The fragile beauty of bone architecture

Louis-Georges STE-MARIE,MD
Natalie DION PhD
Centre Hospitalier de l’Université de Montréal
Université de Montréal – Montréal, CANADA

The fragile beauty of bone architecture

by N. Dion and L. G. Ste-Marie, Canada

In order to resist biomechanical loading and torsion while allowing movement, bone needs to be stiff, flexible, and light. These properties are determined by a complex set of interdependent factors, including bone mass, geometry, and tissue material composition, that define bone quality and maintain structural integrity and strength. Throughout life, the material and structural properties of bone are modulated to better respond to stresses such as growth, menopause, and aging. Inability to adapt its macro and microarchitecture to such stresses makes bone fragile and may initiate fracture. This review focuses on the components that define the macro and microarchitecture of bone. It describes their structural differences, relationships to skeletal sites, and respective roles. It discusses the influence of major life stresses on structural bone adaptation, and addresses structural bone fragility in terms of the abnormalities in bone material composition observed in some bone diseases. Better understanding of the biomechanical properties of bone is needed in order to maintain bone health and prevent or treat bone disease. This requires methods that evaluate overall bone quality in terms of the correlations between material composition and three-dimensional structure.

Medicographia. 2012;34:163-169 (see French abstract on page 169)

The structure of bone must be strong enough to support body weight and, in some cases, such as the skull and ribs, to protect vital organs. However, it must also be light enough to make movement possible.

Structural differences per skeletal site

Bone achieves its mechanical performance by virtue of its geometric properties and biomaterial composition. These two parameters determine bone strength, which is a balance between stiffness/flexibility and lightness/mass. During impact loading, bone must be stiff enough to resist deformation. It must also be elastic or flexible enough to avoid fracture by absorbing energy. Like a spring, bone must be able to change its shape to absorb compression energy and light enough to allow rapid movement.

In other words, depending on its location and specific role in the body, bone adopts different shapes allowing a balance between load resistance, bone mass, and structural flexibility. These specifications produce five types of macroarchitecture: long bone, flat bone, irregular bone, short bone, and sesamoid bone, the first three of which we characterize briefly below.

Figure 1
Figure 1. Architectural organization of bone
(inspired by Chappard et al3).

A. Pelvic x-ray showing a variety of bone geometry.
B. Undecalcified transiliac bone biopsy showing external cortical bone and internal trabecular bone within the medullary cavity.
C. Microarchitectural analysis using 3D micro-computed tomography.
D. Microarchitectural analysis using 2D histomorphometry (Goldner’s trichrome stain).
E. Basic structural unit (hemiosteon) of trabecular bone (hematoxylin phloxine saffron stain under polarized light).
F. Basic structural unit (osteon) of cortical bone (toluidine blue stain under polarized light).

Long bones, such as the femur, tibia, or humerus, are levers allowing load and movement, achieved mostly by a structural design that emphasizes rigidity over flexibility. One characteristic is that they are longer than they are wide, having a growth plate (epiphysis) at either end with a hard compact outer surface (cortical bone) and a spongy cancellous marrow-containing interior (trabecular bone). Hyaline cartilage covers each end for protection and shock absorption.

Flat bones, such as the pelvis, protect vital organs and anchor muscles. The anterior and posterior surfaces are basically formed of compact bone to provide good mechanical strength while the center consists of marrow-containing cancellous bone. In adults, red blood cells are formed mostly in the marrow of flat bones.

Irregular bones, such as vertebrae, have a spring action and consist primarily of cancellous bone under a thin outer layer of compact bone.

The macroarchitecture of bone refers to the length, size, and shape of the intact adult skeleton, which is mostly genetically determined. In addition, bones have special angulations and curvatures enabling them to resist compression, tension, and torsion. However, the final shape and mass of the adult skeleton depends on interaction between the genetic contribution and mechanical loading and modeling during growth and development. It also reflects nutrition, intercurrent illness, and other factors encountered during growth and development.1

Roles of cortical and trabecular bone tissue

At the macrostructural level, bone can be classified as cancellous (trabecular) and compact (cortical). However, each type is best distinguished by its specific microarchitecture, structural organization, and role in bone strength. Their relative proportions vary considerably between sites. The trabecular:cortical ratio is about 75:25 in vertebrae, 50:50 in the femoral head, and 95:5 in the shaft (diaphysis) of the radius.2

