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This minute lattice work, or the cancelli which constituted the interior structure of bone, have still reference to the forces acting on the bone.

—Sir Charles Bell, 1827

INTRODUCTION

  1. Top of page
  2. INTRODUCTION
  3. THE ROLE OF MICROARCHITECTURE IN THE TREATMENT OF OSTEOPOROSIS
  4. QUANTITATIVE ASSESSMENT OF TRABECULAR CONNECTIVITY IN THREE DIMENSIONS
  5. Acknowledgements
  6. REFERENCES

For many years now the Consensus Development Conference definition of osteoporosis has attributed the cause of the enhanced bone fragility to both “low bone mass and microarchitectural deterioration of bone tissue.”(1) Although the changes in trabecular architecture that occur in women after menopause have been recognized as a major contributory factor to the higher fracture incidence in this population, the role of trabecular architecture in men with osteoporosis has received relatively little attention. In this issue of the Journal, Legrand et al. provide convincing evidence that compromised trabecular architecture is an important, and independent, causal factor in the pathogenesis of vertebral fractures.(2) The authors studied 108 men with osteoporosis as defined by the World Health Organization criterion of a bone mineral density (BMD) T score of ≤ −2.5. Subjects were divided into two groups: those with at least one vertebral deformity in their spinal radiographs and those without such deformities (controls). These deformities were defined as a >20% reduction in anterior, middle, or posterior vertebral height, as determined independently by two observers. Transiliac crest biopsy specimens from the same subjects were analyzed for a number of measured and derived variables related to bone mass and structure. After adjusting for age, body mass index and BMD, the authors found that the interconnectivity index (ICI), free end–to–free end strut length (a measure of trabecular discontinuity), and trabecular spacing were all higher in the fracture cases versus the controls. Note that the variable that they refer to as the ICI measures the level of connectivity of the marrow cavities, not that of the trabecular lattice. An increase in ICI, therefore, implies a reduction in trabecular connectivity. Conversely, the fracture cases displayed lower values for trabecular number and node-to-node strut length, an index of trabecular connectivity. Furthermore, in a logistic regression analysis, only the architectural variables were significant predictors of the presence of a single vertebral fracture.

Several factors should be borne in mind when reading the paper by Legrand et al. First, fractures and microarchitecture were assessed at different skeletal sites. While there are significant correlations between structural variables measured at the iliac crest and in the lumbar vertebrae, the correlation coefficients are only ∼0.7 at best.(3) Second, there are functional differences between the two sites; the vertebrae are weight-bearing, whereas the iliac crest is not. Third, as a consequence of the functional difference, the structure of cancellous bone differs between the two sites.(4) In normal subjects, cancellous bone in the iliac crest is anisotropic, whereas in the spine the trabeculae are oriented in vertical and horizontal planes. If microarchitecture and fractures could both have been assessed in the spine, or even better in the same vertebra, perhaps the relationship between the two would have been even stronger in the study by Legrand et al.(2)

THE ROLE OF MICROARCHITECTURE IN THE TREATMENT OF OSTEOPOROSIS

  1. Top of page
  2. INTRODUCTION
  3. THE ROLE OF MICROARCHITECTURE IN THE TREATMENT OF OSTEOPOROSIS
  4. QUANTITATIVE ASSESSMENT OF TRABECULAR CONNECTIVITY IN THREE DIMENSIONS
  5. Acknowledgements
  6. REFERENCES

Although there is no doubt that deterioration of trabecular architecture is a contributory factor to the bone fragility in osteoporosis, is it necessary to repair the architectural defects to prevent fractures? The good news is that, although it would be desirable, it appears to be not necessary. It seems unlikely that we will be able to develop treatment regimens that will be capable of reconnecting the disconnected trabecula (arrow) in the sample of osteoporotic bone shown in Figure 1B. Restoration of the normal microarchitecture, shown in Figure 1A, is even less likely. However, it is important to note that the remaining rods and single trabecular plate in Figure 1B are still connected to each other. By preserving these rods and, preferably, thickening them, we may be able to maintain sufficient mechanical strength to reduce the risk of future fractures. Figure 2 illustrates, in an animal model, that it is not necessary to restore trabecular connectivity to restore mechanical strength. Here a potent anabolic agent, parathyroid hormone (PTH), was used to restore mechanical strength simply by thickening the remaining trabeculae with no significant improvement in trabecular connectivity. Furthermore, recent clinical trials of antiremodeling agents, such as calcium plus vitamin D, calcitonin, and raloxifene, indicate that significant protection against fractures may be achieved with smaller than expected improvements in bone mass.(4–6) Reducing activation frequency will have a modest effect on both bone mass and trabecular thickness as a result of a reduction in the remodeling space. However, probably a more important factor in this regard is the reduction in the number of resorption cavities that are present at any particular time. In a trabecular network that is already compromised by a loss of bone, resorption cavities act as stress risers, increasing the risk of mechanical failure.(7) If it is in a crucial position in the lattice, preservation of even a single trabecula by reducing the number of stress risers could theoretically protect against fracture.

