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Stiffness and strength of bone in osteoporotic patients treated with varying durations of oral bisphosphonates

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Abstract

Summary

Apparent modulus and failure stress of trabecular bone structure from 45 women with osteoporosis treated with bisphosphonates for varying durations were studied using finite element analyses and statistical modeling. Following adjustments for patient age and bone volume, increasing bisphosphonate treatment duration for up to 7.3 years was associated with treatment–time-dependent increases in bone apparent modulus and failure stress. Treatment durations exceeding 7.3 years were associated with time-dependent decreases in apparent modulus and failure stress from the peak values observed.

Introduction

The purpose of this study was to clarify the relationship between bisphosphonate (BP) treatment duration and human bone quality. This study quantified changes in the apparent modulus and failure stress of trabecular bone biopsied from patients with osteoporosis who were treated with BPs for widely varying durations.

Methods

Forty-five iliac crest bone samples were obtained from women with osteoporosis who were continuously treated with oral BPs for varying periods of up to 16 years. Micro-CT imaging was used to develop three-dimensional virtual models of the trabecular bone from these samples. Apparent modulus and failure stress of these virtual models were determined using finite element analyses (FEA). Polynomial regression and cubic splines, adjusted for relevant (age and BV/TV) covariates, were used to statistically model the data and quantify the relationships between BP treatment duration and apparent modulus or failure stress.

Results

Second-order polynomial models were needed to relate apparent modulus or failure stress to BP treatment duration. These models showed that these bone quality parameters (a) increased with increasing BP treatment duration up to approximately 7.3 years, (b) reached a maximum at this (~7.3 years) time, and then (c) declined with BP treatment durations exceeding ~7.3 years. A similar result was obtained by modeling with cubic splines.

Conclusions

Changes in FEA-derived apparent stiffness and failure stress are attributable to changes in trabecular bone structure, which in turn are related to the duration of BP treatment. These relationships are evident even after adjustments are made in the statistical models for changes in age and BV/TV. According to these models, increases in trabecular bone apparent stiffness and failure stress linked to BPs cease and appear to reverse after approximately 7.3 years of treatment. Conclusions regarding optimal BP therapy duration await study of additional bone quality parameters.

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References

  1. Schmidt GA, Horner KE, McDanel DL, Ross MB, Moores KG (2010) Risks and benefits of long-term bisphosphonate therapy. Am J Health Syst Pharm 67(12):994–1001

    Article  CAS  PubMed  Google Scholar 

  2. Chavassieux PM, Arlot ME, Reda C, Wei L, Yates AJ, Meunier PJ (1997) Histomorphometric assessment of the long-term effects of alendronate on bone quality and remodeling in patients with osteoporosis. J Clin Invest 100(6):1475–1480

  3. Drake MT, Clarke BL, Khosla S (2008) Bisphosphonates: mechanism of action and role in clinical practice. Mayo Clin Proc 83(9):1032–1045

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Plotkin LI, Weinstein RS, Parfitt AM, Roberson PK, Manolagas SC, Bellido T (1999) Prevention of osteocyte and osteoblast apoptosis by bisphosphonates and calcitonin. J Clin Invest 104(10):1363–1374

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Liberman UA, Weiss SR, Broll J et al (1995) Effect of oral alendronate on bone mineral density and the incidence of fractures in postmenopausal osteoporosis. The Alendronate Phase III Osteoporosis Treatment Study Group. N Engl J Med 333(22):1437–1443

    Article  CAS  PubMed  Google Scholar 

  6. Cummings SR, Black DM, Thompson DE et al (1998) Effect of alendronate on risk of fracture in women with low bone density but without vertebral fractures: results from the Fracture Intervention Trial. JAMA 280(24):2077–2082

    Article  CAS  PubMed  Google Scholar 

  7. Harris ST, Watts NB, Genant HK et al (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(14):1344–1352

    Article  CAS  PubMed  Google Scholar 

  8. Bilezikian JP (2009) Efficacy of bisphosphonates in reducing fracture risk in postmenopausal osteoporosis. Am J Med 122(2 Suppl):S14–S21

