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Evaluating bone quality in patients with chronic kidney disease

Nature Reviews Nephrology volume 9, pages 671–680 (2013)Cite this article

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Abstract

Bone of normal quality and quantity can successfully endure physiologically imposed mechanical loads. Chronic kidney disease–mineral and bone disorder (CKD–MBD) adversely affects bone quality through alterations in bone turnover and mineralization, whereas bone quantity is affected through changes in bone volume. Changes in bone quality can be associated with altered bone material, structure, or microdamage, which can result in an elevated rate of fracture in patients with CKD–MBD. Fractures cannot always be explained by reduced bone quantity and, therefore, bone quality should be assessed with a variety of techniques from the macro-organ level to the nanoscale level. In this Review, we demonstrate the importance of evaluating bone from multiple perspectives and hierarchical levels to understand CKD–MBD-related abnormalities in bone quality. Understanding the relationships between variations in material, structure, microdamage, and mechanical properties of bone in patients with CKD–MBD should aid in the development of new modalities to prevent, or treat, these abnormalities.

Key Points

  • Chronic kidney disease–mineral and bone disorder (CKD–MBD) is accompanied by histological bone changes (encompassing abnormalities in bone turnover, mineralization, and volume) called renal osteodystrophy

  • Loss of bone quantity (mass) can increase fracture susceptibility, but loss of mass alone is insufficient to explain the increased occurrence of fractures, suggesting bone quality is also involved

  • Bone quality, the ability to perform the mechanical functions needed, can be evaluated on various levels to quantify the structural, material, and microdamage parameters influencing the load-bearing capabilities of bone

  • Abnormalities in bone structure, materials, and microdamage are associated with reduced bone-quality metrics; notably, abnormal bone modulus, strength, and toughness and can be observed in patients with CKD–MBD

  • Current therapies address changes in bone turnover, mineralization, and volume; consideration should also be given to reversal of abnormalities known to influence the load-bearing capabilities of bone

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Figure 1: Illustration of the hierarchical methods and parameters used to assess bone quality.
Figure 2: Fourier transform infrared spectra from bone biopsy samples from patients with stage 5D chronic kidney disease with low, normal, and high turnover.
Figure 3: Idealized stress–strain and load–deformation curves defining important mechanical performance metrics.
Figure 4: Load and unload cycle for nanoindentation of bone from patients on dialysis with stage 5 chronic kidney disease with low, normal, and high turnover.
Figure 5: 3D images of an iliac crest bone sample.

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References

  1. Bouxsein, M. L. Bone quality: where do we go from here? Osteoporos. Int. 14 (Suppl. 5), S118–S127 (2003).

    Article  Google Scholar 

  2. Felsenberg, D. & Boonen, S. The bone quality framework: determinants of bone strength and their interrelationships, and implications for osteoporosis management. Clin. Ther. 27, 1–11 (2005).

    Article  Google Scholar 

  3. Chesnut, C. H. 3rd & Rosen, C. J. Reconsidering the effects of antiresorptive therapies in reducing osteoporotic fracture. J. Bone Miner. Res. 16, 2163–2172 (2001).

    Article  CAS  Google Scholar 

  4. Watts, N. B. Bone quality: getting closer to a definition. J. Bone Miner. Res. 17, 1148–1150 (2002).

    Article  Google Scholar 

  5. Malluche, H. H. et al. Bone histology in incipient and advanced renal failure. Kidney Int. 9, 355–362 (1976).

    Article  CAS  Google Scholar 

  6. Malluche, H. H., Werner, E. & Ritz, E. Intestinal absorption of calcium and whole-body calcium retention in incipient and advanced renal failure. Min. Elec. Metab. 4, 263–270 (1978).

    Google Scholar 

  7. Moe, S. M. et al. KDIGO clinical practice guideline for the diagnosis, evaluation, prevention, and treatment of chronic kidney disease–mineral and bone disorder (CKD–MBD). Kidney Int. 76, S1–S130 (2009).

    Google Scholar 

  8. Hruska, K. A. & Teitelbaum, S. L. Renal osteodystrophy. N. Engl. J. Med. 333, 166–174 (1995).

    Article  CAS  Google Scholar 

  9. Malluche, H. & Faugere, M. Atlas of Mineralized Bone Histology (Karger, 1986).

    Google Scholar 

  10. Sherrard, D. J. et al. The spectrum of bone disease in end-stage renal failure—an evolving disorder. Kidney Int. 43, 436–442 (1993).

