The relative contributions of non-enzymatic glycation and cortical porosity on the fracture toughness of aging bone

The risk of fracture increases with age due to the decline of bone mass and bone quality. One of the age-related changes in bone quality occurs through the formation and accumulation of advanced glycation end-products (AGEs) due to non-enzymatic glycation (NEG). However as a number of other changes including increased porosity occur with age and affect bone fragility, the relative contribution of AGEs on the fracture resistance of aging bone is unknown. Using a high-resolution nonlinear finite element model that incorporate cohesive elements and micro-computed tomography-based 3d meshes, we investigated the contribution of AGEs and cortical porosity on the fracture toughness of human bone. The results show that NEG caused a 52% reduction in propagation fracture toughness (R-curve slope). The combined effects of porosity and AGEs resulted in an 88% reduction in propagation toughness. These findings are consistent with previous experimental results. The model captured the age-related changes in the R-curve toughening by incorporating bone quantity and bone quality changes, and these simulations demonstrate the ability of the cohesive models to account for the irreversible dynamic crack growth processes affected by the changes in post-yield material behavior. By decoupling the matrix-level effects due to NEG and intracortical porosity, we are able to directly determine the effects of NEG on fracture toughness. The outcome of this study suggests that it may be important to include the age-related changes in the material level properties by using finite element analysis towards the prediction of fracture risk.     

Cohesive finite element modeling of age-related toughness loss in human cortical bone

Although the age-related loss of bone quality has been implicated in bone fragility, a mechanistic understanding of the relationship is necessary for developing diagnostic and treatment modalities in the elderly population at risk of fracture. In this study, a finite element based cohesive zone model is developed and applied to human cortical bone in order to capture the experimentally shown rising crack growth behavior and age-related loss of bone toughness. The cohesive model developed here is based on a traction–crack opening displacement relationship representing the fracture processes in the vicinity of a propagating crack. The traction–displacement curve, defining the cohesive model, is composed of ascending and descending branches that incorporate material softening and nonlinearity. The results obtained indicate that, in contrast to initiation toughness, the finite element simulations of crack growth in compact tension (CT) specimens successfully capture the rising R-curve (propagation toughness) behavior and the age-related loss of bone toughness. In close correspondence with the experimentally observed decrease of 14–15% per decade, the finite element simulation results show a decrease of 13% in the R-curve slope per decade. The success of the simulations is a result of the ability of cohesive models to capture and predict the parameters related to bone fracture by representing the physical processes occurring in the vicinity of a propagating crack. These results illustrate that fracture mechanisms in the process zone control bone toughness and any modification to these would cause age-related toughness loss.     

Anisotropy of age-related toughness loss in human cortical bone: a finite element study

A mechanistic understanding of the role of bone quality on fracture processes is essential for determining the underlying causes of age-related changes in the mechanical response of the human bone. In this study, a previously developed cohesive finite element model was used to investigate the effects of age-related changes and the orientation of crack growth on the toughening behavior of human cortical bone. The change in the anisotropy of toughening mechanisms with age was also studied. Finite element method (FEM) simulations showed that the initiation toughness decreased by 3% and 8%/decade for transverse and longitudinal crack growth, respectively. In contrast, fracture resistance curve slope for transverse and longitudinal crack growth decreased by 2% and 3%/decade, respectively. Initiation fracture toughness values were higher for the transverse than for the longitudinal for a given age. On the other hand, propagation fracture toughness values were higher for longitudinal than for transverse crack growth for a given age. With respect to age, the toughness ratio for crack initiation decreased by 6%/decade, but that for propagation showed almost no change (less than 1%). In light of these findings, an analytical model evaluating the crack arresting feature of cement lines, is proposed to explain the factors that determine crack penetration into osteons or its deflection by cement lines.     

Fatigue microcracks that initiate fracture are located near elevated intracortical porosity but not elevated mineralization

