February 2011

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Bone Quality & Osteoporotic Fracture

Mary L. Bouxsein, Ph.D.

 

Editor's Introduction

Strategies to reduce fracture risk must be based on a sound understanding of the cellular, molecular, and biomechanical mechanisms that underlie the increased risk of fractures with aging. Whereas low bone mineral density (BMD) is among the strongest risk factors for fracture, a number of clinical studies have demonstrated the limitations of BMD measurements in assessing fracture risk[1-5]and monitoring the response to therapy. These observations have brought renewed attention to the broader array of factors that influence fracture risk, including those that are directly related to skeletal fragility[6,7]as well as those related to skeletal loading.[8,9]

In this issue of Osteoporosis Clinical Updates, we will take a look at current research in the field of bone quality and discuss its implications for osteoporosis patient care.

 

Case Study: 65-Year-Old Woman on Bisphosphonate

This patient is a 65-year-old woman who started antiresorptive (bisphosphonate) therapy about 5 years ago after developing a vertebral fracture. Her baseline bone density T-scores were –2.3 at the spine and –1.8 at the hip. (This highlights a key finding that patients with BMD above the WHO threshold T-score of –2.5 can have osteoporosis, as evidenced by this patient’s history of vertebral fracture.) Follow-up bone density testing has shown no changes from baseline. Her family doctor is concerned that therapy is not working. The patient has been healthy and active. She has had no further fractures and has no current problems.

Should therapy be changed?

The decision to change therapy would depend on careful analysis of how the patient was taking the medication and probably a measurement of bone turnover (link), such as N-telopeptide crosslinks (NTX). If this were in the low range (below 30 for example) one might not change. On the other hand, if NTX is high, one might change medication or adjust the way in which the patient is taking it. It is important to note that the risk of fracture is reduced in patients, such as this one, who do not lose bone on antiresorptive therapy. This reduction in fracture risk despite little change in BMD is likely attributable to an increase in  bone strength due to a reduction in bone turnover leading to fewer resorption cavities, a maintenance of trabecular and cortical architecture, and increased mineralization of the bone matrix itself.

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What Do We Mean By Bone Strength?

The 2001 NIH Consensus Conference (link) defined osteoporosis as “a skeletal disorder characterized by compromised bone strength leading to an increased risk of fracture.”[10] This definition underscores the role of bone strength as the key to understanding fracture risk. The ability of a bone to resist fracture (or “whole bone strength”) depends on the amount of bone (i.e., mass), the spatial distribution of the bone mass (i.e., shape and microarchitecture), and the intrinsic properties of the materials that comprise the bone. Bone remodeling, specifically the balance between formation and resorption, is the biologic process that mediates changes in the traits that influence bone strength. Thus, diseases and drugs that impact bone remodeling will influence bone’s resistance to fracture.

In considering these determinants of bone strength, one must keep in mind several important concepts. First, unlike most engineering materials, bone is continually adapting to changes in its mechanical and hormonal environment, and is capable of self-renewal and repair. Thus, in response to increased mechanical loading, bone may adapt by altering its size, shape, and/or matrix properties. A second important concept concerns the hierarchical nature of the factors that influence whole bone strength. Thus, properties at the cellular, matrix, microarchitectural, and macroarchitectural levels may all impact bone mechanical properties. Importantly though, the various factors are interrelated. Therefore, one cannot expect that changes in a single property will be solely predictive of changes in bone mechanical behavior.

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Figure 1. Determinants of skeletal fragility that are used in clinical practice (shaded) or clinical research (solid line), along with those factors that currently cannot be measured non-invasively (dashed line). © ML Bouxsein 2003

Role of Bone Geometry in Bone Strength

The loads applied to the skeleton generally are a combination of compression or tension (outward-pulling) forces with bending or torsional (twisting) moments. The resistance to bending and torsional loading is particularly important, as the highest stresses in the appendicular skeleton are due to these loading modes. (The highest stresses on the vertebral skeleton are due to compression loading.)

The most efficient design for resisting bending and torsional loads involves distributing the bone material far from the neutral axis of bending or torsion (generally this axis is near the center of the bone). The distribution of mass around the neutral bending axis is quantitatively described by a geometric property called the area moment of inertia. Importantly, the area moment of inertia of a solid circular bar is proportional to its diameter to the fourth power. Thus, small increases in the external diameter of a long bone can markedly improve its  resistance to bending and torsional loading. Considerable evidence indicates that age-related declines in the material properties of bone tissue are accompanied by a redistribution of cortical and trabecular bone. Specifically, in the appendicular skeleton, these changes involve endosteal resorption within bone combined with periosteal apposition on bone’s exterior. This leads to an age-related increase in the diameter of long bones but a decrease in cortical thickness. This increase in outer diameter helps to maintain the resistance to bending and torsional loads.

