Burr, David B.

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Bone quality: Understanding what matters

184IntroductionAlthough bone strength and fracture risk are generallyassessed by measuring bone mineral density (BMD), themechanical properties of bone are in fact determined notonly by bone mass, but also by the architecture/geometry ofthe bone and by the intrinsic material properties of the tissue.Fracture risk increases with age, partly as a function ofchanges in BMD. However, the risk of fracture in a 75-year-old woman is 4-7 times that in a 45-year-old woman with anidentical bone mass1. This demonstrates that there is a com-ponent to bone fragility that is independent of bone mass, anddetermined by bone quality. This has been emphasizedrecently by the observation that anti-resorptive treatments forosteoporosis all have about the same fracture efficacy, thoughthere is a seven-fold difference in their effect on BMD.Bone quality is defined by at least four factors: (1) the rateof bone turnover; (2) properties of the collagen/mineralmatrix; (3) microdamage accumulation; (4) architecture/geom-etry of cancellous and cortical bone.Bone turnoverVertebral fracture risk is determined by both BMD andturnover rate2. Rapid turnover accelerates osteoclasticresorption on trabecular surfaces that can reduce theirresistance to buckling and make failure more likely3.Resorption lacunae on trabecular surfaces are responsiblefor larger decreases in bone stiffness than in trabecular thin-ning4. Additionally, the resorption bays create stress concen-trations that may promote the initiation of microcracks.More rapid turnover also increases the probability for perfo-ration and elimination of trabecular struts. A 50% reductionin turnover can result in a 4-fold reduction in trabecular per-foration5. However, agents such as teriparatide that increaseturnover also may lower fracture risk by increasing net boneformation on trabecular surfaces.Matrix mineralizationThe amount of energy that can be absorbed before frac-ture is reduced by either hypo- or hypermineralization of thebone tissue6,7. Suppression of remodeling increases tissuemineralization by lengthening the period of time over whichsecondary mineralization can occur8-12. This may increase thetendency for microcracks to initiate. As importantly, remod-eling suppression increases tissue homogeneity, possiblymaking crack growth easier as well. However, the magnitudeof the effect is probably determined by the amount of sup-pression. On the other hand, teriparatide stimulatesincreased bone turnover and increases the heterogeneity ofthe tissue matrix.CollagenThe collagen matrix has a profound effect on bone’smechanical properties13. The risk of vertebral fracture is sig-nificantly increased in subjects with the Sp1 polymorphismof the COL1A1 gene14. Changes in collagen with aging areknown to affect the amount of energy required to cause frac-ture15. This may have to do either with the amount of colla-gen in the matrix, or with the extent or nature of its cross-linking. Anti-resorptive treatments probably increase theamount of cross-linking, but whether this is a positive or anegative change is unclear at this time.MicrodamageMicrodamage accumulation reduces bone’s strength, stiff-ness and toughness16. Bone from older women is more sus-ceptible to the initiation of microcracks17 and must be inher-ently more fragile than bone from younger women. This mayJ Musculoskel Neuron Interact 2004; 4(2):184-186Bone quality: Understanding what mattersD.B. BurrDept. of Anatomy and Cell Biology and Dept. of Orthopaedic Surgery, Indiana University School of Medicine, Indianapolis, IN, USAKeywords: Osteoporosis, Bone Quality, Mineralization, Microdamage, ArchitecturePerspective Article HylonomeThe