In vivo microcracks in cortical bone are typically observed within more highly mineralized interstitial tissue, but postmortem investigations are inherently limited to cracks that did not lead to fracture which may be misleading with respect to understanding fracture mechanisms. We hypothesized that the one fatigue microcrack which initiates fracture is located spatially adjacent to elevated intracortical porosity but not elevated mineralization. Therefore, the spatial correlation between intracortical porosity, elevated mineralization, and fatigue microdamage was investigated by combining, for the first time, sequential, nondestructive, three-dimensional micro-computed tomography (micro-CT) measurements of each in cortical bone specimens subjected to compressive fatigue loading followed by a tensile overload to fracture. Fatigue loading resulted in significant microdamage accumulation and compromised mechanical properties upon tensile overload compared to control specimens. The microdamage that initiated fracture upon tensile overload was able to be identified in all fatigue-loaded specimens using contrast-enhanced micro-CT and registered images. Two-point (or pair) correlation functions revealed a spatial correlation between microdamage at the fracture initiation site and intracortical porosity, but not highly mineralized tissue, confirming the hypothesis. This difference was unique to the fracture initiation site. Intracortical porosity and highly mineralized tissue exhibited a significantly lower and higher probability, respectively, of being located spatially adjacent to all sites of microdamage compared to the fracture initiation site. Therefore, the results of this study suggest that human cortical bone is tolerant of most microcracks, which are generally compartmentalized within the more highly mineralized interstitial tissue, but a single microcrack of sufficient size located in spatial proximity to intracortical porosity can compromise fracture resistance.     

Age-related properties at the microscale affect crack propagation in cortical bone

The increased risk for fracture with age is associated not only with reduced bone mass but also with impaired bone quality. At the microscale, bone quality is related to porosity, microstructural organization, accumulated microdamage and intrinsic material properties. However, the link between these characteristics and fracture behavior is still missing. Bone tissue has a complex structure and as age-related compositional and structural changes occur at all hierarchical length scales it is difficult to experimentally identify and discriminate the effect of each mechanism. The aim of this study was therefore to use computational models to analyze how microscale characteristics in terms of porosity, intrinsic toughness properties and microstructural organization affect the mechanical behavior of cortical bone. Tensile tests were simulated using realistic microstructural geometries based on microscopy images of human cortical bone. Crack propagation was modelled using the extended finite element method where cement lines surrounding osteons were modelled with an interface damage law to capture crack deflections along osteon boundaries. Both increased porosity and impaired material integrity resulted in straighter crack paths with cracks penetrating osteons, similar to what is seen experimentally for old cortical bone. However, only the latter predicted a more brittle failure behavior. Furthermore, the local porosity influenced the crack path more than the macroscopic porosity. In conclusion, age-related changes in cortical bone affect the crack path and the mechanical response. However, increased porosity alone was not driving damage in old bone, but instead impaired tissue integrity was required to capture brittle failure in aging bone.     

Material heterogeneity,microstructure, and microcracks demonstrate differential influence on crack initiation and propagation in cortical bone

The recent studies have shown that long-term bisphosphonate use may result in a number of mechanical alterations in the bone tissue including a reduction in compositional heterogeneity and an increase in microcrack density. There are limited number of experimental and computational studies in the literature that evaluated how these modifications affect crack initiation and propagation in cortical bone. Therefore, in this study, the entire crack growth process including initiation and propagation was simulated at the microscale by using the cohesive extended finite element method. Models with homogeneous and heterogeneous material properties (represented at the microscale capturing the variability in material property values and their distribution) as well as different microcrack density and microstructure were compared. The results showed that initiation fracture resistance was higher in models with homogeneous material properties compared to heterogeneous ones, whereas an opposite trend was observed in propagation fracture resistance. The increase in material heterogeneity level up to 10 different material property sets increased the propagation fracture resistance beyond which a decrease was observed while still remaining higher than the homogeneous material distribution. The simulation results also showed that the total osteonal area influenced crack propagation and the local osteonal area near the initial crack affected the crack initiation behavior. In addition, the initiation fracture resistance was higher in models representing bisphosphonate treated bone (low material heterogeneity, high microcrack density) compared to untreated bone models (high material heterogeneity, low microcrack density), whereas an opposite trend was observed at later stages of crack growth. In summary, the results demonstrated that tissue material heterogeneity, microstructure, and microcrack density influenced crack initiation and propagation differently. The findings also elucidate how possible modifications in material heterogeneity and microcrack density due to bisphosphonate treatment may influence the initiation and propagation fracture resistance of cortical bone.     

