Bone quality: the material and structural basis of bone strength

J Bone Miner Metab (28) 2:1 8 Springer 28 DOI 1.17/s774-7-793-5 REVIEW ARTICLE Ego Seeman Bone quality: the material and structural basis of bone strength Received: August 1, 27 / Accepted: August 13, 27 Abstract The material composition and structural design of bone determine its strength. Structure determines loads that can be tolerated but loads also determine structure. Bone modifies its material composition and structure to accommodate loads by adaptive modeling and remodeling. Adaptation is successful during growth but not aging because accumulating insults, including a reduction in the volume of bone formed in the basic multicellular unit (BMU), increased resorption in the BMU, increased remodeling rate in midlife in women and in some men because of sex hormone deficiency, and in both sexes in old age as a consequence of secondary hyperparathyroidism and reduced periosteal bone formation, all of which compromises the material composition of bone and its structure. An understanding of the mechanisms of adaptation and failed adaptation provides rational approaches to interventions that can prevent or restore bone fragility. Key words bone quality material and structural strength Introduction Propulsion against gravity requires levers. Bones are levers and must be stiff they must resist deformation. Impact loading imparts energy to bone. Because energy cannot be destroyed, it must be absorbed by bone. To absorb energy, bone must be flexible. It must be like a spring: able to change shape (deform) without cracking, to shorten and widen in compression and to lengthen and narrow in tension. Bones must also be light to allow rapid movement. E. Seeman (*) Department of Endocrinology and Medicine, Austin Hospital, Austin Health, Heidelberg 384, Melbourne, Australia Tel. +1-3-949-5489; Fax +1-3-949-335 e-mail: egos@unimelb.edu.au The elastic properties of bone allow it to absorb energy by deforming reversibly when loaded [1]. If the load imposed exceeds the bone s ability to deform elastically, it can deform further and change shape permanently by plastic deformation. The permanent change in shape is associated with microcracks that allow energy release, a compromise that is a defense against complete fracture. If these microcracks are small, the bone remains in one piece. If both the elastic and plastic zones are exceeded, the bone fractures. Thus, bone achieves its strength serving contradictory properties stiffness yet flexibility, lightness yet strength by its material composition and structural design. Material composition and structural design of bone The balance between bone s material stiffness and its flexibility is achieved by varying its mineral content [2]. The greater the mineral content, the greater the material stiffness and the lower the flexibility. Nature selects characteristics most suited to the particular function that a given bone usually performs. Ossicles in the human ear, for example, are densely mineralized to vibrate like tuning forks without loss of energy in deformation, whereas the antlers of the deer are less densely mineralized and deform like springs during head butting in mating season but sacrifice peak loading ability. When the antlers collide, the energy of impact imparted by one animal can be absorbed in bending [1] (Fig. 1). Building levers This mineralized bone tissue is fashioned to achieve structural stiffness, flexibility, and lightness by its architectural design. For tubular bones, wider and narrower bone cross sections within a species do not necessarily differ in the amount of material used to construct them. The same amount of material can be used to build a wider tubular bone by fashioning it with a thinner cortex [3]. Nature fashions a bigger bone cross section using the same material by

2 Fig. 1. Bending strength increases as the tissue mineral density (% ash) increases. Antlers have a low tissue density as they must be flexible; the ossicles of the ear have very high tissue density and sacrifice bending strength for stiffness to function as tuning forks. (Adapted from [1]) 3 Bending Strength (Mpa) 2 penguin humerus cow femur tortoise femur human 1 Muntjac antler red deer antler ossicles 5 7 Percentage of ash (mass%) 8 9 creating a bigger marrow cavity. Larger bones have a larger medullary canal, constructed by resorption during intrauterine and postnatal life. Larger bones have a lower apparent volumetric bone mineral density (vbmd) than do smaller bones. The further displacement of the slightly thinner cortex confers greater resistance to bending because bending strength is proportional to the fourth power of the radius [4]. In long bones, stiffness is favored over flexibility. As a long bone grows in length, periosteal apposition increases its diameter while concurrent endocortical resorption excavates the marrow cavity. As periosteal apposition exceeds net endocortical resorption, the lengthening bone develops a wider and wider cortex. The enlarging medullary canal shifts the thickening cortex farther from the neutral axis, producing structural stiffness. In females, earlier completion of longitudinal growth and earlier inhibition of periosteal apposition produces a smaller bone. However, cortical thickness is similar in both sexes because a reduction in endocortical resorption, and perhaps net endocortical apposition, contribute to final cortical thickness [5,]. What differs in men and women is the position of the cortex in