Bone Strength: The Whole Is Greater Than the Sum of Its Parts K. Shawn Davison,* Kerry Siminoski,† J.D. Adachi,‡ David A. Hanley,§ David Goltzman,储 Anthony B. Hodsman,¶ Robert Josse,** Stephanie Kaiser,†† Wojciech P. Olszynski,‡‡ Alexandra Papaioannou,§§ Louis-George Ste-Marie,储储 David L. Kendler,¶¶ Alan Tenenhouse,*** and Jacques P. Brown†††

Objective: To summarize the current knowledge regarding the various determinants of bone strength. Methods: Relevant English-language articles acquired from Medline from 1966 up to January 2005 were reviewed. Searches included the keywords bone AND 1 of the following: strength, remodeling, microcrack, structur*, mineralization, collagen, organic, crystallinity, osteocyte, porosity, diameter, anisotropy, stress risers, or connectivity. Abstracts from applicable conference proceedings were also reviewed for pertinent information. Results: Bone strength is determined from both its material and its structural properties. Material properties such as its degree of mineralization, crystallinity, collagen characteristics, and osteocyte viability have substantial impacts on bone strength. Structural properties such as the diameter and thickness of the cortices, the porosity of the cortical shell, the connectivity and anisotropy of the trabecular network, the thickness of trabeculae, and the presence of trabecular stress risers and microcracks impact bone strength in diverse manners. Remodeling activity either directly or indirectly impacts all of these processes. Conclusions: Bone strength is dependent on numerous, interrelated factors. Remodeling activity has a direct impact on almost all of the components of bone strength and requires further investigation as to its impact on these factors in isolation and in unison. © 2006 Elsevier Inc. All rights reserved. Semin Arthritis Rheum 36:22-31 Keywords: bone, strength, mineralization, architecture, porosity, remodeling, anisotropy, osteocyte, collagen, crystallinity, connectivity, microcracks, stress riser

*Clinical Research Scientist, Department of Medicine, Laval University, Sainte Foy, Quebec, Canada. †Associate Professor of Radiology and Diagnostic Imaging and Internal Medicine, Department of Radiology and Diagnostic Imaging and Division of Endocrinology and Metabolism, Department of Internal Medicine, University of Alberta, Edmonton, Alberta, Canada. ‡Professor, Department of Medicine, Director, Hamilton Arthritis Centre, St. Joseph’s Healthcare–McMaster University, Hamilton, Ontario, Canada. §Department of Medicine, University of Calgary, Calgary, Alberta, Canada. 储Department of Medicine, McGill University, Montreal, Quebec, Canada. ¶Professor, Department of Medicine University of Western Ontario, Director, London Regional Osteoporosis Program, St. Joseph’s Health Centre, London, Ontario, Canada. **Associate Physician-in-Chief, St. Michael’s Hospital, Professor of Medicine, University of Toronto, Toronto, Ontario, Canada. ††Associate Professor of Medicine, Division of Endocrinology and Metabolism, Dalhousie University, Halifax, Nova Scotia, Canada. ‡‡Clinical Professor of Medicine, University of Saskatchewan, Director, Saskatoon Osteoporosis Centre, Saskatoon, Saskatchewan, Canada. § §Associate Professor Department of Medicine, McMaster University, and Hamilton Health Sciences, Hamilton, Ontario, Canada. 储储Associate Professor of Medicine, Faculty of Medicine, Université, de Montréal, Endocrinologist, Centre de Recherche du CHUM, Hôpital Saint-Luc, Montreal, Quebec, Canada. ¶¶Assistant Professor, Department of Medicine (Endocrinology), University of British Columbia, Vancouver, British Columbia, Canada. ***Professor Emeritus, Department of Medicine, McGill University, Montreal, Quebec, Canada. †††A Clinical Professor of Medicine, Laval University, CHUL Research Centre, Sainte-Foy, Quebec, Canada. Address reprint requests to: Dr. K. Shawn Davison, R.R. #5, Site 505, Box 26, Saskatoon, SK S7K 3J8. E-mail: [email protected]

22

0049-0172/06/$-see front matter © 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.semarthrit.2006.04.002

K.S. Davison et al.

T

he World Health Organization definition of osteoporosis put forth in 1993 was “a systemic skeletal disease characterized by low bone density and microarchitectural deterioration of bone tissue, leading to enhanced bone fragility and a consequent increase in fracture risk” (1). This definition highlighted bone mineral density (BMD) as an important component of fracture risk, but it also recognized that there are other factors that contribute to fracture susceptibility. In the more recent 2000 NIH Statement on Osteoporosis, Diagnosis, and Therapy, osteoporosis was defined as “a skeletal disorder characterized by compromised bone strength predisposing to an increased risk of fracture” (2). This newer definition intimates the paradigm shift that has been evolving for the past decade, that measures of bone strength are essential for fracture prediction and that, while BMD is a surrogate of bone strength, it explains only a portion of it. A bone of sufficient strength does not fracture under normal loading conditions, which includes mild to moderate trauma such as a fall from standing height or less. In simple terms, fracture occurs when local stresses exceed material strength. Fracture can occur either when strength remains constant and the stress to the bone is increased (traumatic fracture) or when the stress on the bone is constant and the strength of the bone is decreased (atraumatic fracture). Occasionally, there are situations where there is both weakened bone and high stresses, such when an osteoporotic individual suffers a fracture from a motorvehicle accident. Both the material strength and the local stresses placed on bone are dictated by a myriad of interrelated factors. Bone strength is altered in one of two ways: by changing the tissue-level material properties of the bone or by changing the structural properties of the bone, and thus the local stresses, through adjustment of the rates of bone resorption and formation (bone remodeling). This review seeks to document the material and structural components of bone strength in an attempt to better understand the mechanisms of fragility fracture. MATERIALS AND METHODS Relevant English-language articles acquired from Medline from 1966 up to January 2005 were reviewed. Searches included the keywords “bone” AND 1 of the following: “strength,” “remodeling,” “microcrack,” “structur*,” “mineralization,” “collagen,” “organic,” “crystallinity,” “osteocyte,” “porosity,” “diameter,” “anisotropy,” “stress risers,” or “connectivity.” All abstracts gathered were reviewed for relevance and those deemed applicable were collected in their full form and reviewed for inclusion in the review. The references cited in collected articles were also scanned for relevant articles that may not have been captured in the Medline search. Relevant conference proceedings were scanned to allow for the capture of recent data that may not have yet been published in its full form. Due to the relative infancy of many