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Figure FIG. 1. Scanning electron micrographs of (A) normal and (B) osteoporotic cancellous bone from human iliac crest. Reproduced from J Bone Miner Res 1986;1:15–21 with permission of the American Society for Bone and Mineral Research.(20)

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Figure FIG. 2. The structural basis of restoration of bone strength may differ from that of its loss. (A) Compressive (mechanical) strength, (B) trabecular thickness, and (C) trabecular connectivity of cancellous bone from sham-operated (Sham), ovariectomized (Ovx), and ovariectomized rats treated with parathyroid hormone (Ovx+PTH). Six-month-old rats were either sham-operated or ovariectomized and were left untreated for 6 weeks. Ovx rats were then treated for 8 weeks with subcutaneous injections of vehicle or 20 μg · kg−1 · day−1 of rat PTH(1–34). Trabecular thickness and connectivity were measured in the proximal tibial metaphysis; compressive strength of cancellous bone was measured in the distal femoral metaphysis by using an indentation technique(20) (XW Meng, Liang XG, Birchman R, Wu DD, Dempster DW, Lindsay R, Shen V, unpublished observations, 1996).

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In an analogy suggested to me by Dr. Marc Drezner, failure of individual trabeculae can be likened to the felling of a tree (Figure 3). The lumberjack does not need to saw completely through the trunk to bring down the tree. He simply makes a notch (i.e., a stress riser) on one side, or two notches on opposite sides of the trunk, and gravity does the rest. Remodeling sites, particularly in the resorptive phase of the cycle, are equivalent to the notches in the trunk. Reducing or eliminating the notches (or the resorption cavities) allows the tree (or the trabecula) to withstand the forces upon it. This analogy seems particulary apt when we recall that the vertical trabeculae in the human vertebra becoming increasingly unsupported and prone to buckling with age as a result of the preferential loss of the horizontal trabeculae.(7,8) The unsupported trabecula is like a tree whose root structure has been damaged in a storm and, as a result, is unstable and requires even less work (fewer, smaller notches) by the lumberjack to bring it down. Bear in mind also that the mass of wood removed in the notches is negligible compared with the mass of the tree, and so too is the mass of the resorption cavity compared with that of the trabecula. Therefore, reducing remodeling frequency can have a positive effect on bone strength that is disproportionate to its effect on mass.

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Figure FIG. 3. The tree on the left was stable, but two notches on opposite sides of the trunk were sufficient to bring it down. The tree on the right was already unstable because it had been partially uprooted; one notch on the right side was sufficient to fell it.

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QUANTITATIVE ASSESSMENT OF TRABECULAR CONNECTIVITY IN THREE DIMENSIONS

  1. Top of page
  2. INTRODUCTION
  3. THE ROLE OF MICROARCHITECTURE IN THE TREATMENT OF OSTEOPOROSIS
  4. QUANTITATIVE ASSESSMENT OF TRABECULAR CONNECTIVITY IN THREE DIMENSIONS
  5. Acknowledgements
  6. REFERENCES

Legrand et al.(2) assessed trabecular architecture in two dimensions, but cancellous bone is, of course, a three-dimensional structure, and its mechanical properties will depend on the manner in which the bone is distributed in three-dimensional space. Significant progress is being made in techniques that allow quantitative assessment of trabecular architecture in three dimensions using high-resolution, computer-generated reconstructions of cancellous bone. For example, by applying microcomputed tomography (μCT) to biopsy samples in vitro, cancellous bone can be imaged with a spatial resolution as low as 2 μm.(9) These three-dimensional reconstructions can then be used to calculate structural variables such as cancellous bone volume, trabecular number, spacing, and thickness, and also the degree of anisotropy. Furthermore, application of microstructural finite-element analysis to the data allows calculation of mechanical properties such as Young's moduli, shear moduli, and Poisson's ratios.(10) This approach also permits quantification of the tissue stresses and strains in trabecular bone under normal and abnormal loading conditions.(11) μCT analysis at a resolution level of 14 μm allows good quantification of trabecular microarchitecture, and at the 2 μm level it allows visualization of irregularities on the surface of individual trabeculae and of remodeling sites.(9) Thus, with reference to the discussion above, it may soon be feasible to study the effects of a drug on the three-dimensional distribution of stress risers on individual trabeculae.

High-resolution computed tomography can also be used to assess cancellous bone architecture in vivo. Although this has obvious advantages over assessment of biopsy samples and does permit assessment of the number of trabeculae, the spatial resolution (∼150 μm) is still not sufficiently good to allow accurate measurement of trabecular thickness. However, Laib and Ruegsegger(12) have recently calibrated an in vivo, three-dimensional, peripheral, quantitative computed tomography (3D pQCT) scanner with “gold-standard” μCT measurements on the same bones samples. Structural variables such as trabecular number and mean trabecular thickness and separation, obtained with the 3D pQCT scanner, correlated with the μCT data, with r2 values in the range of 0.81–0.96. Application of the calibration equations obtained should lead to improvements in the in vivo assessment of trabecular microarchitecture. Two other imaging techniques that are currently being explored for in vivo assessment of trabecular architecture are magnetic resonance microscopy(13,14) and synchrotron computed tomography.(9,15) A number of studies have examined the relationship between three-dimensional indices of trabecular microarchitecture, measured either in vitro or in vivo, and biomechanical properties. In general, the addition of trabecular structural parameters to bone mass measurements improves the prediction of biomechanical properties as well as the ability to differentiate between patients with and without fractures.(10,16–19)

