THIS ISSUE of the Journal includes an article by Beck et al. entitled “Structural Trends in the Aging Femoral Neck and Proximal Shaft: Analysis of the NHANES III DCS Data.”(1) The authors show a change in the geometry of femurs with age, which appears to maintain the mechanical integrity of the femoral neck. Furthermore, the authors suggest that a loss in bone mass in the proximal femur may not be indicative of an increase in fracture risk, because of this geometric compensatory factor. These results, as well as others in the literature, encourage us to “step back” and review what we understand about fractures of the aging skeleton and what factors seem to be associated most with an increase in fracture risk.

Popular conventional wisdom suggests that the most dominant factor related to skeletal fragility due to aging or osteoporosis is reduced bone mass. However, on further questioning, many experts would caution that measures of bone mass or density alone cannot reliably predict fracture risk in patients. Given this controversy and the fact that hundreds of studies have been conducted to examine the factors associated with osteoporotic fractures, it seems appropriate to revisit current perspectives. The following statements were excerpted directly from the literature and illustrate the continuing disagreements about fracture risk factors.

  • The recent interim report from the World Health Organization (WHO) Task Force for Osteoporosis, although briefly mentioning microstructure, recommends using only bone mineral density (BMD) for determining fracture risk, and their research recommendations focus on methods to assess and alter BMD and bone turnover.(2)

  • “Mechanically, osteoporosis is rather simple: there is not enough bone tissue, and therefore the bone structure is weak and fractures occur. The complexity is in the bone remodeling biology that leads to diminished bone structure.”(3)

  • “ … the predictive ability of bone mass was … better than that of serum cholesterol for cardiovascular disease.”(4)

  • “ …the osteoporosis model proposed by the World Health Organization (WHO), which assumes that fragility depends only on a single mean value of bone mineral density (BMD) for a patient, is over-simplistic and requires upgrading to include indices representing the distribution of bone mineral.”(5)

  • “Risk factors not related to bone mass contribute significantly to hip fracture risk.”(6)

  • “Recent studies have shown that factors related to fall biomechanics may play as important a role in the etiology of hip fracture as age-related bone loss.”(7)

  • “ … there is no doubt that deterioration of trabecular architecture is a contributor factor to the bone fragility in osteoporosis … ”(8)

  • “Measurements of bone mineral density can predict fracture risk but cannot identify individuals who will have a fracture. We do not recommend a programme of screening menopausal women for osteoporosis by measuring bone density.”(4)

How has the community arrived at such opposing viewpoints about a single condition? Is it a single condition? Osteoporosis and skeletal fragility in general are extremely complex, cross many hierarchical levels, and may be impacted by many physiological variables. From a biomechanical perspective, there are a variety of factors to consider:

