Bisphosphonates alter trabecular bone collagen cross-linking and isomerization in beagle dog vertebra
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Changes in organic matrix may contribute to the anti-fracture efficacy of anti-remodeling agents. Following one year of treatment in beagle dogs, bisphosphonates alter the organic matrix of vertebral trabecular bone, while raloxifene had no effect. These results show that pharmacological suppression of turnover alters the organic matrix component of bone.
The collagen matrix contributes significantly to a bone’s fracture resistance yet the effects of anti-remodeling agents on collagen properties are unclear. The goal of this study was to assess changes in collagen cross-linking and isomerization following anti-remodeling treatment.
Skeletally mature female beagles were treated for one year with oral doses of vehicle (VEH), risedronate (RIS; 3 doses), alendronate (ALN; 3 doses), or raloxifene (RAL; 2 doses). The middle dose of RIS and ALN and the lower dose of RAL approximate doses used for treatment of post menopausal osteoporosis. Vertebral trabecular bone matrix was assessed for collagen isomerization (ratio of α/β C-telopeptide [CTX]), enzymatic (pyridinoline [PYD] and deoxypyridinoline [DPD]), and non-enzymatic (pentosidine [PEN]) cross-links.
All doses of both RIS and ALN increased PEN (+34–58%) and the ratio of PYD/DPD (+14–26%), and decreased the ratio of α/β CTX (−29–56%) compared to VEH. RAL did not alter any collagen parameters. Bone turnover rate was significantly correlated to PEN (R = −0.664), α/β CTX (R = 0.586), and PYD/DPD (R = −0.470).
Bisphosphonate treatment significantly alters properties of bone collagen suggesting a contribution of the organic matrix to the anti-fracture efficacy of this drug class.
KeywordsAlendronate Anti-remodeling Bone markers Pentosidine Raloxifene Risedronate
The authors thank Dr. Keith Condon, Diana Jacob, Mary Hooser, and Lauren Waugh for histological preparation. This work was supported by NIH Grants AR047838 and AR007581 and research grants from The Alliance for Better Bone Health (Procter & Gamble Pharmaceuticals and sanofi-aventis), and Lilly Research Laboratories, as well as an unrestricted grant from Eli Lilly to INSERM. Merck and Co. kindly provided the alendronate. This investigation utilized an animal facility constructed with support from Research Facilities Improvement Program Grant Number C06 RR10601-01 from the National Center for Research Resources, National Institutes of Health.
Conflict of interest statement
Matthew R. Allen has current research funding from Eli Lilly, Amgen, and the Alliance for Better Bone Health.
Diana Julie Leeming is a full-time employee of Nordic Bioscience.
David B. Burr has research funding from the Alliance for Better Bone Health, Eli Lilly and Co., and Amgen. He serves as a consultant and speaker for Procter and Gamble Pharmaceuticals and for Eli Lilly and Company.
- 1.Black DM, Cummings SR, Karpf DB, Cauley JA, Thompson DE, Nevitt MC, Bauer DC, Genant HK, Haskell WL, Marcus R, Ott SM, Torner JC, Quandt SA, Reiss TF, Ensrud KE (1996) Randomized trial of effect of alendronate on risk of fracture in women with existing vertebral fractures. Fracture Intervention Trial Research Group. Lancet 348:1535–1541PubMedCrossRefGoogle Scholar
- 2.Harris ST, Watts NB, Genant HK, McKeever CD, Hangartner T, Keller M, Chesnut CH 3rd, Brown J, Eriksen EF, Hoseyni MS, Axelrod DW, Miller PD (1999) Effects of risedronate treatment on vertebral and nonvertebral fractures in women with postmenopausal osteoporosis: a randomized controlled trial. Vertebral Efficacy With Risedronate Therapy (VERT) Study Group. JAMA 282:1344–1352PubMedCrossRefGoogle Scholar
- 3.Reginster J, Minne HW, Sorensen OH, Hooper M, Roux C, Brandi ML, Lund B, Ethgen D, Pack S, Roumagnac I, Eastell R (2000) Randomized trial of the effects of risedronate on vertebral fractures in women with established postmenopausal osteoporosis. Vertebral Efficacy with Risedronate Therapy (VERT) Study Group. Osteoporos Int 11:83–91PubMedCrossRefGoogle Scholar
- 4.Ettinger B, Black DM, Mitlak BH, Knickerbocker RK, Nickelsen T, Genant HK, Christiansen C, Delmas PD, Zanchetta JR, Stakkestad J, Gluer CC, Krueger K, Cohen FJ, Eckert S, Ensrud KE, Avioli LV, Lips P, Cummings SR (1999) Reduction of vertebral fracture risk in postmenopausal women with osteoporosis treated with raloxifene: results from a 3-year randomized clinical trial. Multiple Outcomes of Raloxifene Evaluation (MORE) Investigators. Jama 282:637–645PubMedCrossRefGoogle Scholar
