation in normal and ovariectomized mice. Bone 22:361–365PubMedCrossRef Okada Y, Morimoto I, Ura K, Nakano Y, Tanaka Y, Nishida S, Nakamura T, Eto S (1998) Short-term treatment of recombinant murine interleukin-4 rapidly inhibits bone formation in normal and ovariectomized mice. Bone 22:361–365PubMedCrossRef
46.
go back to reference Ward WE, Fonseca D (2007) Soy isoflavones and fatty acids: effects on bone tissue postovariectomy in mice. Mol Nutr Food Res 51:824–831PubMedCrossRef Ward WE, Fonseca D (2007) Soy isoflavones and fatty acids: effects on bone tissue postovariectomy in mice. Mol Nutr Food Res 51:824–831PubMedCrossRef
47.
go back to reference Waarsing JH, Day JS, Verhaar JA, Ederveen AG, Weinans H (2006) Bone loss dynamics result in trabecular alignment in aging and ovariectomized rats. J Orthop Res 24:926–935PubMedCrossRef Waarsing JH, Day JS, Verhaar JA, Ederveen AG, Weinans H (2006) Bone loss dynamics result in trabecular alignment in aging and ovariectomized rats. J Orthop Res 24:926–935PubMedCrossRef
48.
go back to reference Brouwers JEM, van Rietbergen B, Huiskes R (2007) No effects of in vivo micro-CT radiation on structural parameters and bone marrow cells in proximal tibia of Wistar rats detected after eight weekly scans. J Orthop Res 25:1325–1332PubMedCrossRef Brouwers JEM, van Rietbergen B, Huiskes R (2007) No effects of in vivo micro-CT radiation on structural parameters and bone marrow cells in proximal tibia of Wistar rats detected after eight weekly scans. J Orthop Res 25:1325–1332PubMedCrossRef
Metadata
Title
Longitudinal Assessment of In Vivo Bone Dynamics in a Mouse Tail Model of Postmenopausal Osteoporosis
Authors
Floor M. Lambers
Gisela Kuhn
Friederike A. Schulte
Kathleen Koch
Ralph Müller
Publication date
01-02-2012
Publisher
Springer-Verlag
Published in
Calcified Tissue International / Issue 2/2012
Print ISSN: 0171-967X
Electronic ISSN: 1432-0827
DOI
https://doi.org/10.1007/s00223-011-9553-6

Other articles of this Issue 2/2012

Calcified Tissue International 2/2012 Go to the issue