  • (1)
    The loss of bone mass or BMD is an extremely important feature related to osteoporotic fractures. BMD explains a significant portion of the risk of osteoporotic fractures (9–11) and correlates significantly with bone strength. (12–16) The risk of fracture increases by 50-150% with each SD decrease in bone mass as measured by dual-energy X-ray absorptiometry (DXA).(4) In fact, the performance of BMD in predicting fracture is at least as good as that of blood pressure in predicting stroke and better than the use of serum cholesterol in predicting cardiovascular disease.(4) However, BMD by itself does not determine if an individual will sustain a fracture.(4,17) There is substantial overlap between the normal and osteoporotic populations.(18) The relationship between BMD and fracture risk is less consistent for vertebral fractures than for hip fractures.(14)
  • (2)
    The geometry of the bones and the distribution of bone mass play an important role in determining bone strength and appear to differ in ways that parallel the risk of osteoporotic fracture.(19,20) The hip axis length has been found to be correlated with the risk of hip fracture,(9,21) and may be an explanation for racial differences in hip fracture(22) and the secular trends for increasing hip fracture since the 1950s.(23) The accompanying article and others(24) have shown aging trends in the geometry of the aging femur. Sandor,(5) Cody,(25) and McCubbrey(26) have shown that the distribution patterns of bone mass, not just its quantity, are important in predicting whole bone strength. Likewise, the cross-sectional area of vertebrae is important in determining their strength. (27–31) Although cortical thickness has been shown to decrease with age,(17) geometric changes, particularly periosteal expansion, (32–35) may more than compensate for this loss by increasing the structural resistance to load.
  • (3)
    The force applied to each bone must be greater than its strength in order for a fracture to occur. Hayes et al.(36) have clearly described that there are two factors that determine whether a bone fractures, the applied load and the fracture load. They incorporate these into a fraction, applied load/fracture load, which describes the risk of fracture. The force applied to the bone is influenced by padding (artificial or body fat), the distribution of mass (including any carried weight), and the direction of the fall.(7,37) These are particularly important relative to hip fractures. Loading rate also has been shown to influence fracture strength,(38) by modifying the strength of the bone.
  • (4)
    Trabecular bone microarchitecture, separate from density or bone volume fraction, is another important determinant of bone strength(8) and appears to differ between osteoporotic and normal individuals and with age.(19, 32, 33) Several studies measuring microarchitecture in two and three dimensions have correlated measures of density and architectural organization with trabecular bone stiffness and strength. (39–41) In addition, changes in architectural features with age and differences between males and females have been documented.(42,43) In a recent, more direct study, trabecular bone from hip fracture patients was found to be more anisotropic than a matched cohort of female subjects who died without fracture.(44)
  • (5)
    Microdamage and/or increased remodeling density may play roles in weakening bone tissue, predisposing to fracture. (45–47)
  • (6)
    Changes in the bone tissue properties may be associated with osteoporotic fracture. Shifts in the mineral content of the tissue will influence its stiffness(48) and strength, and have been related to bone fragility.(17, 49, 50) Recent data suggest that there may be greater variability in local mineral content (even without differences in average mineral content) in hip fracture patients compared with controls.(51)
  • (7)
    Genetics, body size, and environmental factors may influence fracture risk through expression of many of the factors described previously. For example, it has been reported that up to 80-85% of BMD is determined by genetics.(52,53)
  • (8)
    Currently approved therapies are able, at best, to increase bone density by up to 10%,(54) although the risk of fracture decreases by a much larger extent.(14)
  • (9)
    Recent experiments investigating biomechanics at the level of the cell have found no evidence of factors at this scale that appear to contribute to increased fracture risk. It has been suggested that degradation in the ability of osteocytes to sense strain could be responsible for the loss of bone associated with osteoporosis. This change in the ability of the cell to sense strain could be caused by changes in the geometry of the osteocyte and its lacuna, changes within the cell, changes in the fluid flow surrounding the cell, etc. It has been shown that there are no differences in the shape of the osteocyte lacunae in osteoporotic individuals compared with those without fracture.(51) Other experimental measurements of potential biomechanical changes at this level are technically difficult and to our knowledge have not been attempted to date.
  • (10)
    Achieving effective and efficient experimental designs in the study of osteoporosis is extremely difficult. First, it is difficult to define and then find a true control. Should the control be a young adult, age-matched without a fracture, or age-matched and BMD-matched without a fracture? Is tissue from a cadaver without fracture “normal”? Would a fracture have occurred within a few days had the individual lived longer? Second, it is often difficult to obtain experimental samples for in vitro research. Fractured vertebrae are not removed after fracture, and hip fractures are most often fixed without the need for arthroplasty. Tissue, which is obtained after fracture, therefore is not representative of all osteoporotic fractures. Prospective clinical trials are difficult and expensive because of the long follow-up times and the large number of individuals required to provide statistically significant and meaningful data. A further complication arises with the variations across different fracture sites. These variations have been hypothesized to be caused by two types of osteoporosis(55) and also may be a function of further site-specific factors.
  • (11)
    The etiologies of osteoporosis, whether biomechanical, molecular, cellular, environmental, or otherwise, are still relatively unknown.