Experimental validation of a microcracking-based toughening mechanism for cortical bone

It has been proposed that cortical bone derives its toughness by forming microcracks during the process of crack propagation (J. Biomech. 30 (1997) 763; J. Biomech. 33 (2000) 1169). The purpose of this study was to experimentally validate the previously proposed microcrack-based toughening mechanism in cortical bone. Crack initiation and propagation tests were conducted on cortical bone compact tension specimens obtained from the antlers of red deer. For these tests, the main fracture crack was either propagated to a predetermined crack length or was stopped immediately after initiating from the notch. The microcracks produced in both groups of specimens were counted in the same surface area of interest around and below the notch, and crack growth resistance and crack propagation velocity were analyzed. There were more microcracks in the surface area of interest in the propagation than in initiation specimens showing that the formation of microcracks continued after the initiation of a fracture crack. Crack growth resistance increased with crack extension, and crack propagation velocity vs. crack extension curves demonstrated the characteristic jump increase and decrease pattern associated with the formation of microcracks. The scanning electron micrographs of crack initiation and propagation displayed the formation of a frontal process zone and a wake, respectively. These results support the microcrack-based toughening mechanism in cortical bone. Bone toughness is, therefore, determined by its ability to form microcracks during fracture.     

Rising crack-growth-resistance behavior in cortical bone: implications for toughness measurements

Fracture mechanics studies have characterized bone's resistance to fracture in terms of critical stress intensity factor and critical strain energy release rate measured at the onset of a fracture crack. This approach, although useful, provide a limited insight into fracture behavior of bone because, unlike classical brittle materials, bone is a microcracking solid that derives its resistance to fracture during the process of crack propagation from microfracture mechanisms occurring behind the advancing crack front. To address this shortfall, a crack propagation-based approach to measure bone toughness is described here and compared with crack initiation approach. Post hoc analyses of data from previously tested bovine and antler cortical bone compact specimens demonstrates that, in contrast to crack initiation approach, the crack propagation approach successfully identifies the superior toughness properties of red deer's antler cortical bone. Propagation-based slope of crack growth resistance curve is, therefore, a more useful parameter to evaluate cortical bone fracture toughness.     

Prediction of Colles’ fracture load in human radius using cohesive finite element modeling

Osteoporotic and age-related fractures are a significant public health problem. One of the most common osteoporotic fracture sites in the aging population is distal radius. There is evidence in the literature that distal radius fractures (Colles’ fracture) are an indicative of increased risk of future spine and hip fractures. In this study, a nonlinear fracture mechanics-based finite element method is applied to human radius to assess its fracture load as a function of cortical bone geometry and material properties. Seven three-dimensional finite element models of radius were created and the fracture loads were determined by using cohesive finite element modeling which explicitly represents the crack and the fracture process zone behavior. The fracture loads found in the simulations (731–6793 N) were in the range of experimental values reported in the literature. The fracture loads predicted by the simulations decreased by 4–5% per decade based only on material level changes and by 6–20% per decade when geometrical changes were also included. Cortical polar moment of inertia at 15% distal radius showed the highest correlation to fracture load (r²=0.97). These findings demonstrate the strength of fracture mechanics-based finite element modeling and show that combining geometrical and material properties provides a better assessment of fracture risk in human radius.     

Equine cortical bone exhibits rising R-curve fracture mechanics

Previous studies of the fracture properties of cortical bone have suggested that the fracture toughness increases with crack length, which is indicative of rising R-curve behavior. Based on this indirect evidence and the similarity of bone to ceramic matrix composites, we hypothesized that bone would exhibit rising R-curve behavior in the transverse orientation and that the characteristics of the R-curves would be regionally dependent within the cortex due to variations in bone microstructure and toughening mechanisms. To test these hypotheses, we conducted R-curve experiments on specimens from equine third metacarpal bones using standard fracture mechanics testing methods. Compact type specimens from the dorsal and lateral regions in the middle of the diaphysis were oriented for crack propagation transverse to the longitudinal axis of the bone.The test results demonstrate that equine cortical bone exhibits rising R-curve behavior during transverse crack propagation as hypothesized. Statistical analyses of the crack growth initiation toughness, K0, the peak toughness, Kpeak, and the crack extension at peak toughness, deltaa, revealed significant regional differences in these characteristics. Specifically, the lateral cortex displayed higher crack growth initiation and peak toughnesses. The dorsal cortex exhibited greater crack extension at the peak of crack growth resistance. Scanning electron microscopy revealed osteon pullout on fracture surfaces from the dorsal cortex and but not in the lateral cortex. Taken together, the significant differences in R-curves and the SEM fractography indicate that the fracture mechanisms acting in equine cortical bone are regionally dependent.     