relationship to the long axis of the long bone. Similarly, among races, the main difference is the position of the cortex relative to the long axis of the long bone, not the thickness of the cortex (Fig. 2). Thus, the absolute and relative growth of the periosteal and endocortical surfaces vary by sex, pubertal stage, and type of bone and vary in degree at every position along and around the bone. At each level, these traits are determined by the interaction between bone formation on the periosteum and endocortical bone resorption and formation. Long Male Female Before Puberty Periosteal surface During Puberty Aging Endocortical surface Neutral axis Fig. 2. Sex differences in periosteal apposition and endocortical resorption in tubular bones. Before puberty, there is little sex difference in the bone diameters and bone mass. During puberty, periosteal apposition continues in the male, thickening the cortex, while little change occurs in endocortical resorption

3 1 Area (mm 2 ) 8 Total CSA Medullary Area (A) (B) (C) 4 Total Bone Area 2 Cortical Trabecular 8 CT (mm) 4 8 4 8 4 % 2% 4% % 8% 1% Shaft- Neck junction distance along the femoral neck Neck-Head junction 2 2 2-18 -9 9 18-18 -9 9 18-18 -9 9 18 Sup Ant Inf Post Sup Sup Ant Inf Post Sup Sup Ant Inf Post Sup Fig. 3. Total and medullary cross-sections varied along the femoral neck but total bone area was constant. The distribution and apportioning of the constant amount of bone varied such that the femoral neck (FN) was elliptical and largely cortical adjacent to the femoral shaft and became more circular, less cortical, and more trabecular adjacent to the femoral head. The bottom three panels demonstrate the varying thickness and distribution of cortical bone around the perimeter (see text). CT, computed tomography; Sup, superior; Ant, anterior; Inf, inferior; Post, posterior bones are not drinking straws; they do not have the same diameter and cortical thickness throughout. The complex and irregular periosteal and endocortical perimeters of long bone shafts create elliptical and triangular structures adapted locally to the loads to which they are exposed by differing degrees of modeling and remodeling. Adaptation involves fashioning and refashioning the same amount of bone into shapes and contours suited to tolerate these loads. As an example, consider the complex shape of the femoral neck (Fig. 3). Near the shaft, where bending moments are greatest, the shape is elliptical and the cortex is thicker inferiorly than superiorly. The bone is mainly cortical. Moving proximally, the amount of bone remains constant but the shape of the femoral neck becomes more circular and the proportion of trabecular bone increases. The cortical thickness is similar superiorly and inferiorly. These features are adapted to the loading pattern in this area, which is more compressive than that of the shaft [3]. As shown in the figure (Fig. 3), the distribution of cortical thicknesses varies along the femoral neck, being greater adjacent to the femoral shaft and less adjacent to the femoral head. This variability is likely to be important in determining strength so that loading circumstances can be accommodated by changing geometry, not necessarily mass. This process is successful during growth, but less so after epiphyseal closure. Building springs In the axial skeleton, bone is constructed differently than in the tubular bones, but the principle remains the same: to use space to achieve lightness and to minimize the amount of material needed to achieve the appropriate bone strength. By constructing the mass of bone as an open-celled porous structure, nature fashions spongy or cancellous bones of the vertebral bodies. The vertebral bodies function more as springs or shock absorbers than as levers. The structure is light yet strong; it can deform without cracking. Although tubular bones can deform by only 1% 2% of their original length, vertebral bodies can deform to a greater degree

4 35 (mg/cm 3 ) 325 Vertebral Cancellous Bone Mineral Density 3 275 25 225 2 because of their ability to absorb energy. They sacrifice peak stresses tolerated (load per unit area) in favor of greater peak strain (change in length/original length). The ability to deform facilitates flexion, extension, and rotation of the whole vertebral skeleton. For the vertebrae, increasing bone size by periosteal apposition builds a wider vertebral body in males than in females and in some races than in others. The number of trabeculae, established at the growth plates, does not increase with age [7]. At puberty, trabecular bone mineral density (BMD) increases by increasing the size and thickness of the trabeculae plates to a similar degree in boys and girls. Consequently, males and females have the same vertebral body trabecular BMD (number and thickness of trabeculae) during prepubertal and pubertal growth and at peak young adulthood [8,9]. In other words, growth does not build a denser skeleton in males than females; rather, it builds a bigger skeleton in males than in females. Growth does build a denser skeleton in African Americans than in whites, and this difference is likely to be the result of greater trabecular thickness in African Americans, not trabecular numbers [7 9]. Strength of the vertebral body is greater in young males than females because of the size differences between the sexes (Fig. 4). Bone modeling and remodeling Blacks White I II III IV V Tanner Stage * * Boys Girls Boys Girls Fig. 4. Trabecular density is similar by