What is the “take-home” message? What does this say about the best methods of screening for fracture risk and the future of biomechanics research in osteoporosis?

For robust fracture risk screening, it appears that we can do better than BMD alone with current knowledge and technology. BMD by itself can predict fractures with a detection rate of 30-50% and a false positive rate of about 15%, using a cut-off of 1 SD below the mean BMD and actual hip fracture and BMD data.(4,56) Using a 0.5 SD difference in BMD between individuals who will and will not develop fracture, Law et al.(56) show a 6% detection rate and 2% false positive rate with a cut-off of 2 SD below the mean. Looking at the numbers from a different perspective, 85-95% of white women who fracture have BMD measurements less than 2.5 SD below normal.(57) By combining BMD and some “geometric” factors, either by looking at the size and shape of a bone or further describing the BMD by location within the bone, we can likely identify more accurately those who have or will sustain a fracture. For example, Sandor et al.(5) claim an accuracy of 90% by including the distribution of BMD. It is inappropriate to expect to achieve perfect identification of individuals who will fracture, because there is a varying amount of risk that is attributable to the chance of sufficient loading to fracture the bone (i.e., a significant fall). Although technology appears to be available to improve on BMD alone, clinical trials have not been completed that will enable its acceptance and general use. There is a need for prospective clinical trials to verify previous results in large populations and determine what geometry/location information provides the best fracture prediction. However, once it is indicated, it should require little work to incorporate into current screening protocols.

There are several characteristics of bone that have a potential to further improve our ability to identify those at risk of fracture. Tissue material properties may provide additional information about fracture risk, but it is unlikely that it will become routine in screening for osteoporosis because of its invasive nature. Genetic analysis may, in the future, provide additional methods of screening, and with currently identified candidate genes(53,58) and the recent announcement that the human genome has been mapped, progress may begin to accelerate. In addition, noninvasive means of measuring trabecular bone architecture may soon provide an additional level of insight for screening, although the resolution is currently insufficient. There are likely to be additional attributes that are discovered from ongoing basic science research that correlate with fracture risk. However, it is unclear whether these methods provide improved risk estimates beyond that from BMD and geometry/location.

Biomechanics teaches us that the risk of fracture is dependent on the geometry of the bone, its architecture (at all scales of hierarchy), its material properties and the distribution of material properties, and the character of the imposed load (magnitude, rate, and direction). Genetics can influence the geometry, material properties, architecture, or the propensity for an individual to alter these features in response to the environment or underlying physiological conditions. The environment provides the cues that may trigger an adaptation response over time or the acute conditions that are sufficient to cause a fracture. Noninvasive imaging techniques can provide measures of geometry and a correlate to macroscopic material properties (BMD). Until we have effective methods for measuring microarchitecture and genetic or other biomarkers for individual response dynamics, we should strive to use both geometry and BMD to predict susceptibility to fracture in patients.