    Article  CAS  Google Scholar 

  11. Wesseling-Perry, K. et al. Early skeletal and biochemical alterations in pediatric chronic kidney disease. Clin. J. Am. Soc. Nephrol. 7, 146–152 (2012).

    Article  CAS  Google Scholar 

  12. Malluche, H. H., Mawad, H. W. & Monier-Faugere, M. C. Renal osteodystrophy in the first decade of the new millennium: analysis of 630 bone biopsies in black and white patients. J. Bone Miner. Res. 26, 1368–1376 (2011).

    Article  Google Scholar 

  13. Malluche, H. H. & Monier-Faugere, M. C. Renal osteodystrophy: what's in a name? Presentation of a clinically useful new model to interpret bone histologic findings. Clin. Nephrol. 65, 235–242 (2006).

    Article  CAS  Google Scholar 

  14. Ensrud, K. E. et al. Renal function and risk of hip and vertebral fractures in older women. Arch. Intern. Med. 167, 133–139 (2007).

    Article  Google Scholar 

  15. Alem, A. M. et al. Increased risk of hip fracture among patients with end-stage renal disease. Kidney Int. 58, 396–399 (2000).

    Article  CAS  Google Scholar 

  16. Stone, K. L. et al. BMD at multiple sites and risk of fracture of multiple types: long-term results from the Study of Osteoporotic Fractures. J. Bone Miner. Res. 18, 1947–1954 (2003).

    Article  Google Scholar 

  17. Schuit, S. C. et al. Fracture incidence and association with bone mineral density in elderly men and women: the Rotterdam Study. Bone 34, 195–202 (2004).

    Article  CAS  Google Scholar 

  18. Wainwright, S., Biggs, W., Currey, J. & Gosline, J. Mechanical Design in Organisms (Halsted Press, 1976).

    Google Scholar 

  19. Pienkowski, D. et al. Calcitonin alters bone quality in beagle dogs. J. Bone Miner. Res. 12, 1936–1943 (1997).

    Article  CAS  Google Scholar 

  20. Sabin, M. A., Blake, G. M., MacLaughlin-Black, S. M. & Fogelman, I. The accuracy of volumetric bone density measurements in dual X-ray absorptiometry. Calcif. Tissue Int. 56, 210–214 (1995).

    Article  CAS  Google Scholar 

  21. Yenchek, R. H. et al. Bone mineral density and fracture risk in older individuals with CKD. Clin. J. Am. Soc. Nephrol. 7, 1130–1136 (2012).

    Article  CAS  Google Scholar 

  22. Adragao, T. et al. Low bone volume—a risk factor for coronary calcifications in hemodialysis patients. Clin. J. Am. Soc. Nephrol. 4, 450–455 (2009).

    Article  Google Scholar 

  23. Marshall, D., Johnell, O. & Wedel, H. Meta-analysis of how well measures of bone mineral density predict occurrence of osteoporotic fractures. BMJ 312, 1254–1259 (1996).

    Article  CAS  Google Scholar 

  24. Malluche, H. H., Porter, D. S., Monier-Faugere, M. C., Mawad, H. & Pienkowski, D. Differences in bone quality in low- and high-turnover renal osteodystrophy. J. Am. Soc. Nephrol. 23, 525–532 (2012).

    Article  CAS  Google Scholar 

  25. Gourion-Arsiquaud, S., West, P. A. & Boskey, A. L. Fourier transform-infrared microspectroscopy and microscopic imaging. Methods Mol. Biol. 455, 293–303 (2008).

    Article  CAS  Google Scholar 

  26. Paschalis, E. P., Betts, F., DiCarlo, E., Mendelsohn, R. & Boskey, A. L. FTIR microspectroscopic analysis of human iliac crest biopsies from untreated osteoporotic bone. Calcif. Tissue Int. 61, 487–492 (1997).

    Article  CAS  Google Scholar 

  27. Paschalis, E. P. et al. FTIR microspectroscopic analysis of human osteonal bone. Calcif. Tissue Int. 59, 480–487 (1996).

    Article  CAS  Google Scholar 

  28. Paschalis, E. P. et al. Spectroscopic characterization of collagen cross-links in bone. J. Bone Miner. Res. 16, 1821–1828 (2001).