23

of the topics presented in this review, meta-analyses were not completed as they would not lead to any reliable conclusions. RESULTS Material Properties of Bone The material properties of bone encompass the properties of the constituents of bone itself and are independent of the bone’s size or shape (3). Since bone is essentially a composite of organic and inorganic materials, the investigation of the mechanical properties of either the organic or the mineral phase separately does not give an accurate representation of the properties of the composite as a whole. However, isolation investigations can provide valuable insight as to the roles of the different components of bone tissue with regard to bone strength. Mineralization The mineral phase of bone is responsible for both mechanical and homeostatic functions. Despite common perceptions, bone matrix is not uniformly mineralized, but rather displays a range of mineralization at any given skeletal site. The mean degree of mineralization of bone (MDMB) at a particular remodeling site is largely dependent on its stage of secondary mineralization (4). In an active remodeling sequence, the osteoclasts resorb bone from the remodeling space after which osteoblasts quickly fill the space with a collagenous osteoid. Primary mineralization generally begins 5 to 10 days after osteoid deposition and is typified by a rapid, linear rate of mineralization that proceeds until the remodeling cavity has been filled to 50 to 60% of the mineralization maximum. Following primary mineralization, the rate of mineralization slows and a phase of secondary mineralization begins; secondary mineralization progressively continues for a number of years, if not decades. Mineralization is rarely, if ever, complete and typically stabilizes around 90 to 95% of the maximum level (5). The MDMB and the distribution of mineralization is similar in trabecular and cortical bone, between genders, and over age (6). With normal aging the distribution of mineralization is relatively homogeneous and of higher degree due to reduced bone turnover, but the true volumetric density of the bone tissue is similar because of reduction of bone tissue per volume leading to a similar MDMB (g/cm3). Roschger and coworkers (7), using quantitative backscattered electron imaging, reported that there were no differences in trabecular BMD distribution between ethnicities, skeletal site, age (⬎25 years of age), or gender and that the intraindividual variance between sites was exceedingly small. However, significant interindividual differences were observed in patients with bone disease, such as osteomalacia, when compared with controls. Based on these findings, it was suggested that diagnostic transiliac biopsies would be generally representative of the entire skeleton with regard to mineralization and could be employed to ascertain the average mineralization of

24

Bone strength

A

B

C

D

Figure 1 (A) Normal mineralization; (B) osteomalacia; (C) decelerated bone turnover (such as seen with antiresorptive therapy); and (D) accelerated bone turnover (such as seen during menopause).

patients. With increased levels of bone remodeling, there is less time for complete secondary mineralization to occur, resulting in a lower MDMB. The MDMB of osteoporotic bone is lower than that of controls (8), most likely due to the typically increased remodeling rates. Figure 1 illustrates variability of mineralization in the trabeculae of individuals with (1) normal mineralization; (2) osteomalacia; (3) accelerated bone turnover (such as seen during menopause); and (4) decelerated bone turnover (such as seen with antiresorptive therapy). While an increasing level of bone mineralization is accompanied by an increase in the stiffness of the bone, it comes at the cost of reduced toughness (energy required to cause a fracture) of the bone (9). In other words, as mineralization increases, the tissue becomes more brittle and requires less energy to fracture. Therefore, it is possible for a bone that is hypermineralized to be more fragile than a bone with a lower degree of mineralization. This effect may partially explain the findings of Riggs and coworkers (10), which demonstrated that despite dramatic increases in BMD with fluoride treatment there was a significant increase in the number of patients with nonvertebral fractures in the fluoride group as compared with placebo. Therefore, while increased mineralization is important for imparting stiffness to bones, too high a mineralization can introduce fragility through a decrease in the bone’s toughness.

Crystallinity The strength of a bone is not only dependent on the degree of mineralization, but owes some of its mechanical behavior to the very properties of the minerals within bone. During secondary mineralization, there is a shift toward an increase in the number of crystals, an increase in crystal size, and increases in the degree of crystallinity (11). With increased crystal size there is a trend for a decreased deformation to failure (12); bone with a preponderance of large crystals will be more prone to breaking due to brittleness. In osteoporotic bone, crystal size is generally increased as compared with nonosteoporotic bone (13). However, where bone is relatively homogenous in terms of crystal size, with a preponderance of either small or large crystals, there is a consequent decrease in bone strength, so strength is not solely dependent on crystal size. Heterogeneity of crystal size is posited to be optimal (14). High degrees of crystallinity are associated with bone brittleness; more highly crystalline bone may permit earlier crack initiation by decreasing the amount of deformation that can occur before the formation of a crack and may also create an environment where cracks can easily propagate and coalesce into larger cracks to dramatically increase fracture risk (15). Increases in the crystal size and crystallinity of bone has been demonstrated with increasing age and tissue age (16), and the age-related increase in crystallinity has been shown to result in increased brittleness (12). The impact of bone crys-

K.S. Davison et al.