    Article  CAS  PubMed  Google Scholar 

  9. Black DM, Schwartz AV, Ensrud KE et al (2006) Effects of continuing or stopping alendronate after 5 years of treatment: the Fracture Intervention Trial Long-term Extension (FLEX): a randomized trial. JAMA 296(24):2927–2938

    Article  CAS  PubMed  Google Scholar 

  10. Schuit SC, van der Klift M, Weel AE et al (2004) Fracture incidence and association with bone mineral density in elderly men and women: the Rotterdam Study. Bone 34(1):195–202

    Article  CAS  PubMed  Google Scholar 

  11. Dell RM, Adams AL, Greene DF et al (2012) Incidence of atypical nontraumatic diaphyseal fractures of the femur. J Bone Miner Res 27(12):2544–2550

    Article  PubMed  Google Scholar 

  12. Shane E, Burr D, Ebeling PR et al (2010) Atypical subtrochanteric and diaphyseal femoral fractures: report of a task force of the American Society for Bone and Mineral Research. J Bone Miner Res 25(11):2267–2294

    Article  PubMed  Google Scholar 

  13. Meier RP, Perneger TV, Stern R, Rizzoli R, Peter RE (2012) Increasing occurrence of atypical femoral fractures associated with bisphosphonate use. Arch Intern Med 172(12):930–936

    Article  PubMed  Google Scholar 

  14. Whitaker M, Guo J, Kehoe T, Benson G (2012) Bisphosphonates for osteoporosis—where do we go from here? N Engl J Med 366(22):2048–2051

    Article  CAS  PubMed  Google Scholar 

  15. Adler RA, El-Hajj Fuleihan G, Bauer DC et al (2016) Managing osteoporosis in patients on long-term bisphosphonate treatment: report of a task force of the American Society for Bone and Mineral Research. J Bone Miner Res 31(1):16–35

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Recker RR, Lewiecki EM, Miller PD, Reiffel J (2009) Safety of bisphosphonates in the treatment of osteoporosis. Am J Med 122(2 Suppl):S22–S32

    Article  CAS  PubMed  Google Scholar 

  17. Odvina CV, Zerwekh JE, Rao DS, Maalouf N, Gottschalk FA, Pak CY (2005) Severely suppressed bone turnover: a potential complication of alendronate therapy. J Clin Endocrinol Metab 90(3):1294–1301

    Article  CAS  PubMed  Google Scholar 

  18. Ott SM (2005) Long-term safety of bisphosphonates. J Clin Endocrinol Metab 90(3):1897–1899

    Article  CAS  PubMed  Google Scholar 

  19. Bala Y, Depalle B, Farlay D et al (2012) Bone micromechanical properties are compromised during long-term alendronate therapy independently of mineralization. J Bone Miner Res 27(4):825–834

    Article  CAS  PubMed  Google Scholar 

  20. Nazarian A, Stauber M, Zurakowski D, Snyder BD, Muller R (2006) The interaction of microstructure and volume fraction in predicting failure in cancellous bone. Bone 39(6):1196–1202

    Article  PubMed  Google Scholar 

  21. Karim L, Vashishth D (2011) Role of trabecular microarchitecture in the formation, accumulation, and morphology of microdamage in human cancellous bone. J Orthop Res 29(11):1739–1744

    Article  PubMed  PubMed Central  Google Scholar 

  22. Turner CH (2002) Biomechanics of bone: determinants of skeletal fragility and bone quality. Osteoporos Int 13(2):97–104

    Article  CAS  PubMed  Google Scholar 

  23. Borah B, Dufresne TE, Chmielewski PA, Johnson TD, Chines A, Manhart MD (2004) Risedronate preserves bone architecture in postmenopausal women with osteoporosis as measured by three-dimensional microcomputed tomography. Bone 34(4):736–746

    Article  CAS  PubMed  Google Scholar 

  24. Pazianas M, van der Geest S, Miller P (2014) Bisphosphonates and bone quality. BoneKEy Rep 3:529

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Pistoia W, van Rietbergen B, Lochmuller EM, Lill CA, Eckstein F, Ruegsegger P (2002) Estimation of distal radius failure load with micro-finite element analysis models based on three-dimensional peripheral quantitative computed tomography images. Bone 30(6):842–848