Cortical bone constitutes approximately 80% of the skeleton and provides strength. It consists of mineralized matrix layers stacked tightly to form a solid organized structure (compact bone). The structural and functional unit of compact bone (bone structural unit [BSU]) is the osteon, which contains a central Haversian canal parallel to the long axis of the bone, according to the direction of maximal stress. The canal provides a passage for blood vessels and sympathetic nerve fibers through the hard bone matrix. In addition, the presence of transverse Volkmann’s canals ensures communication between the Haversian canals and circulation between the outer and inner spaces (periosteum and medulla). Under the periosteum, the osteon layer is lined by a number of parallel lamellae constituting the periosteal bone. On the medullary side, the osteons are also covered by lamellae forming the endosteum (Figure 1).3

Osteons are complex composite structures whose lamellae (aligned collagen-mineral fibers) are organized for optimal resistance to the type of load they are required to bear. Three types have been defined: transverse, alternate, and longitudinal (Figure 1F).4,5 Recent numerical compression experiments studying the finite elements of transverse osteons suggest that the composite microstructure has specific biomechanical functions depending on its position (internal or external) in the Haversian canal.6 This new type of experiment helps us to better understand how bone microstructure behaves.

Cortical bone is found mainly in long bones, such as the femur, tibia, and radius, and the outer surfaces of flat bones, such as the skull, mandible, and scapula. A key feature of cortical microarchitecture is the number of pores (porosity). The cortical width and the inner and outer diameters of the main shaft of long bones are also evaluated.

Trabecular bone constitutes approximately 20% of the skeleton and comprises an interconnected network of irregularly arranged (highly anisotropic) trabeculae, allowing maximal strength, allied to a porous lightweight bone structure. The trabecular network is basically composed of plates parallel to the stress lines and connected laterally by transverse rods or pillars that ensure cohesion of the entire organization.7 The trabecular BSU is the arch-like hemiosteon, resembling an incomplete osteon (Figure 1E). Remnants of partially eroded hemiosteons persist between newly laid down BSUs and constitute interstitial trabecular bone. Trabecular bone is normally found within either end of long bones, such as the femur and tibia, and within flat or irregular bones (Figure 1).

The microarchitecture of bone tissue refers mainly to the morphology of the trabecular compartment. Its structural features include the volume, shape, number, thickness, and connectivity of trabeculae present, plus the marrow in the medullary cavity. Turnover is higher in trabecular bone because it has more surface per unit of volume than cortical bone. This also explains why microarchitecture reforms more rapidly in the trabecular compartment.

Structural influence of mechanical, hormonal and nutritional stress

_ Mechanical stress
Bone continually adapts its size, shape, and/or matrix properties to optimize resistance to changes in mechanical load (compression or tension). Adaptation depends on the three dimensional (3D) physical arrangement of trabecular and cortical bone, their relative proportion, and their capacity for self-renewal and repair. Such adaptation is readily observed in tennis players where bone in the dominant arm is larger than in the supporting arm.8 Similarly, recent comparison between elite female soccer players and swimmers highlighted the relative benefit of high-impact sport (soccer) on hip geometry and strength.9

Greater body weight and height account for the larger bone size in men over women at all ages. Hence their greater resistance to loads on the skeleton during regular activity, and their overall pattern of more favorable geometric adaptation.10

Biomechanical behavior influences overall bone size and shape. Even a small increase in the external diameter of a long bone can markedly improve its resistance to mechanical stress since resistance to bending increases to the fourth power of the distance from the neutral axis.11 However, the relationship between bone size and resistance to stress is also heavily dependent on cortical thickness, porosity, and degree of bone matrix mineralization. A power law with mineralization and porosity as explanatory variables accounts for over 80% of the variation in cortical stiffness and strength.12

Immobilization and microgravity influence bone mass and architecture, as has been documented in astronauts. The abnormalities in astronaut bone during spaceflight result from reduced skeletal loading, reminding us that everyday gravitational loading is important in maintaining normal bone mass and architecture.13 Trabecular bone has a higher remodeling level (balance between formation and resorption) than cortical bone. This maximizes adaptability by orienting its principal axes along the most common loading directions, making the trabecular bone network better able to resist mechanical forces.14 The growth phase exemplifies trabecular adaptability. Where as in childhood trabecular bone mostly consists of a dense network of plates in a frequently isotropic 3D distribution (ie, uniform in all directions), in adults the plates gradually change their preferential orientation along the direction of the primary stress exerted on the bone.15