tallinity in osteoporosis-related bone fragility is unclear; however, an investigation by Rubin and coworkers (17) concluded that there were no substantial differences in crystal length or thickness between osteoporotic and nonosteoporotic trabecular bone. For optimal bone strength there should be a wide distribution of crystal sizes and moderate levels of crystallinity. Organic Component of Bone Increasing collagen content in bone increases the energy that must be absorbed before a bone will fracture (its toughness), most specifically after it begins to deform (18), but has little to directly do with the stiffness of bone (19). However, collagen content will indirectly act on stiffness as the more protein present in the organic matrix, the lower the MDMB must be, thereby decreasing stiffness. Collagen fibril size and orientation limit the size of bone crystals and control their orientation. Further, collagen plays an important role as a primary inhibitor of crack propagation, decreasing the probability of microcrack coalescence and fracture. Perhaps the best model of the importance of collagen in fracture susceptibility is that of osteogenesis imperfecta—where even single point mutations in the collagen molecule will dramatically increase the susceptibility for fracture (20). Much of the tensile strength in bone comes from the action of collagen covalent crosslinkages. In bone, triple helical collagen molecules (most often Type I collagen), stabilized by numerous bonds, are aggregated together first by divalent bonds (immature crosslinks) and then by stable trivalent bonds (mature crosslinks) to form microfibrils (21). Changes in collagen molecules and crosslinks may affect the mechanical integrity of the collagen network and subsequently lead to altered bone strength and toughness (22,23). Collagen denaturation and unwinding lead to decreases in strength and toughness and increases in compliance. Collagen crosslinks may play an important role in the mechanical integrity of the collagen network after collagen denaturation occurs; these crosslinks act to sustain mechanical integrity in the face of collagen denaturation (24). The enzymatic cleavage of amide links between amino acids in collagen chains may also decrease the strength of bone (25). In vertebral bone from individuals with osteoporosis there is a 20 to 34% reduction in the measurable number of stabilizing pyrrole crosslinks, with no differences in pyridinoline crosslinks as compared with age-matched controls (26). Aging has a larger impact on the plastic properties of bone, which are largely determined by the organic phase, as compared with the elastic properties (27). The agerelated reduction in toughness may play a large role in fracture susceptibility with aging. Collagen denaturation is related to the age-dependent decrease in bone toughness (28). Wang and coworkers (18) demonstrated that a 35% decrease in strength and 50% decrease in the toughness of the collagen network are associated with age-related de-

25

clines in whole-bone strength and the amount of energy required to cause fracture. Osteocytes likely have a dual role within bone: they act in a mechanosensory role for assessing the presence of microdamage and act as regulators of bone remodeling to alter bone in a manner most appropriate for the loading situation or to repair microdamage (29). Osteocyte density is low in areas of high microcrack density, which may be a sign of osteocyte death, thereby allowing high densities of microcracks to occur (30). Osteocyte death has been demonstrated to increase with age and is correlated with an increase in the accumulation of fatigue damage (30,31). Osteocyte lacunar density in human cortical bone is negatively associated with microcracks during aging (32). With aging there is an increase in empty lacunae and a fall in the percentage of osteocyte-occupied lacunae in deep, but not superficial, bone (29). Individuals with lower osteocyte densities generally possess a higher fracture risk. The organic components play a large role in bone toughness, allowing the bone to undergo some deformation before experiencing fracture. The osteocytes are a vital link between the strains engendered in the bone, the resulting microdamage, and bone turnover. Structural Properties of Bone When investigating the structural properties of bone, the contributions of the cortical shell and the trabecular network will be addressed separately, as is commonplace, despite the reality that they act in unison in vivo in manners that are still largely not understood. Cortical Architecture Diameter and thickness. The diameter and the thick-

ness of the cortex have a dramatic impact on the biomechanical integrity of the bone (33,34). In long bones the material constituents of the cortex gain strength as they are moved away from the neutral axis of the bone—the bending strength of a particular area of bone is proportional to the fourth power of its distance form the neutral axis. The outer diameter of a long bone has been demonstrated to predict up to 55% of the variation in bone strength (35) and individuals with thinner cortices are more prone to fracture (36). Figure 2 illustrates the changes in strength associated with alterations in cortical bone diameter and width. The loads encountered during life are a function of body mass, stature, and bending moments created by muscles, and the ability to resist these forces are a function of the cross-sectional area of the bone and the volumetric BMD (37). With normal aging, the diameter of bones increases, which increases their strength (38), despite losses of bone mass from the endocortical surface that are greater than the bone deposited on the periosteal surface. The cortical shell of vertebrae increases in cross-sectional area with age, increasing the biomechanical strength (39,40), especially in men (41,42). Men have larger bones

26

Bone strength Increasing diameter of cortex (Cortical thickness constant)

Increasing thickness of cortex (endosteal apposition; cortical diameter constant)

Increasing diameter of cortex while moderately* decreasing bone mass and cortical thickness (endosteal absorption > periosteal apposition) *radius:cortical thickness ratio <10

Figure 2 The impact of changing cortical diameter and width on bone strength.

than women, which allows them a greater mechanical bending strength (43). However, on average, men’s greater body mass, greater stature, and greater muscle mass also create a larger load for men to such an extent that the load per cross-sectional area of bone is similar in men and women at the vertebrae (44). In other investigations that examined the femoral neck region it was found that there were thinner cortices and no differences in the density of the trabecular bone in fracture cases when compared with nonfractured controls (36,45), highlighting the importance of structure in fracture susceptibility. A large diameter bone with thick cortices is ideal for strength and fracture avoidance. Porosity. Small increases in porosity lead to dispropor-

tionately large losses in bone strength (34). Porosity in the endocortex has less impact on bone strength than porosity on the outer diameter or periosteal surface. In adults younger than age 60, increases in both pore number and pore size with aging have been observed, whereas in adults over the age of 60 years there continued to be increases in pore size, but a decrease in pore number as the pores began to coalesce (46). Cortical porosity generally originates on the endosteal surface and progressively expands toward the periosteal surface (47). In men the changes in pore size and number seem to be even across the cortical shell, whereas in women there tends to be a concentration around the endocortical surface. Women have greater amounts of cortical porosity as compared with men after the age of 70 (27). Patients who have sustained fractures of the femoral neck tend to have higher cortical porosity, particularly in the anterior-inferior cortex, compared with matched controls (48). Figure 3 demonstrates typical changes in cortical porosity associated with aging and accelerated bone remodeling. Ideally for bone strength, there should be minimal porosity within bone, with only those cavities that are required for the living tissues.