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  • 1
    Beck TJ, Looker AC, Ruff CB, Sievanen H, Wahner HW 2000 Structural trends in the aging femoral neck and proximal shaft: Analysis of the Third National Health and Nutrition Examination Survey dual-energy X-ray absorptiometry data. J Bone Miner Res Int 15:22972304.
  • 2
    Genant HK, Cooper C, Poor G, Reid I, Ehrlich G, Kanis J, Nordin BEC, Barrett-Connor E, Black D, Bonjour J-P, Dawson-Hughes B, Delmas PD, Dequeker J, Eis SR, Gennari C, Johnell O, Johnston CC, Jr, Lau EMC, Liberman UA, Lindsay R, Martin TJ, Masri B, Mautalen CA, Meunier PJ, Miller PD, Mithal A, Morii H, Papapoulos S, Woolf A, Yu W, Khaltaev N 1999 Interim report and recommendations of the World Health Organization task-force for osteoporosis. Osteoporos Int 10:259264.
  • 3
    Martin RB, Burr DB, Sharkey NA 1998 Skeletal Tissue Mechanics, Springer-Verlag, New York, NY, USA, p. 276.
  • 4
    Marshall D, Johnell O, Wedel H 1996 Meta-analysis of how well measures of bone mineral density predict occurrence of osteoporotic fractures. BMJ 312:12541259.
  • 5
    Sandor T, Felsenberg D, Brown E 1999 Comments on the hypotheses underlying fracture risk assessment in osteoporosis as proposed by the World Health Organization. Calcif Tissue Int 64:267270.
  • 6
    Allolio B 1999 Risk factors for hip fracture not related to bone mass and their therapeutic implications. Osteoporos Int 2(Suppl):S9S16.
  • 7
    Pinilla TP, Boardman KC, Bouxsein ML, Myers ER, Hayes WC 1996 Impact direction from a fall influences the failure load of the proximal femur as much as age-related bone loss. Calcif Tissue Int 58:231235.
  • 8
    Dempster DW 2000 The contribution of trabecular architecture to cancellous bone quality. J Bone Miner Res 15:2023.
  • 9
    Faulkner KG, Cummings SR, Black D, Palermo L, Glüer C-C, Genant HK 1993 Simple measurement of femoral geometry predicts hip fracture: The study of osteoporotic fractures. J Bone Miner Res 8:12111217.
  • 10
    Melton LJ III, Atkinson EJ, O'Connor MK, O'Fallon WM, Riggs BL 2000 Determinants of bone loss from the femoral neck in women of different ages. J Bone Miner Res 15:2431.
  • 11
    Melton LJ III, Atkinson EJ, O'Fallon WM, Wahner HW, Riggs BL 1993 Long-term fracture prediction by bone mineral assessed at different skeletal sites. J Bone Miner Res 8:12271233.
  • 12
    Mosekilde L, Bentzen SM, Ortoft G, Jorgensen J 1989 The predictive value of quantitative computed tomography for vertebral body compressive strength and ash density. Bone 10:465470.
  • 13
    Veenland JF, Link TM, Konermann W, Meier N, Grashuis JL, Gelsema ES 1997 Unraveling the role of structure and density in determining vertebral bone strength. Calcif Tissue Int 61:474479.
  • 14
    Faulkner KG 2000 Bone matters: Are density increases necessary to reduce fracture risk? J Bone Miner Res 15:183187.
  • 15
    Hansson T, Roos B, Nachemson A 1980 The bone mineral content and ultimate compressive strength of lumbar vertebrae. Spine 5:4655.
  • 16
    Carter DR, Hayes WC 1977 The compressive behavior of bone as a two-phase porous structure. Am J Bone Joint Surg 59A:954962.
  • 17
    Boyce TM, Bloebaum RD 1993 Cortical aging differences and fracture implications for the human femoral neck. Bone 14:769778.
  • 18
    Cummings SR 1985 Are patients with hip fractures more osteoporotic? Review of the evidence. Am J Med 78:487494.
  • 19
    Glüer C-C, Cummings SR, Pressman A, Li J, Glüer K, Faulkner KG, Grampp S, Genant HK, The Study of Osteoporotic Fractures Research Group 1994 Prediction of hip fractures from pelvic radiographs: The study of osteoporotic fractures. J Bone Miner Res 9:671677.