race and sex until Tanner stage 3, then increases similarly by sex but is greater in blacks than whites. (Adapted from [8]) The shape of bone is contained within the genetic code selected for survival in an anticipated environment, as shown by the fact that when lower limb buds are removed from a fetus and grown in vitro, they still take on the shape of the proximal femur [1]. The reverse, that loads determine structure, is less obvious but is key to understanding the pathogenesis of bone fragility. Bone can accommodate the loading circumstance by adaptive modeling and remodeling. This process occurs throughout life, but its purpose during growth (preepiphyseal closure) is different from its purpose during adulthood (postepiphyseal closure). During growth, the purpose of bone modeling and remodeling is to construct the skeleton from its miniaturized form in the fetus. During this time, remarkable adaptations to loading are achieved by modeling and remodeling, as reported in a wealth of literature on skeletal morphology in elite athletes [11]. This capacity for modeling and remodeling accounts for the complex shape of bone already described. For example, animal studies have shown that collagen abnormalities in the MOV13 mutant mouse result in reduced bone strength but vigorous adaptive modeling by periosteal apposition produces bone strength above that seen in the wild type [12]. Similarly, in mouse models of osteogenesis imperfecta, adaptations in material composition, rather than structure, compensate with varying success [13]. This adaptive modeling and remodeling compensate for abnormalities in one trait that reduce whole-bone strength to modify another trait. If the abnormality is too severe [14], or the compensatory mechanism is abnormal, then adaptation fails and bone fragility occurs. The emergence of bone fragility during aging may be regarded as the net result of accumulating abnormalities caused by disease, hormonal deficiency, and excess exposure to risk factors, as well as abnormalities in the cellular machinery of bone modeling and remodeling itself, leading to changes in the material composition and structure that form the basis of bone fragility. Bone fragility can be viewed as a disorder of adaptation. Bone modeling and remodeling in adulthood The remodeling rate is rapid during growth because each remodeling event deposits only a small moiety of bone as it is constructed [15]. As growth nears its programmed completion, rapid remodeling is no longer needed. Its pace slows, and there may be a progressive lessening of the degree of positive balance at the level of the bone metabolic unit (BMU). After longitudinal growth is completed and bone modeling and remodeling has achieved peak bone strength, its purpose is to maintain bone strength. The first abnormality signaling the onset of a change in bone structure is likely to be a reduction in bone formation at the cellular level [1 18]. Evidence for a decline in the volume of bone formed in the BMU is documented beginning around 5 years of age, but there is evidence of a decline in peak bone mineral mass and trabecular bone volume well before that age [19 21]. Bone resorption con-

5 8 MWT (µm) Bone Formation in the BMU 9 µm Bone Resorption in the BMU 4 Ac. F /yr) 3 Remodeling rate 7 4 5 2 2 3 1 2 4 8 Age (yrs) 1 1 5 Age (yrs) 9 2 4 Age (yr) 8 Fig. 5. Left panel: decrease in mean wall thickness with advancing age (adapted from [19]). Middle panel: volume of bone resorbed in the basic multicellular unit (BMU) decreases as age advances. (Adapted from [2].) Right panel: activation frequency (Ac.F) increases at midlife in women. MWT, mean wall thickness. (From J. Compston, with permission) 15 Porosity (%) 12 25 Ultimate Stress (MPA) 2 Toughness G IIc (N/m) 8 9 15 Tibia 1 4 3 5 2 Femur 2 4 8 Age (yrs).2. 4..8 1. Porosity 5 1 15 2 25 3 % Porosity Fig.. Cortical porosity increases with advancing age and is associated with a reduction in ultimate stress tolerated and toughness. (Adapted from [32,33] and [34], respectively) tinues, and indeed the volume of bone may decrease as age advances, even though at midlife there may be a temporary increase in the volume of bone resorbed within each BMU. The combination of continued resorption in each BMU plus a decline in the volume of bone formed in each BMU produce the negative BMU balance. Bone loss is exacerbated by the third abnormality, the rise in the rate of bone remodeling accompanying the loss of sex hormones in females (Fig. 5). After closure of the epiphyses, the need for rapid periosteal apposition ceases and becomes meager. The bone enlarges no more than a few millimeters during the next years [22 24]. Endocortical resorption continues and comes to exceed periosteal apposition. As a result, the diameter of the bone continues to enlarge minimally, while the cortex becomes thinner and thinner (see Fig. 2). The negative bone balance within each BMU produces intracortical porosity, which is accompanied by a reduction in toughness as cracks may travel with less resistance through the more porous cortices (Fig. ). The increasing porosity of cortical bone effectively trabecularizes the cortex [25,2]. The surface/volume ratio increases so that remodeling continues vigorously in cortical bone, producing cortical fragility. The same loads on bone are imposed on a structure diminished in crosssectional area, so that the stresses on bone (load per unit area) increase, predisposing to buckling, microdamage, and, ultimately, fracture. The amount of