Trabecular architecture. The microarchitecture of the trabecular network has a substantial impact on bone strength. An investigation by Parkinson and Fazzalari (49) reported that the strength of the trabecular bone structure was dependent on bone volume in a nonlinear manner. At very low bone volumes (under 15% bone per volume), there was a precipitous loss of mechanical competency compared with greater volumes. This underscores the importance of preventing large volumes of bone from being lost to avoid high fracture risk. Connectivity and anisotropy. Trabecular bone strength and stiffness are related to trabecular connectivity and orientation (50). The more inline the orientation of the trabeculae are to their loading environment, the better they are able to resist engendered strains. As Figure 4 demonstrates, an equivalent amount of bone distributed as widely separated, disconnected thick trabeculae is biomechanically less competent than when arranged as more numerous, connected, thin trabeculae (51,52). Increased connectivity reduces the unsupported length of trabecular struts; increasing connectivity is crucial as strut strength is related inversely to the square of the unsupported length (53,54). Euler’s theorem states that, in general terms, the strength of a vertical trabeculum is inversely proportional to the square power of its effective length (54). To further complicate matters, a loss of a single cross tie will typically affect 2 trabeculae. There is a preferential loss of horizontal trabeculae with aging (55,56) and a decreased trabecular interconnectedness (57). Guo and Kim (58) performed a 3-dimensional simulation of mass changes in trabecular bone and concluded that bone loss due to trabecular loss had a substantially larger impact on strength than an equal mass loss due to trabecular thinning. Therefore, for preventive therapies to be most effective, they should not only possess attributes that will preserve bone mass, but also preserve trabecular connectivity. Aaron and coworkers (59) reported that despite similar trabecular mass between vertebral fracture and nonfracture cases, there was an almost 4-fold increase in the number of

Porosity size and number increase

30-year-old woman

Porosity size increases and pores coalesce

55-year-old woman

70-year-old woman

Figure 3 The impact of cortical porosity on bone strength.

K.S. Davison et al.

A

27

B

Figure 4 (A) Equal bone mass—thinner trabeculae, connected, stronger; (B) equal bone mass—thicker trabeculae, less connected, weaker.

trabecular perforations in the fracture group (from iliac crest biopsies). Another investigation found that women who had fractured had a mass-independent difference of 4 times the real trabecular termini (a measure of trabecular disconnectedness) compared with nonfractured controls (59). Moreover, recent research has shown that the previously held belief that trabecular perforations within vertebrae could not be reversed was erroneous— examples of reversal were found in all subjects investigated (60). Anisotropy is the trait of an object that possesses different values for a given parameter, such as strength, when measured in different directions. With trabecular bone, an anisotropic structure is one that would demonstrate different strength or mechanical integrity attributes dependent on the direction of loading. With aging there is a preferential loss of horizontal trabeculae in vertebral bodies (55,56), likely as a consequence of reduced loading (Fig. 5). This loss of horizontal trabeculae decreases the strength of the trabecular network due to a loss in connectivity and an increase in the length of unsupported trabeculae. After thinning or resorption of the horizontal trabeculae there is an increased

A

load on the trabeculae that lie in the primary loading direction, causing them to either maintain or increase in thickness (61,62). These preferential losses in horizontal trabeculae and augmentation of vertically oriented trabeculae cause trabecular anisotropy in that the strength of the trabecular structure measured in the primary loading direction is significantly higher than when measured in a direction not typically exposed to loading. In individuals with osteoporosis the vertical trabeculae are typically maintained, and in fact, become thicker to withstand the greater loads typically applied to them; however, the horizontal trabeculae are generally lost to a greater extent compared with controls without osteoporosis (56,63). Homminga and coworkers (64) concluded that individuals with osteoporotic fractures of the hip do not have weaker bone tissue, but rather display greater trabecular anisotropy with overadapted strength in the primary loading plane and underadapted bone in the nonprimary loading plane. This makes the bone weaker in the nonprimary loading direction, which is generally loaded during a fall (in the situation of the hip). Another investigation found that bone from hip fracture patients had significantly more anisotropic structure compared with controls with proportionately fewer trabecular elements transverse to the primary load axis, even after matching for bone volume (65). Microfinite element models have shown that tissue strains in the head of an osteoporotic femur were 70% higher, on average, and less uniformly distributed than in a healthy femur (66). Trabecular thickness. Not only is the connectedness of the trabecular network important, but also trabecular thickness is a factor in determining strength. Trabecular failure occurs by buckling and bending and the strength of the trabecular strut is proportional to the square of its radius (53,54). However, Silva and Gibson (67) have demonstrated that for an equal loss in mass, a perforation or removal of a trabeculae was 2- to 3-fold worse than a thinning of the trabeculae with regards to strength of the unit. Similarly, Guo and Kim (58) reported that, for a relative loss in trabecular bone, it was far more detrimental to the mechanical

B

Figure 5 (A) Isotropic—relatively equal strength in all loading directions; (B) anisotropic—weak in the horizontal plane, strong in the vertical.

Figure 6 The impact of altering trabecular width and length on bone strength.

28

competency of the bone to lose a trabecular connection than to have overall thinning of the trabecular network. Figure 6 illustrates the effect of changing trabecular length or width on trabecular strength. Therefore, while thicker trabeculae are stronger, if losses must occur in trabecular mass, then it is far better structurally to have the structure thin than perforate it. Stress risers. A stress riser is an area of an object at which stress will tend to be concentrated as a result of a particular shape or consistency of material. Resorption pits in bone produce local stress risers that contribute to fracture tendency, particularly in architecturally sensitive areas, such as thin trabeculae. In trabecular bone, stress risers cause reductions in bone strength greater than what would be expected due to loss of mineral alone. Van der Linden and coworkers (68) used finite element modeling to demonstrate that the removal of only 7% of bone from a resorption cavity has the same impact on mechanical sufficiency as the removal of 50% of bone through trabecular thinning. These findings explain why a reduction in the number and the size of resorption cavities due to antiresorptive drug treatment can result in large reductions of fracture risk, with relatively small increases in bone mass. Due to the almost irreversible nature of trabecular deterioration, particularly perforation, it is important to ensure that those individuals with early disease are treated as soon as possible. Microdamage. The capacity to accumulate microdam-

age, while preventing damage from growing and coalescing, is one of the key features that give composite materials their toughness and superior fatigue resistance. Materials resistant to structural fatigue often derive the ability to accumulate microdamage from their resistance to crack growth rather than resistance to crack initiation (69). In bone, repeated fatigue loading causes microcracks to accumulate and coalesce, which may lead to fracture (70,71). Cement lines and lamellar interfaces are critical microstructural characteristics that act to stop or deter crack progression, delaying microcrack coalescence to postpone the inevitable formation of the fatal crack (72,73). The accumulation of microcracks is associated with a decrease in the stiffness, strength, toughness, elastic modulus, and resistance to crack initiation of cortical bone (72,74,75). The occurrence of microdamage and its subsequent repair is a normal process, but the accumulation of bone microdamage may elevate fracture risk (76,77). Bone remodeling helps to maintain tissue integrity by selectively replacing damaged bone with new bone (76). Microdamage increases as a function of suppression of bone turnover. The level of bone turnover below which microcrack accumulation leads to bone fragility is unknown in humans (15), and thus the risk of fractures in humans that is attributable to microdamage remains to be established.