author is a consultant for Elli Lilly Co. and Procter & GamblePharmaceuticals and holds stock in Elli Lilly Co.Corresponding author: David B. Burr, Ph.D., Department of Anatomy & Cell Biol-ogy, MS 5053, Indiana University School of Medicine, Indianapolis, IN, USA 46202E-mail: dburr@iupui.eduAccepted 28 May 2004D.B. Burr: Bone quality185be why there is a significant accumulation of microdamage atseveral anatomical sites with age18-21. Suppression of remod-eling pharmaceutically also increases damage accumula-tion22,23; the extent of this increase is probably dependent onthe magnitude of the suppression24.Architecture/GeometryCancellous bone that is more plate-like, with thicker andmore trabeculae, enhances strength. Trabecular architecturethat is more isotropic, having similar mechanical propertiesin all directions, may lower fracture risk further. This couldprovide a rationale for the clinical observation that fracturerisk decreases by 50-60% in the first year of bisphosphonatetherapy with only a 5% increase in bone mineral density.Teriparatide increases trabecular number and connectivityvia longitudinal tunneling, converting thickened trabeculaeto multiple struts of normal thickness25. Although it increas-es cortical porosity, the porosity is located close to the mar-row cavity where its mechanical effect is small26,27.Simultaneously, teriparatide allows periosteal apposition,which maintains or improves cortical bone strength28.ConclusionIt is quite clear that the assessment of bone quality asdefined here, in addition to BMD measurement, is impor-tant to determine fracture risk, but techniques to measurethese properties are nascent. Development of new non-inva-sive techniques will be necessary to provide better pre-frac-ture evaluations of tissue quality. These will need to be madeaccessible and convenient for the health practitioner.References1. Hui S, Slemenda CW, Johnston CC. Age and bone massas predictors of fracture in a prospective study. J ClinInvest 1988; 81:1804-1809.2. Riggs BL, Melton LJ III. Bone turnover matters: theraloxifene treatment paradox of dramatic decreases invertebral fractures without commensurate increases inbone density. J Bone Miner Res 2002; 17:11-14.3. Parfitt AM. High bone turnover is intrinsically harmful:two paths to a similar conclusion. J Bone Miner Res2002; 17:1558-1559.4. Van der Linden JC, Verhaar JAN, Weinans H. A 3-Dsimulation of age-related remodeling in cancellousbone. J Bone Miner Res 2001; 16:688-696.5. Weinans H. Architectural changes independent of bonemineral in osteoporosis. Presented at the 32ndInternational Sun Valley Hard Tissue Workshop; 2002.6. Currey JD. The effect of strain rate, reconstruction andmineral content on some mechanical properties ofbovine bone. J Biomech 1975; 8:81-86.7. Currey JD, Brear K, Zioupos P. The effects of agingand changes in mineral content in degrading the tough-ness of human femora. J Biomech 1996; 29:257-260.8. Meunier PJ, Boivin G. Bone mineral density reflectsbone mass but also the degree of mineralization ofbone: therapeutic implications. Bone 1997; 21:373-377.9. Boivin G, Chavassieux PM, Santora AC, Yates, J,Meunier PJ. Alendronate increases bone strength byincreasing the mean degree of mineralization of bonetissue in osteoporotic women. Bone 2000; 27:687-694.10. Roschger P, Rinnerhtaler S, Yates J, Rodan GA, FratzlP, Klaushofer K. Alendronate increases degree and uni-formity of mineralization in cancellous bone anddecreases the porosity in cortical bone of osteoporoticwomen. Bone 2001; 29:185-191.11. Nuzzo S, Lafage-Proust MH, Martin-Badosa E, Boivin G,Thomas T, Alexandre C, Peyrin F. Synchrotron radiationmicrotomography allows the analysis of three-dimension-al microarchitecture and degree of mineralization ofhuman iliac crest biopsy