trabecular bone lost during aging in women and men is similar, or only slightly less in men than women [4,5]. However, trabecular bone loss occurs mainly by thinning in men and mainly by loss of connectivity in women [27 29]. Loss of connectivity is the result of the accelerated loss of bone that occurs in midlife in women as a result of estrogen deficiency. Estrogen deficiency is associated with increased remodeling on the endosteal surface. In addition, imbalance in the BMU increases as estrogen deficiency increases the lifespan of osteoclasts and reduces that of osteoblasts. Increased numbers of BMUs, coupled with continued resorption in each BMU, result in the loss of connectivity seen in women [27 29]. Strength of the vertebrae is compromised more by loss of connectivity than by trabecular thinning [28] (Fig. 7). The contribution of trabecular bone loss to overall bone loss decreases as trabecular plates perforate and disappear because there is less trabecular surface available for remod-

25% Loss Of Strength % 1..75.5.25 5 1 15 % Density Reduction Trabecular Thickness Trabecular Number Fig. 7. For a given deficit of 1% in trabecular density, the loss of strength is greater when this is caused by reduced trabecular number than by reduced trabecular thickness. (Adapted from [28]) eling. In men, there is no midlife acceleration of remodeling; bone loss occurs as the result of reduced bone formation and thinning of trabeculae. Relatively greater maintenance of connectivity in men results in persistence of the trabecular surfaces available for remodeling, so that trabecular bone loss probably continues longer in men than in women. The amount of trabecular surface available for bone remodeling in old age appears to be greater in men than in women [27]. Periosteal bone formation during aging Periosteal bone formation during aging, if it occurs, may offset bone loss from the endosteal surfaces. Periosteal apposition continues in premenopausal women and offsets endocortical bone resorption incompletely, so there is loss of cortical thickness but the shift of the thinned cortex increases section modulus despite bone loss. In perimenopausal women, endocortical resorption increases and is less offset by periosteal apposition, which decreases further, but the slight outward displacement of the thinned cortex results in no net change in bending strength. After menopause, periosteal apposition is very modest and endocortical resorption remains vigorous. Now, bending strength decreases [3] (Fig. 8). Periosteal apposition may be greater at some anatomical sites in men than in women so that the similar loss of bone from the endosteal surface is more greatly offset in men than in women [31,32]. BMD declines less in the spine in men than in women because the reduction in cortical bone is less in men. However, the better maintenance of cortical mass in men may be the result of greater periosteal bone formation, not less endosteal resorption. Sex differences in fragility fractures The larger skeleton in men produces a bone that tolerates larger absolute loads than does a woman s skeleton. However, the load per unit area (stress) on the vertebral body is no different in men and women because larger bone is subjected to correspondingly larger loads. In young men and women, fragility fractures are uncommon because loads are less than the ability of the bone to withstand them. Structural failure emerges during aging because of the changing relationship between the load and the bone s ability to tolerate it. Although still controversial, periosteal apposition may increase cross-sectional area more in men at some sites, but not all, and so load imposed per unit area may decrease more in males than in females while bone strength probably decreases less in men than in women. Consequently, a lower proportion of elderly men than elderly women have architectural and material properties such as microdamage, altered tissue mineral density, loss of connectivity, porosity, and trabecular and cortical thinning below the critical level at which the loads on the bone are greater than the bone s ability to tolerate them. Structural failure occurs less in men than in women because the relationship between load and bone strength is better maintained in men than in women. Conclusion Bones must be stiff so that they do not bend when loaded. Bones must also be flexible so they can absorb the energy imposed by loading as potential energy by elastic then plastic deformation. Structural failure may occur if bones deform too little or too much. Age- and menopause-related abnormalities in bone remodeling produce loss of material and structural properties. High remodeling reduces the mineral content of bone, resulting in loss of stiffness. Sex hormone deficiency increases the volume of bone resorbed and reduces the volume of bone formed in each BMU. The contributions made by differences in material composition (tissue mineral content, collagen type and cross-linking) and structure (bone size, cortical thickness and porosity, trabecular number, thickness, connectivity), and other factors (microdamage burden, osteocyte density) to sex and racial differences in bone fragility remain poorly defined. The challenge is to measure these specific material and structural determinants of bone strength. Whether a combination of these material and structural properties will more accurately identify women likely to sustain fractures, or improve approaches to drug therapy is unknown, but it is likely.