Bone strength

Microdamage increases with age at both cortical (78,79) and trabecular sites (30,80). A number of studies have shown that ability of internal interfaces degrade with age and may lead to greater accumulations of microdamage (18,81). Therefore, a strong bone would be typified by a relatively low volume of microdamage (with short microcracks) that would be easily replaced by normal remodeling activity. Bone Mass An important part of any structure is its mass. Bone mass has a large role in the strength of bone. Simply put, a more massive bone is a stronger bone. During life there are 3 processes that can alter bone mass: longitudinal growth, modeling, and remodeling. Longitudinal growth and modeling. During growth there are dramatic increases in long bone growth and bone modeling at which time there is a substantial accrual of bone mass. Approximately a third of all adult bone is accrued in a 4-year period surrounding the time of most rapid statural growth (adolescence) (82). These increases in mass provide a great deal of biomechanical strength as there is typically expansion at both the endocortical and the periosteal surfaces, leading to both a wider diameter bone and a wider cortex. However, during times of rapid bone accrual, such as during growth, the mean degree of mineralization is low (83). Further, during very rapid growth there have been reports of increased fracture susceptibility, perhaps as a result of increased cortical porosity (84). Therefore, while there are rapid gains made in bone mass during adolescence, there is still a component of weakness, perhaps as a consequence of some of the other components of bone quality transiently degrading. Bone mass and remodeling. In both cortical and trabecular bone small changes in the mineral content of bone will result in disproportionate losses in bone strength and stiffness (85). The degree of mineralization in adults is largely a reflection of the rate of bone turnover by remodeling (86). Bone remodeling refers to the turnover of bone, the process where old bone is resorbed and replaced with new bone and is driven by both structural and metabolic needs. During growth, remodeling plays a small part in the changes in bone mass, but after skeletal maturation it plays a dominant role. Typically, small losses in bone mass are observed over time in adults, which is thought to be a consequence of a small imbalance between osteoclast and osteoblast activity, with the former removing more bone per remodeling site than is replaced by the latter. During times of high turnover, such as menopause, there is both an acceleration of active remodeling and a slightly greater discrepancy between bone resorption and formation resulting in significant bone loss. These losses, either gradual over most of 1’s adult life, or rapid, such as

K.S. Davison et al.

with menopause, decrease the mass of bone which will directly impact bone strength, independent of architectural changes. Lips and coworkers (87) have demonstrated that, with aging, there is a gradual decrease in the wall thickness of trabecular packets laid down, which is indicative of a decreased level of bone formation. The small, persistent losses of bone mass by subtle imbalance in bone remodeling over decades significantly decreases the strength of bone. Remodeling and Its Impact on Bone Strength Bone remodeling impacts almost all of the factors that determine bone strength, both material and structural (microarchitecture, stress risers, degree of mineralization, organic components, bone mineral density, etc). Accordingly, the rates of bone turnover have a dramatic effect on bone strength and, therefore, fracture risk. Remodeling has both mechanical and homeostatic roles (88). The relationship between bone turnover and strength may be best described as an inverted “U”-shaped curve where very low or very high levels of bone turnover are associated with lower bone strength (89). While a minimum amount of turnover is essential for repair of microdamage (5), too little or too much can lead to bone fragility. If bone remodeling is markedly reduced, there is a resulting increase in microdamage accumulation, which will, if taken alone, weaken bone (90). With an increase in turnover the amount of collagen within bone will increase as a consequence of more active remodeling sites and therefore a larger proportion of undermineralized bone since it takes several months before primary mineralization is complete. While this will improve the ductility of the bone, it comes at the cost of lower stiffness. However, the remodeling process itself transiently decreases the strength of the area that is undergoing remodeling. Osteoclastic activity creates resorption pits, which decrease both the local mass of bone and the architectural integrity (primarily via stress risers that represent temporarily weakened trabecular bone) of the site during mechanical loading, particularly for load-bearing vertically oriented trabeculae (91). It is likely that the increased number of active resorption sites seen in high-turnover states creates an increased number of stress risers, in turn leading to mechanical weakness and increased fracture susceptibility. High turnover can have dramatic effects on cortical bone. The increased porosity and increased thinning of the cortical region of the femoral neck are significantly associated with increased Haversian remodeling in patients with hip fracture (45). Also, in aging individuals who have suffered a femoral neck fracture, there are areas of both decreased bone formation and increased resorption within the endocortical region (92). Therefore, increased rates of bone remodeling are associated not only with large losses of bone mass, but also with deterioration of microarchitectural integrity.