    Article  CAS  Google Scholar 

  29. Goodyear, S. R. & Aspden, R. M. Raman microscopy of bone. Methods Mol. Biol. 816, 527–534 (2012).

    Article  CAS  Google Scholar 

  30. Bloebaum, R. D., Skedros, J. G., Vajda, E. G., Bachus, K. N. & Constantz, B. R. Determining mineral content variations in bone using backscattered electron imaging. Bone 20, 485–490 (1997).

    Article  CAS  Google Scholar 

  31. Mitome, J. et al. Nonenzymatic cross-linking pentosidine increase in bone collagen and are associated with disorders of bone mineralization in dialysis patients. Calcif. Tissue Int. 88, 521–529 (2011).

    Article  CAS  Google Scholar 

  32. Pothuaud, L. et al. Fractal dimension of trabecular bone projection texture is related to three-dimensional microarchitecture. J. Bone Miner. Res. 15, 691–699 (2000).

    Article  CAS  Google Scholar 

  33. Nickolas, T. L. et al. Bone mass and microarchitecture in CKD patients with fracture. J. Am. Soc. Nephrol. 21, 1371–1380 (2010).

    Article  Google Scholar 

  34. Macneil, J. A. & Boyd, S. K. Bone strength at the distal radius can be estimated from high-resolution peripheral quantitative computed tomography and the finite element method. Bone 42, 1203–1213 (2008).

    Article  Google Scholar 

  35. Dall'Ara, E., Pahr, D., Varga, P., Kainberger, F. & Zysset, P. QCT-based finite element models predict human vertebral strength in vitro significantly better than simulated DEXA. Osteoporos. Int. 23, 563–572 (2012).

    Article  CAS  Google Scholar 

  36. Chappard, C., Marchadier, A. & Benhamou, L. Interindividual and intraspecimen variability of 3-D bone microarchitectural parameters in iliac crest biopsies imaged by conventional micro-computed tomography. J. Bone Miner. Metab. 26, 506–513 (2008).

    Article  Google Scholar 

  37. D'Elia, G., Caracchini, G., Cavalli, L. & Innocenti, P. Bone fragility and imaging techniques. Clin. Cases Miner. Bone Metab. 6, 234–246 (2009).

    PubMed  PubMed Central  Google Scholar 

  38. Nemec, S. F. et al. High-resolution magnetic resonance imaging and conventional magnetic resonance imaging on a standard field-strength magnetic resonance system compared to arthroscopy in patients with suspected meniscal tears. Acad. Radiol. 15, 928–933 (2008).

    Article  Google Scholar 

  39. Link, T. M. et al. High-resolution MRI vs multislice spiral CT: which technique depicts the trabecular bone structure best? Eur. Radiol. 13, 663–671 (2003).

    PubMed  Google Scholar 

  40. Bhagat, Y. A. et al. Performance of muMRI-based virtual bone biopsy for structural and mechanical analysis at the distal tibia at 7T field strength. J. Magn. Reson. Imaging 33, 372–381 (2011).

    Article  Google Scholar 

  41. Wu, Y. et al. Bone mineral imaged in vivo by 31P solid state MRI of human wrists. J. Magn. Reson. Imaging 34, 623–633 (2011).

    Article  Google Scholar 

  42. Robson, M. D., Gatehouse, P. D., Bydder, G. M. & Neubauer, S. Human imaging of phosphorus in cortical and trabecular bone in vivo. Magn. Reson. Med. 51, 888–892 (2004).

    Article  CAS  Google Scholar 

  43. Techawiboonwong, A., Song, H. K., Leonard, M. B. & Wehrli, F. W. Cortical bone water: in vivo quantification with ultrashort echo-time MR imaging. Radiology 248, 824–833 (2008).

    Article  Google Scholar 

  44. K/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classification, and stratification. Am. J. Kidney Dis. 39, S1–S266 (2002).

  45. Carvalho, A. B. et al. Vertebral bone density by quantitative computed tomography mirrors bone structure histomorphometric parameters in hemodialysis patients. J. Bone Miner. Metab. http://dx.doi.org/10.1007/s00774-013-0442-0.