7 Fig. 8. Periosteal apposition (black bars) continues in premenopausal (PRE) women and partly offsets endocortical bone loss (white bars). Cortical bone loss occurs, but as the thinner cortex is shifted outward, section modulus increases, despite bone loss. In perimenopausal (PERI) women, periosteal apposition has decreased, but endocortical resorption has increased so now there is greater cortical thinning, but there is no change in section modulus because of the outward shift of the thinner cortex. In postmenopausal (POST) women, there is little periosteal apposition and worsening endocortical resorption, so cortical thinning is worse, and now section modulus decreases. (Adapted from [35]) Rate of Change ( m/yr) 7 35 Periosteal Apposition PRE PERI POST Endocortical Resorption Net cortical thickness -35 Section Modulus (mm 3 /yr) - References 1. Currey JD (22) Bones. Structure and mechanics. Princeton University Press, Princeton, NJ 2. Seeman E, Delmas PD (2) Bone quality: the material and structural basis of bone strength and fragility. N Engl J Med 354:225 221 3. Zebaze RMD, Jones A, Welsh F, Knackstedt M, Seeman E (25) Femoral neck shape and the spatial distribution of its mineral mass varies with its size: clinical and biomechanical implications. Bone (NY) 37:243 252 4. Ruff CB, Hayes WC (1988) Sex differences in age-related remodeling of the femur and tibia. J Orthop Res :88 89 5. Duan Y, Wang XF, Evans A, Seeman E (25) Structural and biomechanical basis of racial and sex differences in vertebral fragility in Chinese and Caucasians. Bone (NY) 3:987 998. Wang XF, Duan Y, Beck T, Seeman ER (25) Varying contributions of growth and ageing to racial and sex differences in femoral neck structure and strength in old age. Bone (NY) 3:978 98 7. Parfitt AM, Travers R, Rauch F, Glorieux FH (2) Structural and cellular changes during bone growth in healthy children. Bone (NY) 27:487 494 8. Gilsanz V, Roe TF, Stefano M, Costen G, Goodman WG (1991) Changes in vertebral bone density in black girls and white girls during childhood and puberty. N Engl J Med 325:1597 1 9. Gilsanz V, Gibbens DT, Roe TF, Carlson M, Senac MO (1988) Vertebral bone density in children: effect of puberty. Radiology 1:847 5 1. Murray PDF, Huxley JS (1925) Self-differentiation in the grafted limb bud of the chick. J Anat 59:379 384 11. Seeman E (22) An exercise in geometry. J Bone Miner Res 17: 373 38 12. Bonadio J, Jepsen KJ, Mansoura MK, Jaenisch R, Kuhn JL, Goldstein SA (1993) A murine skeletal adaptation that significantly increases cortical bone mechanical properties. Implications for human skeletal fragility. J Clin Invest 92:197 175 13. Kozloff KM, Carden A, Bergwitz C, Forlino A, Uveges TE, Morris MD, Marini JC, Goldstein SA (24) Brittle IV mouse model for osteogenesis imperfect IV demonstrates postpubertal adaptations to improve whole bone strength. J Bone Miner Res 19: 14 22 14. McBride DJ Jr, Shapiro JR, Dunn MG (1998) Bone geometry and strength measurements in aging mice with the oim mutation. Calcif Tissue Int 2:172 17 15. Szulc P, Seeman E, Delmas PD (2) Biochemical measurements of bone turnover in children and adolescents. Osteoporosis Int 11:281 294 1. Nishida S, Endo N, Yamagiwa H, Tanizawa T, Takahashi HE (1999) Number of osteoprogenitor cells