Contribution, development and morphology of microcracking in cortical bone during crack propagation

A fracture mechanics study of cortical bone is presented to investigate the contribution, development morphology of microcracking in cortical bone during crack propagation. Post-hoc analyses of microcrack orientation, crack propagation velocity and fracture surface roughness were conducted on previously tested human and bovine bone compact tension specimens. It was found that, consistent with its higher toughness, bovine bone formed significantly more longitudinal, transverse and inclined microcracks than human bone. However, in human bone more of the microcracks that formed were longitudinal than transverse or inclined, a feature that would optimise bone's toughness. Crack propagation velocity in human and bovine bone displayed the same characteristic pattern with crack extension, where an increase in velocity is followed by a consequent decrease and vice versa. On the basis of this pattern, a model or crack propagation has been proposed. It provides a detailed account of mocrocrack formation and contribution towards the propagation of a fracture crack. Analyses of fracture surfaces indicated that, consistent with its higher toughness, bovine bone displays a rougher surface than human bone but they both have the same basic fractured element, i.e. a mineralised collagen fibril.     

Atypical subtrochanteric femoral shaft fractures: role for mechanics and bone quality

Bisphosphonates are highly effective agents for reducing osteoporotic fractures in women and men, decreasing fracture incidence at the hip and spine up to 50%. In a small subset of patients, however, these agents have recently been associated with ''atypical femoral fractures'' (AFFs) in the subtrochanteric region or the diaphysis. These fractures have several atypical characteristics, including occurrence with minimal trauma; younger age than typical osteoporotic fractures; occurrence at cortical, rather than cancellous sites; early radiographic appearance similar to that of a stress fracture; transverse fracture pattern rather than the familiar spiral or transverse-oblique morphologies; initiation on the lateral cortex; and high risk of fracture on the contralateral side, at the same location as the initial fracture. Fracture is a mechanical phenomenon that occurs when the loads applied to a structure such as a long bone exceed its load-bearing capacity, either due to a single catastrophic overload (traumatic failure) or as a result of accumulated damage and crack propagation at sub-failure loads (fatigue failure). The association of AFFs with no or minimal trauma suggests a fatigue-based mechanism that depends on cortical cross-sectional geometry and tissue material properties. In the case of AFFs, bisphosphonate treatment may alter cortical tissue properties, as these agents are known to alter bone remodeling. This review discusses the use of bisphosphonates, their effects on bone remodeling, mechanics and tissue composition, their significance as an effective therapy for osteoporosis, and why these agents may increase fracture risk in a small population of patients.     

The dependence of the elastic properties of osteoporotic cancellous bone on volume fraction and fabric

Osteoporosis is a progressive systemic skeletal condition characterized by low bone mass and microarchitectural deterioration, with a consequent increase in susceptibility to fracture. Hence, osteoporosis would be best diagnosed by in vivo measurements of bone strength. As this is not clinically feasible, our goal is to estimate bone strength through the assessment of elastic properties, which are highly correlated to strength. Previously established relations between morphological parameters (volume fraction and fabric) and elastic constants could be applied to estimate cancellous bone stiffness in vivo. However, these relations were determined for normal cancellous bone. Cancellous bone from osteoporotic patients may require different relations. In this study we set out to answer two questions. First, can the elastic properties of osteoporotic cancellous bone be estimated from morphological parameters? Second, do the relations between morphological parameters and elastic constants, determined for normal bone, apply to osteoporotic bone as well? To answer these questions we used cancellous bone cubes from femoral heads of patients with (n=26) and without (n=32) hip fractures. The elastic properties of the cubes were determined using micro-finite element analysis, assuming equal tissue moduli for all specimens. The morphological parameters were determined using microcomputed tomography. Our results showed that, for equal tissue properties, the elastic properties of cancellous bone from fracture patients could indeed be estimated from morphological parameters. The morphology-based relations used to estimate the elastic properties of cancellous bone are not different for women with or without fractures.     