    Article  CAS  PubMed  Google Scholar 

  26. Chevalier Y, Pahr D, Allmer H, Charlebois M, Zysset P (2007) Validation of a voxel-based FE method for prediction of the uniaxial apparent modulus of human trabecular bone using macroscopic mechanical tests and nanoindentation. J Biomech 40(15):3333–3340

    Article  PubMed  Google Scholar 

  27. Macneil JA, Boyd SK (2008) Bone strength at the distal radius can be estimated from high-resolution peripheral quantitative computed tomography and the finite element method. Bone 42(6):1203–1213

    Article  PubMed  Google Scholar 

  28. Harrison NM, McDonnell P, Mullins L, Wilson N, O’Mahoney D, McHugh PE (2013) Failure modelling of trabecular bone using a non-linear combined damage and fracture voxel finite element approach. Biomech Model Mechanobiol 12(2):225–241

    Article  PubMed  Google Scholar 

  29. Zysset PK, Dall’ara E, Varga P, Pahr DH (2013) Finite element analysis for prediction of bone strength. BoneKEy Rep 2:386

    Article  PubMed  PubMed Central  Google Scholar 

  30. Britton JM, Davie MW (1990) Mechanical properties of bone from iliac crest and relationship to L5 vertebral bone. Bone 11(1):21–28

    Article  CAS  PubMed  Google Scholar 

  31. Mosekilde L, Viidik A, Mosekilde L (1985) Correlation between the compressive strength of iliac and vertebral trabecular bone in normal individuals. Bone 6(5):291–295

    Article  CAS  PubMed  Google Scholar 

  32. Neo M, Herbst H, Voigt CF, Gross UM (1998) Temporal and spatial patterns of osteoblast activation following implantation of beta-TCP particles into bone. J Biomed Mater Res 39(1):71–76

    Article  CAS  PubMed  Google Scholar 

  33. Malluche HH, Monier–Faugere MC (1997) In: Avioli LV, Krane SM (eds) Bone biopsies: a modern approach in metabolic bone disease, 3rd edn. WB Saunders Co, Philadelphia, pp 237–273

    Google Scholar 

  34. Malluche HHMH, Monier-Faugere MC (2008) Bone biopsy in patients with osteoporosis. Curr Osteoporos Rep 5(4):146–152

    Article  Google Scholar 

  35. Malluche HH M-FM (1986) Atlas of mineralized bone histology. Karger

  36. Malluche HH, Porter DS, Monier-Faugere MC, Mawad H, Pienkowski D (2012) Differences in bone quality in low- and high-turnover renal osteodystrophy. J Am Soc Nephrol 23(3):525–532

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. van Rietbergen B, Weinans H, Huiskes R, Odgaard A (1995) A new method to determine trabecular bone elastic properties and loading using micromechanical finite-element models. J Biomech 28(1):69–81

    Article  PubMed  Google Scholar 

  38. Waarsing JH, Day JS, Weinans H (2004) An improved segmentation method for in vivo micro-CT imaging. J Bone Miner Res 19(10):1640–1650

  39. Ruegsegger P, Koller B, Muller R (1996) A microtomographic system for the nondestructive evaluation of bone architecture. Calcif Tissue Int 58(1):24–29

    Article  CAS  PubMed  Google Scholar 

  40. Ding M, Odgaard A, Hvid I (1999) Accuracy of cancellous bone volume fraction measured by micro-CT scanning. J Biomech 32(3):323–326

    Article  CAS  PubMed  Google Scholar 

  41. Wilkerson LT (2012) Finite element analysis of cancellous bone. Theses and Dissertations: Mechanical Engineering, University of Kentucky

  42. Burkhart TA, Andrews DM, Dunning CE (2013) Finite element modeling mesh quality, energy balance and validation methods: a review with recommendations associated with the modeling of bone tissue. J Biomech 46(9):1477–1488

    Article  PubMed  Google Scholar 

  43. Polly BJ, Yuya PA, Akhter MP, Recker RR, Turner JA (2012) Intrinsic material properties of trabecular bone by nanoindentation testing of biopsies taken from healthy women before and after menopause. Calcif Tissue Int 90(4):286–293

    Article  CAS  PubMed  Google Scholar 

  44. Bevill G, Keaveny TM (2009) Trabecular bone strength predictions using finite element analysis of micro-scale images at limited spatial resolution. Bone 44(4):579–584