in human bone marrow markedly decreases after skeletal maturation. J Bone Miner Metab 17: 171 177 17. Stenderup K, Justesen J, Eriksen EF, Rattan SI, Kassem M (21) Number and proliferative capacity of osteogenic stem cells are maintained during aging and in patients with osteoporosis. J Bone Miner Res 1:112 1129 18. Oreffo RO, Bord S, Triffitt JT (1998) Skeletal progenitor cells and ageing human populations. Clin Sci 94:549 555 19. Lips P, Courpron P, Meunier PJ (1978) Mean wall thickness of trabecular bone packets in the human iliac crest: changes with age. Calcif Tissue Res 1:13 17 2. Vedi S, Compston JE, Webb A, Tighe JR (1984) Histomorphometric analysis of dynamic parameters of trabecular bone formation

8 in the iliac crest of normal British subjects. Metab Bone Dis Relat Res 5:9 74 21. Gilsanz V, Gibbens DT, Carlson M, Boechat I, Cann CE, Schulz ES (1987) Peak trabecular bone density: a comparison of adolescent and adult. Calcif Tissue Int 43:2 22 22. Balena R, Shih M-S, Parfitt AM (1992) Bone resorption and formation on the periosteal envelope of the ilium: a histomorphometric study in healthy women. J Bone Miner Res 7:1475 1482 23. Seeman E (23) Periosteal bone formation: a neglected determinant of bone strength. N Engl J Med 349:32 323 24. Ahlborg HG, Johnell O, Turner CH, Rannevik G, Karlsson MK (23) Bone loss and bone size after the menopause. N Engl J Med 349:327 334 25. Brown JP, Delmas PD, Arlot M, Meunier PJ (1987) Active bone turnover of the cortico-endosteal envelope in postmenopausal osteoporosis. J Clin Endocrinol Metab 4:954 959 2. Foldes J, Parfitt AM, Shih M-S, Rao DS, Kleerekoper M (1991) Structural and geometric changes in iliac bone: relationship to normal aging and osteoporosis. J Bone Miner Res :759 7 27. Aaron JE, Makins NB, Sagreiy K (1987) The microanatomy of trabecular bone loss in normal aging men and women. Clin Orthop Relat Res 215:2 271 28. Van der Linden JC, Homminga J, Verhaar JAN, Weinans H (21) Mechanical consequences of bone loss in cancellous bone. J Bone Miner Res 1:457 45 29. Manolagas SC (2) Birth and death of bone cells: basic regulatory mechanisms and implications for the pathogenesis and treatment of osteoporosis. Endocr Rev 21:115 137 3. Duan Y, Turner CH, Kim BT, Seeman E (21) Sexual dimorphism in vertebral fragility is more the results of gender differences in bone gain than bone loss. J Bone Miner Res 1:227 2275 31. Duan Y, Beck TJ, Wang X-F, Seeman E (23) Structural and biomechanical basis of sexual dimorphism in femoral neck fragility has its origins in growth and aging. J Bone Miner Res 18: 17 1774 32. Brockstedt H, Kassem M, Eriksen EF, Mosekilde L, Melsen F (1993) Age- and sex-related changes in iliac cortical bone mass and remodeling. Bone 14:81 91 33. Martin RB, Ishida J (1989) The relative effects of collagen fiber orientation, porosity, density and mineralization on bone strength. J Biomech 22:419 42 34. Yeni YN, Brown CU, Wang Z, Norman TL (1997) The influence of bone morphology on fracture toughness of the human femur and tibia. Bone (NY) 21:453 459 35. Szulc P, Seeman E, Duboeuf F, Sornay-Rendu E, Delmas PD (2) Bone fragility: failure of periosteal apposition to compensate for increased endocortical resorption in postmenopausal women. J Bone Miner Res 21:185 183