29

DISCUSSION Bone strength is determined by a large number of interrelated factors. While many investigations have sought to quantify the impact of these components on bone strength, the nature of their interrelatedness only allows a cursory understanding of the roles each independently plays. The material properties of bone have a large impact on bone strength with increased strength reported for higher, but not hypermineralized, bone, crystal-size heterogeneity, and lower levels of crystallinity. The organic content of bone plays a large role in its ability to allow deformation and to accumulate energy before fracturing. The structure of the cortical shell has a dramatic impact on bone strength with greater strength being reported for wider diameter bones, thick cortices, and minimal cortical porosity. Increased mechanical competency is realized in trabecular bone with greater connectivity, decreased anisotropy, thicker trabeculae, and few resorption pits, which act as focally weak stress risers. While the accumulation of microcracks is certainly associated with a decrease in bone strength at some point, this level is not currently known. If rates of bone remodeling are too high or too low, bone fragility is increased. Bone turnover, or remodeling, impacts on almost all of the determinants of bone strength. As remodeling decreases, the mean mineralization and the homogeneity of mineralization increases. Correspondingly, as remodeling decreases, the proportion of collagen decreases. Further, high rates of remodeling result in a greater number of active resorption pits, which act as stress risers within the trabecular bone, and greater cortical porosity. Extremely low levels of bone remodeling are associated with an increase in the presence of microcracks. Therefore, while the independent impact of each component of bone strength is likely far from being established in vivo, it seems logical to alter bone turnover to attain the best possible protection from increased fragility and fracture risk. REFERENCES 1. Consensus development conference: diagnosis, prophylaxis, and treatment of osteoporosis. Am J Med 1993;94:646-50. 2. Osteoporosis prevention, diagnosis, and therapy. NIH consensus statement. 2000;17(1):1-45. 3. van der Meulen MC, Jepsen KJ, Mikic B. Understanding bone strength: size isn’t everything. Bone 2001;29:101-4. 4. Roschger P, Fratzl P, Eschberger J, Klaushofer K. Validation of quantitative backscattered electron imaging for the measurement of mineral density distribution in human bone biopsies. Bone 1998;23:319-26. 5. Boivin G, Meunier PJ. Changes in bone remodeling rate influence the degree of mineralization of bone. Connect Tissue Res 2002; 43:535-7. 6. Boivin G, Meunier PJ. The degree of mineralization of bone tissue measured by computerized quantitative contact microradiography. Calcif Tissue Int 2002;70:503-11. 7. Roschger P, Gupta HS, Berzlanovich A, Ittner G, Dempster DW, Fratzl P, et al. Constant mineralization density distribution in cancellous human bone. Bone 2003;32:316-23.

30 8. Roschger P, Rinnerthaler S, Yates J, Rodan GA, Fratzl P, Klaushofer K. Alendronate increases degree and uniformity of mineralization in cancellous bone and decreases the porosity in cortical bone of osteoporotic women. Bone 2001;29:185-91. 9. Currey JD, Brear K, Zioupos P. The effects of ageing and changes in mineral content in degrading the toughness of human femora. J Biomech 1996;29:257-60. 10. Riggs BL, Hodgson SF, O’Fallon WM, Chao EY, Wahner HW, Muhs JM, et al. Effect of fluoride treatment on the fracture rate in postmenopausal women with osteoporosis. N Engl J Med 1990; 322:802-9. 11. Paschalis EP, DiCarlo E, Betts F, Sherman P, Mendelsohn R, Boskey AL. FTIR microspectroscopic analysis of human osteonal bone. Calcif Tissue Int 1996;59:480-7. 12. Freeman JJ, Wopenka B, Silva MJ, Pasteris JD. Raman spectroscopic detection of changes in bioapatite in mouse femora as a function of age and in vitro fluoride treatment. Calcif Tissue Int 2001;68:156-62. 13. Mendelsohn R, Paschalis E, Boskey AL. Infrared spectroscopy, miscroscopy, and microscopic imaging of mineralizing tissues. Spectra-structure correlations from human iliac crest biopsies. J Biomed 1999;4:14-21. 14. Boskey AL. Bone mineral crystal size. Osteoporos Int 2003;14: S16-21. 15. Burr D. Microdamage and bone strength. Osteoporos Int 2003; 14(Suppl 5):67-72. Epub;2003 Aug 29:67-72. 16. Hanschin RG, Stern WB. X-ray diffraction studies on the lattice perfection of human bone apatite (Crista iliaca). Bone 1995;16: 355S-363S. 17. Rubin MA, Jasiuk I, Taylor J, Rubin J, Ganey T, Apkarian RP. TEM analysis of the nanostructure of normal and osteoporotic human trabecular bone. Bone 2003;33:270-82. 18. Wang X, Shen X, Li X, Agrawal CM. Age-related changes in the collagen network and toughness of bone. Bone 2002;31:1-7. 19. Zioupos P. Accumulation of in-vivo fatigue microdamage and its relation to biomechanical properties in ageing human cortical bone. J Microsc 2001;201:270-8. 20. Jepsen KJ, Schaffler MB, Kuhn JL, Goulet RW, Bonadio J, Goldstein SA. Type I collagen mutation alters the strength and fatigue behavior of Mov13 cortical tissue. J Biomech 1997;30:1141-7. 21. Knott L, Bailey AJ. Collagen cross-links in mineralizing tissues: a review of their chemistry, function, and clinical relevance. Bone 1998;22:181-7. 22. Boskey AL, Wright TM, Blank RD. Collagen and bone strength. J Bone Miner Res 1999;14:330-5. 23. Puustjarvi K, Nieminen J, Rasanen T, Hyttinen M, Helminen HJ, Kroger H, et al. Do more highly organized collagen fibrils increase bone mechanical strength in loss of mineral density after one-year running training? J Bone Miner Res 1999;14:321-9. 24. Wang X, Li X, Bank RA, Agrawal CM. Effects of collagen unwinding and cleavage on the mechanical integrity of the collagen network in bone. Calcif Tissue Int 2002;71:186-92. 25. Mansell JP, Bailey AJ. Abnormal cancellous bone collagen metabolism in osteoarthritis. J Clin Invest 1998;101:1596-603. 26. Oxlund H, Mosekilde L, Ortoft G. Reduced concentration of collagen reducible cross links in human trabecular bone with respect to age and osteoporosis. Bone 1996;19:479-84. 27. McCalden RW, McGeough JA, Barker MB, Court-Brown CM. Age-related changes in the tensile properties of cortical bone. The relative importance of changes in porosity, mineralization, and microstructure. J Bone Joint Surg Am 1993;75:1193-205. 28. Wang X, Bank RA, TeKoppele JM, Hubbard GB, Athanasiou KA, Agrawal CM. Effect of collagen denaturation on the toughness of bone. Clin Orthop Relat Res 2000;371:228-39. 29. Qiu S, Rao DS, Palnitkar S, Parfitt AM. Reduced iliac cancellous osteocyte density in patients with osteoporotic vertebral fracture. J Bone Miner Res 2003;18:1657-63. 30. Mori S, Harruff R, Ambrosius W, Burr DB. Trabecular bone

Bone strength

31. 32.