_ Hormonal stress
_ Gender differences
The sexual dimorphism of bone becomes apparent during puberty, with men achieving higher peak bone mass, greater bone size, and ultimately a stronger skeleton than women.16 These structural modifications cater for the greater biomechanical load of male weight and height.17 Histomorphometry shows greater bone volume and thicker trabeculae in male vertebrae.18

_ Puberty
During puberty, bones in men become wider, but not denser, as bone mineral acquisition in long bones occurs in proportion to bone volume. Boys develop a larger periosteal perime ter than girls from midpuberty onward. This is generally attributed to the contrasting effects of sex steroids on bone structure inmen and women. As a result, cortical bone in male long bones is further fromthe neutral axis, which confersmore resistance to bending. During aging, initial changes in trabecular bone are similar in both sexes and characterized by decreases in bone volume and trabecular thickness. However, in women, bone fragility becomes more common due to menopause. Estrogen withdrawal accelerates bone loss and produces structural deterioration, due to a combination of rapid remodeling and greater imbalance (reduced osteoblast lifespan with increased osteoclast lifespan) in the bone multicellular unit (BMU).19

_ Growth
In addition to sex hormones, growth hormone (GH) and insulinlike growth factor I (IGF-I) are probably the most important determinants of structural gender differences characterized by wider but not thicker bones. Although it is now well accepted that sex hormones interact with the GH/IGF-I axis to regulate peak cortical bone size, the relative contributions of each have yet to be precisely determined.16,20 Growth is associated with age-related changes in bone geometry in an attempt to preserve whole-bone strength. In the appendicular skeleton, these changes involve the redistribution of cortical and trabecular bone, specifically endosteal resorption and periosteal apposition, resulting in an increase in long bone diameter (ensuring resistance to bending and torsion21-23) and a decrease in cortical thickness. Cross-sectional data have also shown that the bone of the axial skeleton can increase in size with aging.24

_ Aging stress
Although bone stability appears to follow the completion of growth, aging corresponds to a period of bone loss with structural deterioration. During early adulthood, bone is lost in men and women, probably due to a negative BMU balance characterized by early decrease in bone formation within each individual BMU with no change in bone resorption. Thus, aging not only decreases bone mass, it also gradually affects bone microarchitecture by reducing trabecular thickness and connectivity.23 In addition, it affects cortical thickness by increasing endocortical bone resorption and reducing periosteal apposition, thereby altering the overall distribution of the remaining bone.25

Throughout life, mechanical loading produces fatigue damage in the bone matrix. Accumulation of such microdamage or microcracks can initiate fracture, although continuous reparative remodeling is designed to prevent this eventuality. It has been suggested that, in aging bone, accumulated microdamage results from interaction between altered 3D microarchitecture, including changes in trabecular shape and connectivity, and mechanical loading. A study of the relationship between 3D microstructure and the accumulated microdamage induced by compression loading in cancellous bone cores from adult human tibial plateaus of varying ages showed that the bone volume fraction (bone volume/trabecular volume) and changes in microarchitecture predispose trabecular bone to accumulated microdamage.26 Thus, in a less dense trabecular network, rod-like trabeculae may have a greater role in the accumulation of microdamage than impaired removal due to the suppression of bone turnover. This study supports the assumption that 3D microarchitecture has a direct impact on bone fragility.

_ Nutritional stress
An appropriately balanced diet is essential for developing and maintaining a bone structure capable of withstanding daily mechanical loading. Calcium, vitamin D, and protein are the main nutrients required to maintain bone health and prevent diseases such as osteoporosis. Calcium along with phosphorus forms hydroxyapatite crystals, the mineral component of bone, providing the requisite rigidity for weight-bearing. The skeleton contains 99% of the body’s calcium, the remaining 1% being found in blood, extracellular fluid, and soft tissue. In addition to its structural role, calcium has metabolic functions so important that its extracellular concentrations are maintained under fine control. Bone is involved in the regulation of blood calcium levels via bone remodeling, while calcium intake has a reciprocal impact on remodeling: calcium deficiency increases parathormone secretion, which stimulates bone resorption, leading to a decrease in bone density and a gradually weakened bone structure.27