In conclusion, it is clear that further studies are needed to define the relationship between trabecular architecture and fracture risk. Continued development of techniques that permit the quantitative assessment of the microarchitecture of bone will surely allow a better understanding not only of the pathogenesis of osteoporosis but also of how certain therapeutic agents prevent fractures without effecting a substantial increase in bone mass.

REFERENCES

  1. Top of page
  2. INTRODUCTION
  3. THE ROLE OF MICROARCHITECTURE IN THE TREATMENT OF OSTEOPOROSIS
  4. QUANTITATIVE ASSESSMENT OF TRABECULAR CONNECTIVITY IN THREE DIMENSIONS
  5. Acknowledgements
  6. REFERENCES
  • 1
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  • 2
    Legrand E, Chappard D, Pascaretti C, Duquenne M, Krebs S, Rohmer V, Basle M-F, Audran M 2000 Trabecular bone microarchitecture, bone mineral density, and vertebral fractures in men with osteoporosis. J Bone Miner Res 15:646650 13–19.
  • 3
    Mellish RWE, Ferguson-Pell MW, Cochran GVB, Lindsay R, Dempster DW 1991 A new manual method for assessing two dimensional cancellous bone structure: comparison between iliac crest and lumbar vertebra. J Bone Miner Res 6:689696.
  • 4
    Dawson-Hughes B, Harris S, Krall EA, Dallal GE 1997 Effect of calcium and vitamin D supplementation on bone density in men and women 65 years of age or older. N Engl J Med 337:670676.
  • 5
    Silverman SL, Chesnut C, Andriano K, Genant H, Gimona A, Maricic M, Stock J, Baylink D, PROOF Study Group 1998 Salmon calcitonin nasal spray (NS-CT) reduces risk of vertebral fracture(s) (VF) in established osteoporosis and has continuous efficacy with prolonged treatment; Accrued 5 year worldwide data of the PROOF study. J Bone Miner 23(Suppl):S174 (abstract).
  • 6
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    Parfitt AM 1991 Use of bisphosphonates in the prevention of bone loss and fractures. Am J Med 91(Suppl 5B):42S46S.
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  • 11
    van Rietbergen B, Muller R, Ulrich D, Ruegsegger P, Huiskes R 1999 Tissue stresses and strain in trabeculae of a canine proximal femur can be quantified from computer reconstructions. J Biomech 32:443451.
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    Laib A, Ruegsegger P 1999 Calibration of trabecular bone structure measurements of in vivo three-dimensional peripheral quantitative computed tomography with 28-μm-resolution microcomputed tomography. Bone 24:3539.
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    Majumdar S 1998 A review of magnetic resonance (MR) imaging of trabecular bone micro-architecture: contribution to the prediction of biomechanical properties and fracture prevalence. Technol Health Care 6:321327.
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    Kinney JH, Lane NE, Haupt DL 1995 In vivo, three-dimensional microscopy of trabecular bone. J Bone Miner Res 10:264270.
  • 16
    Link TM, Majumdar S, Lin JC, Newitt D, Augat P, Ouyang X, Mathur A, Genant HK 1998 A comparative study of trabecular bone properties in the spine and femur using high resolution MRI and CT. J Bone Miner Res 13:122132.
  • 17
    Majumdar S, Kothari M, Augat P, Newitt DC, Link TM, Lin JC, Lang T, Lu Y, Genant HK 1998 High resolution magnetic resonance imaging: Three-dimensional trabecular bone architecture and biomechanical properties. Bone 22:445454.
  • 18
    Jiang Y, Zhao J, Augat P, Ouyang X, Lu Y, Majumdar S, Genant HK 1998 Trabecular bone mineral and calculated structure of human bone specimens scanned by peripheral quantitative computed tomography: Relation to biomechanical properties. J Bone Miner Res 13:17831790.
  • 19
    Haidekker MA, Andresen R, Werner HJ 1999 Relationship between structural parameters, bone mineral density and fracture load in lumbar vertebrae, based on high-resolution computed tomography, quantitative computed tomography and compression tests. Osteoporos Int 9:433440.
  • 20
    Dempster DW, Shane ES, Horbert W, Lindsay R 1986 A simple method for correlative light and scanning electron microscopy of human iliac crest bone biopsies: qualitative observations in normal and osteoporotic subjects. J Bone Miner Res 1:1521.
  • 21
    Meng XW, Liang XG, Birchman R, Wu DD, Dempster DW, Lindsay R, Shen V 1996 Temporal expression of the anabolic action of PTH in cancellous bone of ovariectomized rats. J Bone Miner Res 11:421429.