33.

34. 35. 36.

37. 38.

39.

40. 41. 42. 43.

44.

45.

46.

47. 48. 49. 50.

volume and microdamage accumulation in the femoral heads of women with and without femoral neck fractures. Bone 1997;21:521-6. Dunstan CR, Somers NM, Evans RA. Osteocyte death and hip fracture. Calcif Tissue Int 1993; 53(Suppl 1):S113-6; discussion S116-7. Vashishth D, Verborgt O, Divine G, Schaffler MB, Fyhrie DP. Decline in osteocyte lacunar density in human cortical bone is associated with accumulation of microcracks with age. Bone 2000;26:375-80. Oxlund H, Ejersted C, Andreassen TT, Torring O, Nilsson MH. Parathyroid hormone (1-34) and (1-84) stimulate cortical bone formation both from periosteum and endosteum. Calcif Tissue Int 1993;53:394-9. Turner CH. Biomechanics of bone: determinants of skeletal fragility and bone quality. Osteoporos Int 2002;13:97-104. Ammann P, Rizzoli R, Meyer JM, Bonjour JP. Bone density and shape as determinants of bone strength in IGF-I and/or pamidronatetreated ovariectomized rats. Osteoporos Int 1996;6:219-27. Crabtree N, Loveridge N, Parker M, Rushton N, Power J, Bell KL, et al. Intracapsular hip fracture and the region-specific loss of cortical bone: analysis by peripheral quantitative computed tomography. J Bone Miner Res 2001;16:1318-28. Biggemann M, Hilweg D, Brinckmann P. Prediction of the compressive strength of vertebral bodies of the lumbar spine by quantitative computed tomography. Skeletal Radiol 1988;17:264-9. Beck TJ, Oreskovic TL, Stone KL, Ruff CB, Ensrud K, Nevitt MC, et al. Structural adaptation to changing skeletal load in the progression toward hip fragility: the study of osteoporotic fractures. J Bone Miner Res 2001;16:1108-19. Link TM, Doren M, Lewing G, Meier N, Heinecke A, Rummeny E. Cross-sectional area of lumbar vertebrae in peri- and postmenopausal patients with and without osteoporosis. Osteoporos Int 2000;11:304-9. Mosekilde L, Mosekilde L. Normal vertebral body size and compressive strength: relations to age and to vertebral and iliac trabecular bone compressive strength. Bone 1986;7:207-12. Duan Y, Seeman E, Turner CH. The biomechanical basis of vertebral body fragility in men and women. J Bone Miner Res 2001;16:2276-83. Mosekilde L, Mosekilde L. Sex differences in age-related changes in vertebral body size, density and biomechanical competence in normal individuals. Bone 1990;11:67-73. Ebbesen EN, Thomsen JS, Beck-Nielsen H, Nepper-Rasmussen HJ, Mosekilde L. Age- and gender-related differences in vertebral bone mass, density, and strength. J Bone Miner Res 1999;14: 1394-403. Duan Y, Turner CH, Kim BT, Seeman E. Sexual dimorphism in vertebral fragility is more the result of gender differences in agerelated bone gain than bone loss. J Bone Miner Res 2001;16: 2267-75. Bell KL, Loveridge N, Power J, Rushton N, Reeve J. Intracapsular hip fracture: increased cortical remodeling in the thinned and porous anterior region of the femoral neck. Osteoporos Int 1999; 10:248-57. Bousson V, Meunier A, Bergot C, Vicaut E, Rocha MA, Morais MH, et al. Distribution of intracortical porosity in human midfemoral cortex by age and gender. J Bone Miner Res 2001;16: 1308-17. Atkinson PJ. Changes in resorption spaces in femoral cortical bone with age. J Pathol Bacteriol 1965;89:173-8. Jordan GR, Loveridge N, Bell KL, Power J, Rushton N, Reeve J. Spatial clustering of remodeling osteons in the femoral neck cortex: a cause of weakness in hip fracture? Bone 2000;26:305-13. Parkinson IH, Fazzalari NL. Interrelationships between structural parameters of cancellous bone reveal accelerated structural change at low bone volume. J Bone Miner Res 2003;18:2200-5. Goulet RW, Goldstein SA, Ciarelli MJ, Kuhn JL, Brown MB,

K.S. Davison et al.

51.

52. 53. 54. 55. 56.

57. 58. 59.

60. 61. 62.

63.

64.

65.

66. 67. 68. 69. 70.