  46. Tamminen, I. S. et al. Reproducibility and agreement of micro-CT and histomorphometry in human trabecular bone with different metabolic status. J. Bone Miner. Metab. 29, 442–448 (2011).

    Article  Google Scholar 

  47. Cohen, A. et al. Assessment of trabecular and cortical architecture and mechanical competence of bone by high-resolution peripheral computed tomography: comparison with transiliac bone biopsy. Osteoporos. Int. 21, 263–273 (2010).

    Article  CAS  Google Scholar 

  48. Hong, S. I., Hong, S. K. & Kohn, D. H. Nanostructural analysis of trabecular bone. J. Mater. Sci. Mater. Med. 20, 1419–1426 (2009).

    Article  CAS  Google Scholar 

  49. Dong, X. N., Almer, J. D. & Wang, X. Post-yield nanomechanics of human cortical bone in compression using synchrotron X-ray scattering techniques. J. Biomech. 44, 676–682 (2011).

    Article  Google Scholar 

  50. Giri, B., Almer, J. D., Dong, X. N. & Wang, X. In situ mechanical behavior of mineral crystals in human cortical bone under compressive load using synchrotron X-ray scattering techniques. J. Mech. Behav. Biomed. Mater. 14, 101–112 (2012).

    Article  Google Scholar 

  51. Almer, J. D. & Stock, S. R. Internal strains and stresses measured in cortical bone via high-energy X-ray diffraction. J. Struct. Biol. 152, 14–27 (2005).

    Article  CAS  Google Scholar 

  52. Boyce, T. M., Fyhrie, D. P., Glotkowski, M. C., Radin, E. L. & Schaffler, M. B. Damage type and strain mode associations in human compact bone bending fatigue. J. Orthop. Res. 16, 322–329 (1998).

    Article  CAS  Google Scholar 

  53. Burr, D. B. & Hooser, M. Alterations to the en bloc basic fuchsin staining protocol for the demonstration of microdamage produced in vivo. Bone 17, 431–433 (1995).

    Article  CAS  Google Scholar 

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

    Article  Google Scholar 

  55. Wang, L., Shao, J., Ye, T., Deng, L. & Qiu, S. Three-dimensional morphology of microdamage in peri-screw bone: a scanning electron microscopy of methylmethacrylate cast replica. Microsc. Microanal. 18, 1106–1111 (2012).

    Article  CAS  Google Scholar 

  56. Schaffler, M. B., Pitchford, W. C., Choi, K. & Riddle, J. M. Examination of compact bone microdamage using back-scattered electron microscopy. Bone 15, 483–488 (1994).

    Article  CAS  Google Scholar 

  57. Larrue, A., Rattner, A., Laroche, N., Vico, L. & Peyrin, F. Feasibility of micro-crack detection in human trabecular bone images from 3D synchrotron microtomography. Conf. Proc. IEEE Eng. Med. Biol. Soc. 2007, 3918–3921 (2007).

    PubMed  Google Scholar 

  58. Diez-Perez, A. et al. Microindentation for in vivo measurement of bone tissue mechanical properties in humans. J. Bone Miner. Res. 25, 1877–1885 (2010).

    Article  Google Scholar 

  59. Oliver, W. C. & Pharr, G. M. An improved technique for determining hardness and elastic modulus using load displacement sensing indentation experiments. J. Mater. Res. 7, 1564–1583 (1992).

    Article  CAS  Google Scholar 

  60. Roy, M. E., Rho, J. Y., Tsui, T. Y., Evans, N. D. & Pharr, G. M. Mechanical and morphological variation of the human lumbar vertebral cortical and trabecular bone. J. Biomed. Mater. Res. 44, 191–197 (1999).

    Article  CAS  Google Scholar 

  61. Isaksson, H. et al. Infrared spectroscopy indicates altered bone turnover and remodeling activity in renal osteodystrophy. J. Bone Miner. Res. 25, 1360–1366 (2010).

    Article  Google Scholar 

  62. Paschalis, E. P. et al. Bone fragility and collagen cross-links. J. Bone Miner. Res. 19, 2000–2004 (2004).

    Article  Google Scholar 

  63. Malluche, H., Porter, D. S., Faugere, M. & Pienkowski, D. Low-energy fractures without low BMD t-scores of osteoporosis: a possible bone matrix disorder. J. Bone Joint Surg. Am. (in press).