specimens: effects of etidronatetreatment. J Bone Miner Res 2002; 17:1372-1382.12. Boivin G, Lips P, Ott SM, Harper KD, Sarkar S, PinetteKV, Meunier PJ. Contribution of raloxifene and calci-um and vitamin D3 supplementation to the increase ofthe degree of mineralization of bone in postmenopausalwomen. J Clin Endocrinol Metab 2003; 88:4199-4205.13. Burr DB. The contribution of the organic matrix tobone’s mechanical properties. Bone 2002; 31:8-11.14. Mann V, Ralston SH. Meta-analysis of COL1A1 Sp1polymorphism in relation to bone mineral density andosteoporotic fracture. Bone 2003; 32:711-717.15. Burr DB, Turner CH. Biomechanical measurements inage-related bone loss. In: Rosen CJ, Glowacki J,Bilezikian JP (eds) The Aging Skeleton. AcademicPress, San Diego; 1999:301-311.16. Burr DB, Forwood MR, Fyhrie DP, Martin RB,Schaffler MB, Turner CH. Bone microdamage andskeletal fragility in osteoporotic and stress fractures. JBone Miner Res 1997; 12:6-15.17. Courtney AC, Hayes WC, Gibson LJ. Age-related dif-ferences in post-yield damage in human cortical bone.Experiment and model. J Biomech. 1996; 29:1463-1471.18. Schaffler MB, Choi K, Milgrom C. Aging and matrixmicrodamage accumulation in human compact bone.Bone 1995; 17:521-525.19. Mori S, Harruff R, Ambrosius W, Burr DB. Trabecularbone volume and microdamage accumulation in thefemoral heads of women with and without femoral neckfractures. Bone 1997; 21:521-526.20. Fazzalari NL, Forwood MR, Smith K, Manthey BA,Herreen P. Assessment of cancellous bone quality insevere osteoarthrosis: bone mineral density, mechanics,and microdamage. Bone 1998; 22:381-388.21. Zioupos P. Accumulation of in vivo fatigue microdam-age and its relation to biomechanical properties in age-ing human cortical bone. J Microsc 2001; 201:270-278.D.B. Burr: Bone quality18622. Mashiba T, Turner CH, Hirano T, Forwood MR,Johnston CC, Burr DB. The effects of suppressed boneturnover by bisphosphonates on microdamage accumu-lation and biomechanical properties in clinically rele-vant skeletal sites of beagles. Bone 2001; 28:524-531.23. Komatsubara S, Mori S, Mashiba T, Ito M, Li J, Kaji Y,Akiyama T, Miyamoto, K, Cao Y, Kawanishi J,Norimatsu H. Long-term treatment of incadronate dis-odium accumulates microdamage but improves the tra-becular bone microarchitecture in dog vertebra. J BoneMiner Res 2003; 18:512-520.24. Mashiba T, Hirano T, Turner CH, Forwood MR,Johnston CC, Burr DB. Suppressed bone turnover bybisphosphonates increases microdamage accumulationand reduces some biomechanical properties in dog rib.J Bone Miner Res 2000; 15:613-620.25. Jerome CP, Burr DB, van Bibber T, Hock JM,Brommage R. Treatment with human parathyroid hor-mone (1-34) for 18 months increases cancellous bonevolume and improves trabecular architecture inovariectomized cynomolgus monkeys (Macaca fascicu-laris). Bone 2001; 28:150-159.26. Hirano T, Burr DB, Turner CH, Sato M, Cain RL,Hock JM. Anabolic effects of human biosyntheticparathyroid hormone fragment (1-34), LY333334, onremodeling and mechanical properties of cortical bonein rabbits. J Bone Miner Res 1999; 14:536-545.27. Burr DB, Hirano T, Turner CH, Hotchkiss C, BrommageR, Hock JM. Intermittently administered human parathy-roid hormone (1-34) treatment increases intracorticalbone turnover and porosity without reducing bonestrength in the humerus of ovariectomized cynomolgusmonkeys. J Bone Miner Res 2001; 16:157-165.28. Zanchetta JR, Bogado CE, Ferretti JL, Wang O, WilsonMG, Sato M, Gaich GA, Dalsky GP, Myers SL.  Effectsof teriparatide (recombinant human parathyroid hor-mone (1-34)) on cortical bone in postmenopausal womenwith osteoporosis. 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Bone quality: Understanding what matters

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