Feldkamp LA. The relationship between the structural and orthogonal compressive properties of trabecular bone. J Biomech 1994;27:375-89. Kleerekoper M, Villanueva AR, Stanciu J, Rao DS, Parfitt AM. The role of three-dimensional trabecular microstructure in the pathogenesis of vertebral compression fractures. Calcif Tissue Int 1985;37:594-7. Weinstein RS, Hutson MS. Decreased trabecular width and increased trabecular spacing contribute to bone loss with aging. Bone 1987;8:137-42. Carter DR, Hayes WC. The compressive behavior of bone as a twophase porous structure. J Bone Joint Surg Am 1977;59:954-62. Bell GH, Dunbar O, Beck JS, Gibb A. Variations in strength of vertebrae with age and their relation to osteoporosis. Calcif Tissue Res 1967;1:75-86. Mosekilde L. Age-related changes in vertebral trabecular bone architecture—assessed by a new method. Bone 1988;9:247-50. Thomsen JS, Ebbesen EN, Mosekilde LI. Age-related differences between thinning of horizontal and vertical trabeculae in human lumbar bone as assessed by a new computerized method. Bone 2002;31:136-42. Compston JE, Mellish RW, Garrahan NJ. Age-related changes in iliac crest trabecular microanatomic bone structure in man. Bone 1987;8:289-92. Guo XE, Kim CH. Mechanical consequence of trabecular bone loss and its treatment: a three-dimensional model simulation. Bone 2002;30:404-11. Aaron JE, Shore PA, Shore RC, Beneton M, Kanis JA. Trabecular architecture in women and men of similar bone mass with and without vertebral fracture: II. Three-dimensional histology. Bone 2000;27:277-82. Banse X, Devogelaer JP, Delloye C, Lafosse A, Holmyard D, Grynpas M. Irreversible perforations in vertebral trabeculae? J Bone Miner Res 2003;18:1247-53. Frost HM. On the trabecular “thickness”—number problem. J Bone Miner Res 1999;14:1816-21. Parfitt AM, Mathews CH, Villanueva AR, Kleerekoper M, Frame B, Rao DS. Relationships between surface, volume, and thickness of iliac trabecular bone in aging and in osteoporosis. Implications for the microanatomic and cellular mechanisms of bone loss. J Clin Invest 1983;72:1396-409. Oda K, Shibayama Y, Abe M, Onomura T. Morphogenesis of vertebral deformities in involutional osteoporosis. Age-related, three-dimensional trabecular structure. Spine 1998;23:1050-5, discussion. Homminga J, McCreadie BR, Ciarelli TE, Weinans H, Goldstein SA, Huiskes R. Cancellous bone mechanical properties from normals and patients with hip fractures differ on the structure level, not on the bone hard tissue level. Bone 2002;30:759-64. Ciarelli TE, Fyhrie DP, Schaffler MB, Goldstein SA. Variations in three-dimensional cancellous bone architecture of the proximal femur in female hip fractures and in controls. J Bone Miner Res 2000;15:32-40. van Rietbergen B, Huiskes R, Eckstein F, Ruegsegger P. Trabecular bone tissue strains in the healthy and osteoporotic human femur. J Bone Miner Res 2003;18:1781-8. Silva MJ, Gibson LJ. Modeling the mechanical behavior of vertebral trabecular bone: effects of age-related changes in microstructure. Bone 1997;21:191-9. van der Linden JC, Homminga J, Verhaar JA, Weinans H. Mechanical consequences of bone loss in cancellous bone. J Bone Miner Res 2001;16:457-65. Currey JD. How well are bones designed to resist fracture? J Bone Miner Res 2003;18:591-8. Carter DR, Caler WE, Spengler DM, Frankel VH. Fatigue be-

31

71. 72. 73. 74. 75. 76. 77. 78. 79. 80.

81.

82. 83. 84. 85. 86. 87. 88. 89. 90.

91.

92.

havior of adult cortical bone: the influence of mean strain and strain range. Acta Orthop Scand 1981;52:481-90. Landorf KB. Clarifying proximal diaphyseal fifth metatarsal fractures. The acute fracture versus the stress fracture. J Am Podiatr Med Assoc 1999;89:398-404. Yeni YN, Fyhrie DP. Fatigue damage-fracture mechanics interaction in cortical bone. Bone 2002;30:509-14. Jepsen KJ, Davy DT, Krzypow DJ. The role of the lamellar interface during torsional yielding of human cortical bone. J Biomech 1999;32:303-10. Zioupos P, Casinos A. Cumulative damage and the response of human bone in two-step loading fatigue. J Biomech 1998;31:82533. Pidaparti RM, Akyuz U, Naick PA, Burr DB. Fatigue data analysis of canine femurs under four-point bending. Biomed Mater Eng 2000;10:43-50. Burr DB, Forwood MR, Fyhrie DP, Martin RB, Schaffler MB, Turner CH. Bone microdamage and skeletal fragility in osteoporotic and stress fractures. J Bone Miner Res 1997;12:6-15. Heaney RP. Is there a role for bone quality in fragility fractures? Calcif Tissue Int 1993;53(Suppl 1):S3-5; discussion S5-6. Norman TL, Wang Z. Microdamage of human cortical bone: incidence and morphology in long bones. Bone 1997;20:375-9. Schaffler MB, Choi K, Milgrom C. Aging and matrix microdamage accumulation in human compact bone. Bone 1995;17:521-5. Fazzalari NL, Forwood MR, Smith K, Manthey BA, Herreen P. Assessment of cancellous bone quality in severe osteoarthrosis: bone mineral density, mechanics, and microdamage. Bone 1998; 22:381-8. Yeni YN, Norman TL. Calculation of porosity and osteonal cement line effects on the effective fracture toughness of cortical bone in longitudinal crack growth. J Biomed Mater Res 2000;51: 504-9. Bailey DA. The Saskatchewan Pediatric Bone Mineral Accrual Study: bone mineral acquisition during the growing years. Int J Sports Med 1997;18(Suppl 3):S191-4. Rauch F, Schoenau E. Changes in bone density during childhood and adolescence: an approach based on bone’s biological organization. J Bone Miner Res 2001;16:597-604. Parfitt AM. The two faces of growth: benefits and risks to bone integrity. Osteoporos Int 1994;4:382-98. Hernandez CJ, Beaupre GS, Keller TS, Carter DR. The influence of bone volume fraction and ash fraction on bone strength and modulus. Bone 2001;29:74-8. Meunier PJ, Boivin G. Bone mineral density reflects bone mass but also the degree of mineralization of bone: therapeutic implications. Bone 1997;21:373-7. Lips P, Courpron P, Meunier PJ. Mean wall thickness of trabecular bone packets in the human iliac crest: changes with age. Calcif Tissue Res 1978;26:13-7. Parfitt AM. Targeted and nontargeted bone remodeling: relationship to basic multicellular unit origination and progression. Bone 2002;30:5-7. Weinstein RS. True strength. J Bone Miner Res 2000;15:621-5. Mashiba T, Turner CH, Hirano T, Forwood MR, Johnston CC, Burr DB. Effects of suppressed bone turnover by bisphosphonates on microdamage accumulation and biomechanical properties in clinically relevant skeletal sites in beagles. Bone 2001;28:524-31. Lafage MH, Balena R, Battle MA, Shea M, Seedor JG, Klein H, et al. Comparison of alendronate and sodium fluoride effects on cancellous and cortical bone in minipigs. A one-year study. J Clin Invest 1995;95:2127-33. Power J, Loveridge N, Lyon A, Rushton N, Parker M, Reeve J. Bone remodeling at the endocortical surface of the human femoral neck: a mechanism for regional cortical thinning in cases of hip fracture. J Bone Miner Res 2003;18:1775-80.