  64. Trombetti, A. et al. Alterations of bone microstructure and strength in end-stage renal failure. Osteoporos. Int. 24, 1721–1732 (2012).

    Article  Google Scholar 

  65. Negri, A. L. et al. Evaluation of bone microarchitecture by high-resolution peripheral quantitative computed tomography (HR-pQCT) in hemodialysis patients. Osteoporos. Int. 23, 2543–2550 (2012).

    Article  CAS  Google Scholar 

  66. Bacchetta, J. et al. Early impairment of trabecular microarchitecture assessed with HR-pQCT in patients with stage II–IV chronic kidney disease. J. Bone Miner. Res. 25, 849–857 (2010).

    PubMed  Google Scholar 

  67. Bell, G. H., Dunbar, O., Beck, J. S. & Gibb, A. Variations in strength of vertebrae with age and their relation to osteoporosis. Calcif. Tissue Res. 1, 75–86 (1967).

    Article  CAS  Google Scholar 

  68. Arici, M. et al. Bone mineral density in haemodialysis patients: a comparative study of dual-energy X-ray absorptiometry and quantitative ultrasound. Nephrol. Dial. Transplant. 15, 1847–1851 (2000).

    Article  CAS  Google Scholar 

  69. Foldes, A. J., Arnon, E. & Popovtzer, M. M. Reduced speed of sound in tibial bone of haemodialysed patients: association with serum PTH level. Nephrol. Dial. Transplant. 11, 1318–1321 (1996).

    Article  CAS  Google Scholar 

  70. Grabe, D. W., Chan, M. & Eisele, G. Open-label pilot study comparing quantitative ultrasound and dual-energy X-ray absorptiometry to assess corticosteroid-induced osteoporosis in patients with chronic kidney disease. Clin. Ther. 28, 255–263 (2006).

    Article  Google Scholar 

  71. Wehrli, F. W., Leonard, M. B., Saha, P. K. & Gomberg, B. R. Quantitative high-resolution magnetic resonance imaging reveals structural implications of renal osteodystrophy on trabecular and cortical bone. J. Magn. Reson. Imaging 20, 83–89 (2004).

    Article  Google Scholar 

  72. Zioupos, P. & Currey, J. D. Changes in the stiffness, strength, and toughness of human cortical bone with age. Bone 22, 57–66 (1998).

    Article  CAS  Google Scholar 

  73. Norman, T. L. & Wang, Z. Microdamage of human cortical bone: incidence and morphology in long bones. Bone 20, 375–379 (1997).

    Article  CAS  Google Scholar 

  74. Nickolas, T. L. et al. Discriminants of prevalent fractures in chronic kidney disease. J. Am. Soc. Nephrol. 22, 1560–1572 (2011).

    Article  Google Scholar 

  75. Cejka, D. et al. Bone microarchitecture in hemodialysis patients assessed by HR-pQCT. Clin. J. Am. Soc. Nephrol. 6, 2264–2271 (2011).

    Article  Google Scholar 

  76. Jamal, S., Cheung, A. M., West, S. & Lok, C. Bone mineral density by DXA and HR pQCT can discriminate fracture status in men and women with stages 3 to 5 chronic kidney disease. Osteoporos. Int. 23, 2805–2813 (2012).

    Article  CAS  Google Scholar 

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Acknowledgements

We acknowledge support from the NIH under grants RO1 DK080770 and RO1 AR061578. We also acknowledge support from the Kentucky Nephrology Research Trust.

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Authors and Affiliations

  1. Division of Nephrology, Bone and Mineral Metabolism, University of Kentucky, Albert B. Chandler Medical Center, 800 Rose Street, Room MN-564, Lexington, 40536-0298, KY, USA

    Hartmut H. Malluche

  2. Center for Biomedical Engineering, University of Kentucky, 600 Rose Street, Lexington, 40506-0070, KY, USA

    Daniel S. Porter & David Pienkowski

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H. H. Malluche, D. S. Porter and D. Pienkowski researched data for the article, reviewed and discussed the literature and obtained data, and wrote and edited the article.

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Correspondence to Hartmut H. Malluche.

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Malluche, H., Porter, D. & Pienkowski, D. Evaluating bone quality in patients with chronic kidney disease. Nat Rev Nephrol 9, 671–680 (2013). https://doi.org/10.1038/nrneph.2013.198

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