Brief communication: Reevaluating osteoporosis in human ribs: the role of intracortical porosity

Osteoporosis is a major health concern in modern society and is continually being evaluated in past populations by quantifying bone loss. Cortical area measures are commonly used in anthropological analyses to assess bone loss in the ribs, but these values are typically based on endosteal expansion and do not account for intracortical bone loss. The objective of this study is to evaluate the effectiveness of using absolute cortical area, compared to traditional cortical area measures to describe global bone loss in elderly ribs. Transverse sections were prepared from sixth ribs of ten elderly subjects, and bone area measurements were made from 100× magnification composites of each rib for calculation of cortical area (Ct.Ar) and percent cortical area (% C/T). In addition, all areas of intracortical porosity were measured and percent porosity area (% Po.Ar) calculated. Absolute cortical area (Ct.Ar(A)) was calculated by subtracting porosity area from cortical area, and a percent absolute cortical area (% C(A)/T) calculated. ANOVA results reveal significant interindividual variation in percent porosity area (% Po.Ar). Percent cortical area and percent absolute cortical area values were compared and results show a mean difference of 4.08% exists across all subjects, with a range of 1.19-11.73%. This suggests that intracortical porosity is variable and does play a role in age-associated bone loss in the rib. All future investigations of osteoporosis should account for intracortical porosity in bone loss.     

Fracture toughness and fatigue crack propagation rate of short fiber reinforced epoxy composites for analogue cortical bone

Third-generation mechanical analogue bone models and synthetic analogue cortical bone materials manufactured by Pacific Research Laboratories, Inc. (PRL) are popular tools for use in mechanical testing of various orthopedic implants and biomaterials. A major issue with these models is that the current third-generation epoxy-short fiberglass based composite used as the cortical bone substitute is prone to crack formation and failure in fatigue or repeated quasistatic loading of the model. The purpose of the present study was to compare the tensile and fracture mechanics properties of the current baseline (established PRL "third-generation" E-glass-fiber-epoxy) composite analogue for cortical bone to a new composite material formulation proposed for use as an enhanced fourth-generation cortical bone analogue material. Standard tensile, plane strain fracture toughness, and fatigue crack propagation rate tests were performed on both the third- and fourth-generation composite material formulations using standard ASTM test techniques. Injection molding techniques were used to create random fiber orientation in all test specimens. Standard dog-bone style tensile specimens were tested to obtain ultimate tensile strength and stiffness. Compact tension fracture toughness specimens were utilized to determine plane strain fracture toughness values. Reduced thickness compact tension specimens were also used to determine fatigue crack propagation rate behavior for the two material groups. Literature values for the same parameters for human cortical bone were compared to results from the third- and fourth-generation cortical analogue bone materials. Tensile properties of the fourth-generation material were closer to that of average human cortical bone than the third-generation material. Fracture toughness was significantly increased by 48% in the fourth-generation composite as compared to the third-generation analogue bone. The threshold stress intensity to propagate the crack was much higher for the fourth-generation material than for the third-generation composite. Even at the higher stress intensity threshold, the fatigue crack propagation rate was significantly decreased in the fourth-generation composite compared to the third-generation composite. These results indicate that the bone analogue models made from the fourth-generation analogue cortical bone material may exhibit better performance in fracture and longer fatigue lives than similar models made of third-generation analogue cortical bone material. Further fatigue testing of the new composite material in clinically relevant use of bone models is still required for verification of these results. Biomechanical test models using the superior fourth-generation cortical analogue material are currently in development.     

Influence of cortical canal architecture on lacunocanalicular pore pressure and fluid flow

Bone is a dynamic tissue that undergoes structural modification in response to its mechanical environment, but how bone cells sense and respond to loading conditions remains incompletely understood. Current theories focus on strain-induced fluid flow for the primary means of mechanotransduction. To examine the influence of age-related cortical rarefaction on lacunocanalicular fluid characteristics, coupled fluid flow and mechanical computational models of bone specimens representing young, mid-age and aged samples were derived artificially from the same original micro-computed tomography image data. Simulated mechanical loading was applied to the bone models to induce pressure-driven interstitial fluid flow. Results demonstrated a decrease in pore pressure and fluid velocity magnitudes with age as a result of increased cortical porosity. Mean canal separation, as opposed to canal size, was implicated as a primary factor affecting age-related fluid dynamics. Future investigations through refinement of the model may implicate fluid stasis or inadequate nutrient transport experienced by osteocytes as a key factor in the initiation of cortical remodelling events.     

Influence of cortical canal architecture on lacunocanalicular pore pressure and fluid flow

Bone is a dynamic tissue that undergoes structural modification in response to its mechanical environment, but how bone cells sense and respond to loading conditions remains incompletely understood. Current theories focus on strain-induced fluid flow for the primary means of mechanotransduction. To examine the influence of age-related cortical rarefaction on lacunocanalicular fluid characteristics, coupled fluid flow and mechanical computational models of bone specimens representing young, mid-age and aged samples were derived artificially from the same original micro-computed tomography image data. Simulated mechanical loading was applied to the bone models to induce pressure-driven interstitial fluid flow. Results demonstrated a decrease in pore pressure and fluid velocity magnitudes with age as a result of increased cortical porosity. Mean canal separation, as opposed to canal size, was implicated as a primary factor affecting age-related fluid dynamics. Future investigations through refinement of the model may implicate fluid stasis or inadequate nutrient transport experienced by osteocytes as a key factor in the initiation of cortical remodelling events.     