    Article  PubMed  Google Scholar 

  45. Un K, Bevill G, Keaveny TM (2006) The effects of side-artifacts on the elastic modulus of trabecular bone. J Biomech 39(11):1955–1963

    Article  PubMed  Google Scholar 

  46. Wood S (2006) Generalized additive models: an introduction with R, 1st edn. Chapman & Hall/CRC, New York

    Google Scholar 

  47. Wahba G (1990) Spline models for observational data, 1st edn. SIAM, Philadelphia

    Book  Google Scholar 

  48. Ruppert D, Wand M, Carrol RJ (2003) Semiparametric regression, 1st edn. Cambridge University Press, New York

    Book  Google Scholar 

  49. Borah B, Dufresne TE, Ritman EL et al (2006) Long-term risedronate treatment normalizes mineralization and continues to preserve trabecular architecture: sequential triple biopsy studies with micro-computed tomography. Bone 39(2):345–352

    Article  CAS  PubMed  Google Scholar 

  50. Day JS, Ding M, Bednarz P et al (2004) Bisphosphonate treatment affects trabecular bone apparent modulus through micro-architecture rather than matrix properties. J Orthop Res 22(3):465–471

    Article  CAS  PubMed  Google Scholar 

  51. Keaveny TM, Hoffmann PF, Singh M et al (2008) Femoral bone strength and its relation to cortical and trabecular changes after treatment with PTH, alendronate, and their combination as assessed by finite element analysis of quantitative CT scans. J Bone Miner Res 23(12):1974–1982

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Imai K, Ohnishi I, Matsumoto T, Yamamoto S, Nakamura K (2009) Assessment of vertebral fracture risk and therapeutic effects of alendronate in postmenopausal women using a quantitative computed tomography-based nonlinear finite element method. Osteoporos Int 20(5):801–810

    Article  CAS  PubMed  Google Scholar 

  53. Lewiecki EM, Keaveny TM, Kopperdahl DL et al (2009) Once-monthly oral ibandronate improves biomechanical determinants of bone strength in women with postmenopausal osteoporosis. J Clin Endocrinol Metab 94(1):171–180

    Article  CAS  PubMed  Google Scholar 

  54. Burghardt AJ, Kazakia GJ, Sode M, de Papp AE, Link TM, Majumdar S (2010) A longitudinal HR-pQCT study of alendronate treatment in postmenopausal women with low bone density: relations among density, cortical and trabecular microarchitecture, biomechanics, and bone turnover. J Bone Miner Res 25(12):2558–2571

    Article  PubMed  PubMed Central  Google Scholar 

  55. What is Osteoporosis? [website]. http://nof.org/articles/7, 2014

  56. Borah B, Dufresne TE, Chmielewski PA, Gross GJ, Prenger MC, Phipps RJ (2002) Risedronate preserves trabecular architecture and increases bone strength in vertebra of ovariectomized minipigs as measured by three-dimensional microcomputed tomography. J Bone Miner Res 17(7):1139–1147

    Article  CAS  PubMed  Google Scholar 

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Author information

Authors and Affiliations

  1. Department of Biomedical Engineering, University of Kentucky, Lexington, KY, USA

    J. Ward & D. Pienkowski

  2. Department of Statistics, University of Kentucky, Lexington, KY, USA

    C. Wood

  3. Department of Mechanical Engineering, University of Kentucky, Lexington, KY, USA

    K. Rouch

  4. Division of Nephrology, Bone and Mineral Metabolism, University of Kentucky, Lexington, KY, USA

    H. H. Malluche

  5. Division of Nephrology, Bone & Mineral Metabolism, University of Kentucky Chandler Medical Center, 800 Rose Street, MN-564, Lexington, KY, 40536-0298, USA

    H. H. Malluche

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  1. J. Ward
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  5. H. H. Malluche
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Correspondence to H. H. Malluche.

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Research support

This study was supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health under award number R01 AR061578 and the Kentucky Nephrology Research Trust. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

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Ward, J., Wood, C., Rouch, K. et al. Stiffness and strength of bone in osteoporotic patients treated with varying durations of oral bisphosphonates. Osteoporos Int 27, 2681–2688 (2016). https://doi.org/10.1007/s00198-016-3661-0

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