Sunlight and diet are the main sources of the vitamin D that helps to maintain blood calcium levels by promoting calcium absorption in the gut. Even moderate vitamin D deficiency causes secondary hyperparathyroidism, impacting bone density and structure. Severe vitamin D deficiency markedly impairs mineralization, rigidity, and structural integrity, producing osteomalacia in adults and rickets in children.27 As well as indirectly affecting bone health, vitamin D has a direct impact on bone cell activity, notably by determining osteoclast differentiation and function, with osteoclasts actually metabolizing vitamin D in an autocrine manner.28 The vitamin D metabolite, 1α,25-dihydroxyvitamin D3, also regulates osteoblast gene transcription, proliferation, and mineralization.29

Selective deficiencies in dietary protein markedly lower bone mass and undermine microarchitecture. Low protein intake is commonly associated with hip fracture in the elderly, while protein supplementation attenuates post-fracture bone loss and increases muscle strength, possibly via an increase in IGF-I, thereby markedly reducing medical complications and hospital stay.30

Structural impairment in bone disease

Bone structure correlates with biomaterial composition and the manner in which this material is fashioned into a 3D structure endowed with stress-resistant geometric properties.Meta- bolic bone disease that distorts biomaterial composition and/ or macro/microarchitecture therefore results in bone fragility. The cellular mechanism by which one component attempts to compensate for abnormalities in another has not been elucidated. There are also few clinically validated methods for assessing and monitoring the microarchitectural response to bone disease and its treatment. However, study of the collagen disorder osteogenesis imperfecta (OI), the mineralization disorder osteomalacia, and postmenopausal osteoporosis (low bone mass plus altered microarchitecture) has highlighted the contribution of each of these components to bone quality and strength (Figure 2).31

Figure 2
Figure 2. Structural impairment in bone disease.

Undecalcified bone biopsies (3D microcomputed tomography or 2D microscopic
histology [Goldner’s stain]). Green: mineralized bone. Red (pink to red
gradient): osteoid (nonmineralized bone) and bone marrow cells.
© The authors.

_ Osteogenesis imperfecta: a collagen disorder
OI is a genetic disorder of collagen synthesis characterized by fragile bones with recurrent fractures resulting in skeletal deformity. The phenotype ranges from cases that are lethal in the perinatal period to mild cases diagnosed in adulthood.32 The abnormal quantity of collagen and its poor quality interfere with mineral crystal size, accounting for low bone mass and bone fragility. Themicroarchitecture is also affected due to fewer and thinner trabeculae and decreased bone formation at cellular level. Taken together, these abnormalities severely impair resistance to load and torsion stress.

_ Osteomalacia: impaired mineralization
Osteomalacia and rickets are characterized by a defect of primary mineralization due to calcium and/or phosphate deficiency. Osteomalacic bone comprises a very small amount ofmineralized tissue with an accumulation of osteoid (nonmineralized newly formed bone), due to delay between bone matrix deposition and mineralization onset. In addition, bone resorption is usually increased, and trabecular microarchitecture impaired, in cases of secondary hyperparathyroidism due to calcium malabsorption. Biomechanical properties are thus markedly impaired, with weakened bones at risk of fracture from minimal trauma.31

_ Osteoporosis: low bone mass and altered microarchitecture
The World Health Organization and International Osteoporosis Foundation define osteoporosis as “a systemic skeletal disease characterized by low-bone mass and microarchitectural deterioration of bone tissue, leading to enhanced bone fragility and a consequent increase in fracture risk.”33 Estrogen deficiency is the most important factor in the pathogenesis of postmenopausal osteoporosis. Its main effects are to increase bone resorption and remodeling. These may be transient, but in combination they accelerate trabecular microarchitectural damage, such as increased spacing (loss of interconnectivity), reduced thickness, induced perforation, and ultimately transformation of the 3D structure from plates to rods.31 Estrogen withdrawal compounds the effect of aging on cortical bone by slowing periosteal apposition while maintaining vigorous endocortical resorption, resulting in a gradually thinner cortex and net bone loss. In more severe cases, erosion of endocortical bone leads to the trabecularization of cortical bone by producing irregularly shaped giant canals and allowing adjacent resorptive cavities to coalesce, thereby blurring the distinction between cortical and trabecular bone. The combination of such cortical changes with structural deterioration of the trabecular network accounts for postmenopausal bone fragility.25