For many years, it has been suggested that men undergo this pattern of favorable geometric adaptation to a greater extent than women, providing one possible explanation for lower fracture rates in elderly men than women. However, recent data from 3D-QCT challenge this paradigm, demonstrating that both men and women undergo favorable geometric changes with aging.

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Figure 2. Effect of periosteal apposition on long bone strength. © ML Bouxsein 2003

Role of Bone Microarchitecture in Bone Strength

Although bone density is among the strongest predictors of the mechanical behavior of trabecular bone, both empirical observations and theoretical analyses show that aspects of trabecular microarchitecture influence trabecular bone strength as well. Previously, assessment of trabecular microarchitecture was possible only by bone biopsy with two-dimensional histomorphometry. However, newer imaging modalities such as high-resolution microcomputed tomography and magnetic resonance imaging (MRI) allow for three-dimensional assessment of trabecular structure on excised bone specimens and in vivo.

Isolated trabeculae may fail by buckling, which describes the failure mode of a long slender column. In this case, the critical buckling load (or buckling strength) is proportional to the cross-sectional area of the column and to its elastic modulus (the measure of resistance to elastic deformation), and is inversely proportional to the square of unsupported length of the column. Therefore, loss of horizontal trabecular elements leads to a marked increase in the unsupported length of a trabecular, markedly decreasing its buckling strength. Inversely, preservation of one or more horizontal struts can profoundly influence trabecular bone buckling strength with very little change in bone mass. Another potential mechanism by which trabecular bone declines with increased bone resorption is the hypothesis that resorption cavities themselves serve as sites of local weakness where cracks in trabeculae may initiate.

Using an analytical model of vertebral trabecular bone, a 20% decline in bone mass was induced either by thinning the entire trabecula structure or by randomly introducing resorption cavities.[11] This lead to two important observations: First, in both cases the predicted decline in vertebral trabecular bone strength was larger (30% for trabecular thinning and 50% for introduction of resorption cavities) than the decline in bone mass. Second, the reduction in bone strength was greater when bone loss occurred by introduction of resorption cavities than by trabecular thinning. These observations confirm the deleterious impact of high bone resorption in the absence of increased bone formation on trabecular bone strength and provide a partial explanation for why small changes in bone mass due to therapy can have marked effects on vertebral fracture risk.

The importance of trabecular bone microarchitecture has since been supported by clinical studies showing altered trabecular microarchitecture in subjects with fragility fractures compared to age-matched controls with no fractures.[12-15] Studies have also shown altered trabecular microarchitecture in people with vertebral fracture[13-15] and have related the extent of microarchitectural deterioration to vertebral fracture severity. A recent study of individuals undergoing organ transplant showed that changes in trabecular architecture distinguished individuals with vertebral fracture, whereas BMD assessed by MRI did not.[14] Moreover, data from iliac crest biopsies obtained during clinical trials suggest that maintenance of trabecular architecture with bisphosphonate therapy[16,17] or improvement of trabecular architecture with teriparatide[18,19] may contribute to the antifracture efficacy of these agents. These clinical observations point to an important role of trabecular architecture in fragility fractures, particularly at skeletal sites rich in trabecular bone such as the spine.

DXA: Not Perfect, but Still the Gold Standard

Dual x-ray absorptiometry (DXA) uses the attenuation of x-rays through bone to measure bone mineral content at a skeletal site. This type of measurement is areal, providing a two-dimensional representation of bone. DXA does not yield a volumetric, or three-dimensional, picture of bone. However, bone strength is directly related to its three-dimensional properties: its microarchitecture and the number and strength of trabeculae (crossbeams inside cancellous bone). The thinner or fewer the trabeculae, the weaker the bone and the higher the risk for fracture. Because DXA does not measure volumetric characteristics of bone, it may not provide an accurate picture of bone health in all people. So how might clinicians compensate for DXA’s shortcomings? One option is to use DXA in conjunction with measurement of markers of bone turnover and risk factor assessment. In this scenario, an increase or no change in BMD and no incident fractures coupled with suppressed markers of bone turnover could be interpreted as a good response to therapy. On the other hand, BMD loss or fracture, while on stable dose drugs, could be interpreted as poor response to treatment and/or increased fracture risk, as could BMD loss coupled with increased markers of bone turnover.