Fracture toughness of manatee rib and bovine femur using a chevron-notched beam test

Bone is an anisotropic material with a hierarchical structure consisting of organic matrix, minerals and water. Fracture toughness (K(C)) has been shown to be a good index to assess the mechanical performance of bone. A chevron-notched (CN) beam test, a standard fracture mechanics test successfully applied to many other materials, was used to determine the transverse-direction fracture toughness in manatee rib and bovine femur cortical bone. Although human and bovine bone has been well studied, there is virtually no information on the toughness of manatee rib bone. As a biological material, manatee rib is interesting for study in that it is a highly mineralized bone. Three major advantages of the CN specimen test are: (1) it is easier to reach plane strain condition; (2) there is no fatigue-precracking needed; and (3) it is relatively easy to produce stable crack propagation before catastrophic fracture. The fracture toughness values of manatee rib and bovine femur were measured to be 4.5 +/- 0.5 MPa m(1/2) and 5.8 +/- 0.5 MPa m(1/2), respectively. Based on the microstructures shown in SEM images, two features that contributed to the greater fracture toughness of bovine femur were identified as greater osteon density and lesser porosity.     

The tensile strength of black bear (Ursus americanus) cortical bone is not compromised with aging despite annual periods of hibernation

Black bears (Ursus americanus) may not develop disuse osteoporosis during long periods of disuse (i.e. hibernation) because they may be able to maintain bone formation. Previously, we found that cortical bone bending strength was not compromised with age in black bears' tibias, despite annual periods of disuse. Here we showed that cortical bone tensile strength (166-198MPa) also does not decrease with age (2-14 years) in black bear tibias. There were also no significant age-related changes in cortical bone porosity in black bear tibias. It is likely that the ability of black bears to maintain bone formation during hibernation keeps bone porosity low (2.3-8.6%) with aging, notwithstanding annual periods of disuse. This low porosity likely preserves ultimate stress with aging. Female bears give birth and nurse during hibernation; however, we found no significant differences between male and female tensile material properties, mineral content, or porosity. Our findings support the idea that black bears, which hibernate 5-7 months annually, have evolved biological mechanisms to mitigate the adverse effects of disuse on bone porosity and strength.     

Bone material properties and mineral matrix contributions to fracture risk or age in women and men

The strength of bone is related to its mass and geometry, but also to the physical properties of the tissue itself. Bone tissue is composed primarily of collagen and mineral, each of which changes with age, and each of which can be affected by pharmaceutical treatments designed to prevent or reverse the loss of bone. With age, there is a decrease in collagen content, which is associated with an increased mean tissue mineralization, but there is no difference in cross-link levels compared to younger adult bone. In osteoporosis, however, there is a decrease in the reducible collagen cross-links without an alteration in collagen concentration; this would tend to increase bone fragility. In older people, the mean tissue age (MTA) increases, causing the tissue to become more highly mineralized. The increased bone turnover following menopause may reduce global MTA, and would reduce overall tissue mineralization. Bone strength and toughness are positively correlated to bone mineral content, but when bone tissue becomes too highly mineralized, it tends to become brittle. This reduces its toughness, and makes it more prone to fracture from repeated loads and accumulated microcracking. Most approved pharmaceutical treatments for osteoporosis suppress bone turnover, increasing MTA and mineralization of the tissue. This might have either or both of two effects. It could increase bone volume from refilling of the remodeling space, reducing the risk for fracture. Alternatively, the increased MTA could increase the propensity to develop microcracks, and reduce the toughness of bone, making it more likely to fracture. There may also be changes in the morphology of the mineral crystals that could affect the homogeneity of the tissue and impact mechanical properties. These changes might have large positive or negative effects on fracture incidence, and could contribute to the paradox that both large and small increases in density have about the same effect on fracture risk. Bone mineral density measured by DXA does not discriminate between density differences caused by volume changes, and those caused by changes in mineralization. As such, it does not entirely reflect material property changes in aging or osteoporotic bone that contribute to bone's risk for fracture.