A prospective study using 2D histomorphometry and 3D microcomputed tomography (μCT) found significant microarchitectural abnormalities in bone biopsies from premenopausal women with idiopathic osteoporosis (IOP) compared with normal women. Cortices were thinner and trabeculae fewer, thin- ner, more widely separated, and heterogeneously distributed.34 Although these architectural changes resemble those in postmenopausal women, high bone turnover does not seem to be involved. Some of the affected women showed osteoblast dysfunction, with repercussions on bone formation and microstructure, but there was no evidence of an association with IGF-I, in contrast to men with IOP, where low serum IGF-I directly induces osteoblast dysfunction, resulting in low bone mineral density. Further studies are needed to determine the factors involved in the pathogenesis of IOP in premenopausal women.

Bone diseases involving very high bone formation rates (fibrous dysplasia, metastatic bone in bone metastases, Paget’s disease) synthesize bone matrix in an anarchic pattern that lays down collagen fibers in random directions. The biomechanical properties of the resulting woven or nonlamellar bone are poorer than those of lamellar bone, despite its greater mineralization.35,36

_ Effects of osteoporosis treatments on bone architecture
Although it is the main aim of osteoporosis treatments, an increase in bone mass only partly accounts for the resulting decrease in fracture incidence. Studies using quantitative techniques are now seeking to identify the effects of these therapies on bone microarchitecture.

In postmenopausal women, a high proportion of nonvertebral fractures occur at sites comprising between 70% and 80% of cortical bone. Recent reports have paid particular attention to the Haversian canals that traverse the cortex carrying blood vessels and sympathetic nerve fibers. They provide an appropriate surface for bone remodeling. 3D μCT quantification has shown that cortical fragility in osteoporotic women is partly due to bone loss associated with increased intracortical porosity. The same study found that antiresorptive agents not only improved trabecular bone microarchitecture, but also lowered the number and size of cortical pores, which could explain the observed reduction in nonvertebral fracture risk.37

Anabolic agents such as parathyroid hormone/recombinant teriparatide improve trabecular and cortical microarchitecture by inducing bone formation at quiescent surfaces and increasing bone turnover with greater stimulation of formation than resorption. Histomorphometry of transiliac bone biopsies from postmenopausal women receiving teriparatide for 12 to 24 months showed significantly higher trabecular and endosteal hemiosteon mean wall thickness than in placebo controls.38

Strontium ranelate is an antiosteoporotic treatment with a dual mode of action. Rizzoli et al recently showed that treatment for 2 years significantly improved bone microarchitecture as well as bone resistance. Improvement was significant not only versus baseline, but also versus bisphosphonate.39

Several agents with different modes of action are available to treat osteoporosis. Yet few studies have investigated the impact of switching therapies on bone cells and microstructure. Jobke et al recently reported that the bone of osteoporotic patients switched from an antiresorptive agent (bisphosphonate) to strontium ranelate responds by trabecular reorganization. Bone biopsy histomorphometry and μCT just one year after the switch to strontium ranelate revealed a substantial increase in bone volume fraction and enhanced indices of connectivity density, structure model index, and trabecular bone pattern factors, indicating that it was the architectural transformation from trabecular rods to plates that was responsible for the bone volume increase, rather than changes in trabecular thickness and number.40


The bone fragility observed in systemic skeletal disease is characterized by low bone mass and poor bone quality in terms of both biomaterial and microarchitecture. Although bone mineral mass is readily accessible and routinely measured, the investigation of bone geometry/structure represents a real challenge. Hence the burgeoning number of studies incorporating 3D iliac crest biopsy data in addition to conventional 2D histomorphometry. However, the technique is invasive, with limitations that include low sample size, sampling variation, and bone site differences (hip versus spine). A number of computerized methods have emerged, such as highresolution magnetic resonance imaging and peripheral quantitative computed tomography, to improve the monitoring of longitudinal changes in bone quality during skeletal disease, recovery, and treatment.3 However, the difficulty of developing a single method for the comprehensive investigation of bone quality reflects the complexity of interdependent factors accounting for both the strength of bone and its fragility. _

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Keywords: cortical bone; fragility; geometry; microarchitecture; osteoporosis; porosity; remodeling; trabecular bone