Other technologies, such as quantitative ultrasound (QUS) and MRI, are being investigated for application in measuring bone mineral density and/or factors related to bone strength, bone quality, and fracture risk.

The bottom line is this: At present, DXA remains the most reliable and accurate method for assessing bone health and fracture risk.

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Role of Bone Matrix Properties in Bone Strength

In addition to macro- and microarchitecture, features of bone matrix itself influence bone mechanical properties. Matrix characteristics that affect bone mechanical properties include:

Mineralization. It is well established that the degree of matrix mineralization, or ash content, strongly influences bone mechanical properties. The stiffness and strength of bone are positively related to the degree of matrix mineralization. However, the ability of bone to absorb energy may either increase (if the bone is relatively undermineralized to begin with) or decrease (if the bone is already fully mineralized) with increasing mineral content.

Drug therapies that decrease bone turnover will eventually increase the degree of matrix mineralization by prolonging the period of secondary mineralization.[20,21] In contrast, agents that increase bone turnover may lead to a transient decrease in the degree of matrix mineralization as new remodeling units are initiated and new bone laid down. Thus, iliac crest biopsies from postmenopausal women treated with antiresorptive therapy (calcium + vitamin D, raloxifene, risedronate and alendronate) show an increase in the degree of mineralization that mirrors the suppression of bone turnover,[22-25] whereas iliac crest biopsies from men treated with teriparatide show a slight temporary decrease in the degree of  mineralization.[26] These effects on matrix mineralization will be reflected in BMD measurements and likely contribute to the anti-fracture efficacy of these agents.[27,28]

Collagen Characteristics. Bone is a composite material with two primary constituents, mineral and collagen. Mounting evidence indicates an important role for age- and disease-related changes in collagen content and structure.[29] The majority of evidence suggests that in normal bone, the mineral provides stiffness and strength, whereas collagen affords bone its ductility and ability to absorb energy before fracturing.[30] The extreme fragility seen in osteogenesis imperfecta underscores the potential for collagen abnormalities to influence bone strength. However, more subtle alterations in collagen, as noted by polymorphisms in the COL1A1 gene, have also been associated with fracture risk independent of BMD status.[31,32] Posttranslational modifications of collagen have also been shown to influence bone mechanical properties,[29] although their contribution to age-related skeletal fragility remains to be defined.

Microdamage. Throughout life, physiologic loading of the skeleton produces fatigue damage in bone. Although the optimal methods to quantify microdamage in bone are under debate, numerous studies show that the accumulation of damage weakens bone.33 Moreover, it appears that microdamage initiates activation of remodeling, presumably to repair the damaged tissue.[34]

This intriguing observation suggests that one important role of bone remodeling is to repair fatigue-induced microdamage in bone. There is ongoing debate regarding the optimal level of bone turnover to prevent architectural deterioration while preserving the ability of bone to maintain calcium homeostasis, respond to altered mechanical loading, and to repair microdamage.[34-36] The role of microdamage in age-related fragility fractures has yet to be established.

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Figure 3. Bone strength paradigm: the balance between bone formation and resorption influences factors that determine whole bone strength (bone size, morphology, and material properties). © ML Bouxsein

Summary

In summary, fractures occur when the loads applied to bone exceed its strength. Therefore strategies to reduce fractures should consider interventions aimed at reducing loads applied to bone as well as to maintaining or increasing bone strength. Second, whole bone strength is determined by the amount of bone (i.e., size or mass), the spatial distribution of the bone mass (i.e., shape or architecture), and the intrinsic properties of the materials that comprise the bone. Areal bone mineral density measurements by DXA reflect some of the components of bone strength, including bone mass, degree of mineralization, and to some extent bone size.

BMD measurements, however, do not reflect other components of bone strength, including the three dimensional distribution of bone mass, trabecular and cortical microarchitecture, and the intrinsic properties of the bone matrix. Although DXA has limitations, it is currently the most useful tool to identify those at risk for fracture. Alternative methods for non-invasive assessment of bone geometry, microarchitecture, and strength are currently being investigated as potential adjuncts to BMD by DXA. Such methods hold promise for more sensitive and specific assessment of fracture risk. Matrix mineralization, collagen characteristics, and microdamage may also be important contributors to skeletal fragility. Unfortunately, because these factors cannot currently be assessed non-invasively, investigations are somewhat limited at this point.