  • 20
    Yoshikawa T, Turner CH, Peacock M, Slemenda CW, Weaver CM, Teegarden D, Markwardt P, Burr DB 1994 Geometric structure of the femoral neck measured using dual-energy x-ray absorptiometry. J Bone Miner Res 9:10531064.
  • 21
    Duboeuf F, Hans D, Schott AM, Kotzki PO, Favier F, Marcelli C, Meunier PJ, Delmas PD 1997 Different morphometric and densitometric parameters predict cervical and trochanteric hip fracture: The EPIDOS study. J Bone Miner Res 12:18951902.
  • 22
    Nakamura T, Turner CH, Yoshikawa T, Slemenda CW, Peacock M, Burr DB, Minzuno Y, Orimo H, Ouchi Y, Johnston CC Jr 1994 Do variations in hip geometry explain differences in hip fracture risk between Japanese and white Americans? J Bone Miner Res 9:10711076.
  • 23
    Reid IR, Chin K, Evans MC, Jones JG 1994 Relationship between increase in length of hip axis in older women between 1950s and 1990s and increase in age specific rates of hip fracture. BMJ 309:508509.
  • 24
    Beck TJ, Ruff CB, Bissessur K 1993 Age-related changes in female femoral neck geometry: Implications for bone strength. Calcif Tissue Int 53(Suppl 1):S41S46.
  • 25
    Cody DD, Goldstein SA, Flynn MJ, Brown EB 1991 Correlations between vertebral regional bone mineral density (rBMD) and whole bone fracture load. Spine 16:146154.
  • 26
    McCubbrey DA, Cody DD, Peterson EL, Kuhn JL, Flynn MJ, Goldstein SA 1995 Static and fatigue failure properties of thoracic and lumbar vertebral bodies and their relation to regional density. J Biomech 28:891899.
  • 27
    Brinckmann P, Biggemann M, Hilweg D 1989 Prediction of the compressive strength of human lumbar vertebrae. Spine 14:606610.
  • 28
    Eriksson SAV, Isberg BO, Lindgren JU 1989 Prediction of vertebral strength by dual photon absorptiometry and quantitative computed tomography. Calcif Tissue Int 44:243250.
  • 29
    Vesterby A, Mosekilde Li, Gundersen HJG, Melsen F, Mosekilde Le, Holem K, Sorensen S 1991 Biologically meaningful determinants of the in vitro strength of lumbar vertebrae. Bone 12:219224.
  • 30
    Gilsanz V, Loro ML, Roe TF, Sayre J, Gilsanz R, Schulz EE 1995 Vertebral size in elderly women with osteoporosis. J Clin Invest 95:23322337.
  • 31
    Lotz JC, Hayes WC 1990 The use of quantitative computed tomography to estimate risk of fracture of the hip from falls. Am J Bone Joint Surg 72A:689700.
  • 32
    Mosekilde L 2000 Age-related changes in bone mass, structure, and strength—effects of loading. Z Rheumatol 59(Suppl 1):19.
  • 33
    Mosekilde L 1989 Sex differences in age-related loss of vertebral trabecular bone mass and structure—biomechanical consequences. Bone 10:425432.
  • 34
    Mosekilde Li, Mosekilde Le 1986 Normal vertebral body size and compressive strength: Relations to age and to vertebral and iliac trabecular bone compressive strength. Bone 7:207212.
  • 35
    Ruff CB, Hayes WC 1988 Sex differences in age-related remodeling of the femur and tibia. J Orthop Res 6:886896.
  • 36
    Hayes WC, Myers ER, Robinovitch SN, Van Den Kroonenberg A, Courtney AC, McMahon TA 1996 Etiology and prevention of age-related hip fractures. Bone 18:77. S-86S
  • 37
    Greenspan SL, Myers ER, Maitland LA, Resnick NM, Hayes WC 1994 Fall severity and bone mineral density as risk factors for hip fracture in ambulatory elderly. JAMA 27:128133.
  • 38
    Courtney AC, Wachtel EF, Myers ER, Hayes WC 1994 Effects of loading rate on strength of the proximal femur. Calcif Tissue Int 55:5258.