- 5.Sambrook PN, Geusens P, Ribot C, Solimano JA, Ferrer-Barriendos J, Gaines K, Verbruggen N, Melton ME (2004) Alendronate produces greater effects than raloxifene on bone density and bone turnover in postmenopausal women with low bone density: results of EFFECT (Efficacy of FOSAMAX versus EVISTA Comparison Trial) International. J Intern Med 255:503–511PubMedCrossRefGoogle Scholar
- 6.Siris ES, Harris ST, Eastell R, Zanchetta JR, Goemaere S, Diez-Perez A, Stock JL, Song J, Qu Y, Kulkarni PM, Siddhanti SR, Wong M, Cummings SR (2005) Skeletal effects of raloxifene after 8 years: results from the continuing outcomes relevant to Evista (CORE) study. J Bone Miner Res 20:1514–1524PubMedCrossRefGoogle Scholar
- 9.Burr DB, Turner CH (2003) Biomechanics of bone. In: Favus M (ed) Primer on the metabolic bone diseases and disorders of mineral metabolism. American Society for Bone and Mineral Research, Washington DC, pp 58–64Google Scholar
- 11.Monier-Faugere MC, Geng Z, Paschalis EP, Qi Q, Arnala I, Bauss F, Boskey AL, Malluche HH (1999) Intermittent and continuous administration of the bisphosphonate ibandronate in ovariohysterectomized beagle dogs: effects on bone morphometry and mineral properties. J Bone Miner Res 14:1768–1778PubMedCrossRefGoogle Scholar
- 18.Komatsubara S, Mori S, Mashiba T, Ito M, Li J, Kaji Y, Akiyama T, Miyamoto K, Cao Y, Kawanishi J, Norimatsu H (2003) Long-term treatment of incadronate disodium accumulates microdamage but improves the trabecular bone microarchitecture in dog vertebra. J Bone Miner Res 18:512–520PubMedCrossRefGoogle Scholar
- 21.Allen MR, Burr DB (2007) Mineralization, microdamage, and matrix: how bisphosphonates influence material properties of bone. BoneKEy 4:49–60; http://www.bonekey-ibms.org/cgi/content/abstract/ibmske;44/42/49 Google Scholar
- 23.Viguet-Carrin S, Roux JP, Arlot ME, Merabet Z, Leeming DJ, Byrjalsen I, Delmas PD, Bouxsein ML (2006) Contribution of the advanced glycation end product pentosidine and of maturation of type I collagen to compressive biomechanical properties of human lumbar vertebrae. Bone 39:1073–1079PubMedCrossRefGoogle Scholar
- 26.Rosen CJ, Hochberg MC, Bonnick SL, McClung M, Miller P, Broy S, Kagan R, Chen E, Petruschke RA, Thompson DE, de Papp AE (2005) Treatment with once-weekly alendronate 70 mg compared with once-weekly risedronate 35 mg in women with postmenopausal osteoporosis: a randomized double-blind study. J Bone Miner Res 20:141–151PubMedGoogle Scholar
- 37.Vashishth D, Wu P, Gibson G (2004) Age-related loss in bone toughness is explained by non-enzymatic glycation of collagen. Trans Orthop Res Soc 29Google Scholar
- 38.Wu P, Koharski C, Nonnenmann H, Vashishth D (2003) Loading on non-enzymatically glycated and damaged bone results in an instantaneous fracture. Trans Orthop Res Soc 28:404Google Scholar
- 39.Catanese J, Bank R, Tekoppele J, Keaveny T (1999) Increased cross-linking by non-enzymatic glycation reduces the ductility of bone and bone collagen. Proc ASME 1999 Bioengineering Conference 42:267–268Google Scholar
- 41.Boxberger J, Vashishth D (2004) Nonenzymatic glycation affects bone fracture by modifying creep and inelastic properties of collagen. Trans Orthop Res Soc 29Google Scholar
- 42.Tang S, Sharan A, Novak E, Ford T, Vashishth D (2005) Nonenzymatic glycation causes loss of toughening mechanisms in human cancellous bone. Trans Orthop Res Soc 30Google Scholar
- 44.Vashishth D, Gibson GJ, Khoury JI, Schaffler MB, Kimura J, Fyhrie DP (2001) Influence of nonenzymatic glycation on biomechanical properties of cortical bone. Bone 28:195–201Google Scholar
- 46.Siegmund T, Allen MR, Burr D (2007) A ductile-to-brittle transition in bone failure due to non-enzymatic collagen-crosslinks - A computational study. Trans Orthop Res Soc 32:1360Google Scholar
- 55.Watts NB, Cooper C, Lindsay R, Eastell R, Manhart MD, Barton IP, van Staa TP, Adachi JD (2004) Relationship between changes in bone mineral density and vertebral fracture risk associated with risedronate: greater increases in bone mineral density do not relate to greater decreases in fracture risk. J Clin Densitom 7:255–261PubMedCrossRefGoogle Scholar