Diseases and therapeutic interventions influence BMD as well as other components of bone strength. As a result, assessment of fracture risk and treatment efficacy in individual patients should ideally take into account the full range of factors that influence bone strength. As more is learned about the impact of various bone characteristics on stiffness and strength, new prevention and treatment modalities can be developed to reduce fracture incidence. For example, alendronate increases bone strength by increasing the mean degree of mineralization of bone tissue in osteoporotic women.

 

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  2. Schuit S, van der Klift M, Weel A, et. al. Fracture incidence and association with bone mineral density in elderly men and women: the Rotterdam Study. Bone. 2004;34(1):195-202. Erratum in: Bone. 2006;38(4):603.
  3. Schuit SC, van der Klift M, Weel AE, et. al. Fracture incidence and association with bone mineral density in elderly men and women: the Rotterdam Study. Bone. 2004;34(1):195-202.
  4. Sornay-Rendu E, Munoz F, Garnero P, et. al. Identification of osteopenic women at high risk of fracture: the OFELY study. J Bone Miner Res. 2005;20(10):1813-9.
  5. Wainwright SA, Marshall LM, Ensrud KE, et. al. Hip fracture in women without osteoporosis. J Clin Endocrinol Metab. 2005;90(5):2787-93.
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  13. Legrand E, Chappard D, Pascaretti C, et. al. Trabecular bone microarchitecture, bone mineral density, and vertebral fractures in male osteoporosis. J Bone Miner Res. 2000;15(1):13-9.
  14. Link TM, Lotter A, Beyer F, et al. Changes in calcaneal trabecular bone structure after heart  transplantation: an MR imaging study. Radiology. 2000;217(3):855-62.
  15. Aaron JE, Shore PA, Shore RC, et al. Trabecular architecture in women and men of similar bone mass with and without vertebral fracture: II. Three-dimensional histology. Bone. 2000;27(2):277-82.
  16. Dufresne TE, Chmielewski PA, Manhart MD, et al. Risedronate preserves bone architecture in early postmenopausal women in 1 year as measured by three dimensional microcomputed tomography. Calcif Tissue Int. 2003;73(5):423-32.
  17. Borah B, Dufresne TE, Chmielewski PA, et al. Risedronate preserves bone architecture in postmenopausal women with osteoporosis as measured by three-dimensional microcomputed tomography. Bone. 2004;34(4):736-46.
  18. Dempster DW, Cosman F, Kurland ES,et al. Effects of daily treatment with parathyroid hormone on bone microarchitecture and turnover in patients with osteoporosis: a paired biopsy study. J Bone Miner Res. 2001;16(10):1846-53.
  19. Jiang Y, Zhao JJ, Mitlak BH, et al. Recombinant human parathyroid hormone (1-34) [teriparatide] improves both cortical and cancellous bone structure. J Bone Miner Res. 2003;18(11):1932-41.
  20. Meunier PJ, Arlot M, Chavassieux P, Yates AJ. The effects of alendronate on bone turnover and bone quality. Int J Clin Pract Suppl. 1999;101:14-7.
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  22. Boivin GY, Chavassieux PM, Santora Bone. 2000; 27(5):687-94.
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  24. Boivin G, Lips P, Ott SM, et.al. Contribution of raloxifene and calcium and vitamin D3  supplementation to the increase of the degree of mineralization of bone in postmenopausal women. J Clin Endocrinol Metab. 2003;88(9):4199-205.
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  27. Delmas PD. How does antiresorptive therapy decrease the risk of fracture in women with osteoporosis? Bone. 2000;27 (1):1-3.
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  29. Burr DB. The contribution of the organic matrix to bone's material properties. Bone. 2002;31(1):8-11.
  30. Currey J. Role of collagen and other organics in the mechanical properties of bone. Osteoporos Int. 2003;14 Suppl 5:29-36.
  31. Mann V, Hobson EE, Li B, et. al. A COL1A1 Sp1 binding site polymorphism predisposes to osteoporotic fracture by affecting bone density and quality. J Clin Invest. 2001;107(7):899-907.
  32. Efstathiadou Z, Tsatsoulis A, Ioannidis JP. Association of collagen Ialpha 1 Sp1 polymorphism with the risk of prevalent fractures: a meta-analysis. J Bone Miner Res. 2001;16(9):1586-92.
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  34. Schaffler M. Role of bone turnover in microdamage. Osteoporos Int. 2003;14 Suppl 5:73-80.
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  36. Burr DB. Targeted and nontargeted remodeling. Bone. 2002;30(1):2-4.

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