  • 39
    Goulet RW, Goldstein SA, Ciarelli MJ, Kuhn JL, Brown MB Feldkamp LA 1994 The relationship between the structural and orthogonal compressive properties of trabecular bone. J Biomech 27:375389.
  • 40
    Goldstein SA, Goulet R, McCubbrey D 1993 Measurement and significance of three-dimensional architecture to the mechanical integrity of trabecular bone. Calcif Tissue Int 53(Suppl 1):S127S133.
  • 41
    Lang SM, Moyle DD, Berg CEW, Detorie N, Gilpin AT, Pappas NJ Jr, Reynolds JC, Tkacik M, Waldron RL 1988 Correlation of mechanical properties of vertebral trabecular bone with equivalent mineral density as measured by computed tomography. Am J Bone Joint Surg 70A:15311538.
  • 42
    Aaron JE, Makins NB, Sagreiya K 1987 The microanatomy of trabecular bone loss in normal aging men and women. Clin Orthop Rel Res 215:260270.
  • 43
    Birkenhäger-Frenkel DH, Courpron P, Hüpscher EA, Clermonts E, Coutinho MF, Schmitz PIM, Meunier PJ 1988 Age-related changes in cancellous bone structure: A two-dimensional study in the transiliac and iliac crest biopsy sites. Bone Miner 4:197216..
  • 44
    Ciarelli TE, Fyhrie DP, Schaffler MB, Goldstein SA 2000 Variations in three-dimensional cancellous bone architecture of the proximal femur in female hip fractures and in controls. J Bone Miner Res 15:3240.
  • 45
    Burr DB, Forwood MR, Fyhrie DP, Martin RB, Schaffler MB, Turner CH 1997 Bone microdamage and skeletal fragility in osteoporotic and stress fractures. J Bone Miner Res 12:615.
  • 46
    Crofts RD, Boyce TM, Bloebaum RD 1994 Aging changes in osteon mineralization in the human femoral neck. Bone 15:147152.
  • 47
    Jordan GR, Loveridge N, Bell KL, Power J, Rushton N, Reeve J 2000 Spatial clustering of remodeling osteons in the femoral neck cortex: A cause of weakness in hip fracture? Bone 26:305313.
  • 48
    Currey JD 1988 The effect of porosity and mineral content on the Young's modulus of elasticity of compact bone. J Biomech 21:131139.
  • 49
    Grynpas MD, Holmyard D 1988 Changes in quality of bone mineral on aging and in disease. Scanniny Microsc 2:10451054.
  • 50
    Grynpas M 1993 Age and disease-related changes in the mineral of bone. Calcif Tissue Int 53(Suppl 1):S57S64.
  • 51
    McCreadie BR 2000 Geometry of osteocyte lacunae and deformation of osteocytes in aging females. Ph.D. thesis, University of Michigan, Ann Arbor, MI, U.S.A.
  • 52
    Nguyen TV, Eisman JA 2000 Genetics of fracture: Challenges and opportunities. J Bone Miner Res 15:12531256.
  • 53
    Ralston SH 1999 The genetics of osteoporosis. Bone 25:8586.
  • 54
    Baylink DJ, Strong DD, Mohan S 1999 The diagnosis and treatment of osteoporosis: Future prospects. Mol Med Today 5:133140.
  • 55
    Riggs BL, Melton J III 1983 Evidence for two distinct syndromes of involutional osteoporosis. Am J Med 75:899901.
  • 56
    Law MR, Wald NJ, Meade TW 1991 Regular review: Strategies for prevention of osteoporosis and hip fracture. BMJ 303:453459.
  • 57
    Miller PD, Bonnick SL, Rosen CJ, Altman RD, Avioli LV, Dequeker J, Felsenberg D, Genant HK, Gennari C, Harper KD, Hodsman AB, Kleerekoper M, Mautalen CA, McClung MR, Meunier PJ, Nelson DA, Peel NF, Raisz LG, Recker RR, Utian WH, Wasnich RD, Watts NB 1996 Clinical utility of bone mass measurements in adults: Consensus of an international panel. Semin Arthritis Rheum 25:361372.
  • 58
    Zmuda JM, Cauley JA, Ferrell RE 1999 Recent progress in understanding the genetic susceptibility to osteoporosis. Genet Epidemiol 16:356367.