Bone heterogeneity in relation to functional requirements
The adult human skeleton has a total of 213 bones in multiple forms: long, short, flat and irregular. Bones serve many physiological functions in human body. They are a reservoir for minerals and hematopoietic cells, they support and protect, and they facilitate the movement via tendons, ligaments and muscles attachments. Composition of the skeleton is 80% cortical bone and 20% trabecular bone. Cortical bone is dense and solid and surrounds the marrow space, whereas trabecular bone is composed of a network of trabecular plates and rods (honeycomb-like) interspersed within the bone marrow compartments. Bone matrix is composed mainly of inorganic calcium phosphate, primarily hydroxyapatite (60%) and organic material Type I collagen (30%). The remaining volume is occupied by water (10%). Bone is a mineralized connective tissue and consist of four types of cells: osteoblasts, bone lining cells, osteocytes and osteoclasts. Mechanical functions of the bone depend on its mechanical stiffness and strength. Julius Wolff’s law describes the observation that bone will adapt accordingly to imposed load, therefore, bone cells are constantly adopting, reinforcing, remodelling and realigning. Furthermore, the properties of bones changes throughout life. They can either improve or deteriorate. Heterogeneity refers to the spatial variation of structure and properties in materials. Heterogeneity of bone plays a key role in determining their mechanical performance.
Keywords: bone, function, mechanical load, heterogeneity
The adult human skeleton has a total of 213 bones in different forms. Bone serves several physiological functions in human body. It is a reservoir for minerals and hematopoietic cells, supports the body, protects vital organs, and is facilitating movement via tendons, ligaments and muscles attachments (Jepsen, 2009).
There are four principal types of bones: long, short, flat and irregular bones. Bone shape is reflection of its function. Long bones in human body include the clavicles, humerus, radius, ulna, metacarpals, femur, tibia, fibula, metatarsals, and phalanges. The long bones are composed of a hollow tubular structure forming a bone shaft, known as diaphysis, cone-shaped metaphysis at the proximal end and rounded epiphysis on distal bone end. Long bones provide strength, structure and mobility (Silverstein et al., 2016). Patellae, tarsal, carpal and sesamoid bones are the short bones. Flat bones include the skull, scapulae, mandible, sternum, and ribs. Flat bones are composed of cortical layers separated by more compliant cancellous bone, known as sandwich structure, role of which is to resist bending. Vertebrae, sacrum, coccyx, and hyoid bone are classified as irregular bones (Clarke, 2008).
Bone (osseous) tissue
Skeletal mass in the adult human skeleton is composed of 80% cortical bone and 20% trabecular bone (Clarke, 2008). Bone diaphysis is primarily composed of thick dense cortical bone and it consists of very little spongy bone. Metaphysis and epiphysis of the long bones are mainly composed of cancellous bone surrounded by thin layer of cortical bone (Clarke, 2008). In the growing animal, the ephipysis and methapysis are separated by a plate of hyaline cartilage known as a growth plate. The growth plate jointly with metaphysis cancellous bone constitutes a region where cancellous bone production and elongation of the cortex occur. Cartilaginous growth plate has been replaced by cancellous bone in adults (Cowin, 2001). The surface of bone is covered by pecriosteum, a sheet of fibrous connective tissue and inner cellular layer of undifferentiated cells. Periosteum has the potential to form bone during fracture healing and growth. The marrow cavity of the diaphysis and the cavities of cortical and cancellous bone are covered with a thin layer called endosteum (internal periosteum). Endosteum is a membrane of bone surface cells (osteoblasts, osteoclasts and bone lining cells) (Cowin, 2001). Cortical bone is usually found in outer wall of all bones and provides for support and protection to the skeleton. Cancellous bone is composed of honeycomb-like network of trabecular plates and rods and is primarily found in the inner parts of the bones. Main function of cancellous bone under synovial joints is to transfer loads to cortical bone, and this is across a joint through correct alignment and deformation. Cortical and cancellous bone are differently distributed in individual bones. They greatly differ in their development, architecture and function, blood supply and levels of age-dependant changes and fractures (Cowin, 2001). Furthermore, cortical bone is usually less metabolically active than cancellous, although this varies between species (Clarke, 2008). Studies has demonstrated that cancellous tissue is 20 to 30% less stiff than cortical tissue, however this is not closely related to the level of mineralisation but to differences between their microstructures (lamellar/collagen organization and orientation). Although numerous studies demonstrated this modulus differences, further studies are required to find the exact values of modulus for cancellous tissue. (Cowin, 2001).
Composition of bone
Bone matrix is composed mainly of inorganic calcium phosphate, primarily hydroxyapatite (60%) and organic material Type I collagen (30%). The remaining volume is occupied by water (10%) (Clarke, 2008). The bone mineral is in the form of small crystals located within collagen fibres (Cowin, 2001). Bone is a composite material and several structural levels has been identified. It is necessary to look at bone at its different structural levels to be able to understand its function and changes related to different internal and external factors throughout development. Not only molecular structure and arrangement of mineral and collagen are important, but also the organization of the bone at its tissue level (Cowin, 2001).
Bone cells responsible for constructing and maintaining bone, include osteoblasts, osteoclasts, osteocytes and bone lining cells (Jepsen, 2009). Osteoblasts are bone-forming cells. They sit on the surface of the bone and secrete non-mineralised collagen Type I, known as osteoid, towards the bone surface. They participate in calcification and resorption of bone. The osteoblasts are brick shaped cuboidal cells, derived from mesenchymal stem cells in the process controlled by transcription factors Runx2 and OSX. Their nucleus is directed away from the bone surface. When the osteoblasts are not in the process of forming new bone they are flattened cells on the bone surface known as bone-lining cells. Some osteoblasts become engulfed in the bone matrix and differentiate into osteocytes. Osteoclasts are bone-resorbing cells, they are multinucleated giant cells (1 to more than 50 nuclei). They are derived from hematopoietic stem cells in the process where osteoblasts produce macrophage colony stimulating factor (M-CSF) which in contact with RANKL produces multinucleated cell (Cowin, 2001). When active, osteoclasts are polarized and have ruffled border, where the bone resorption occurs. It is believed that osteoclasts are attached to the bone surface via cell membrane receptors known as integrins (α2β1, αVβ3). Osteocytes dissolve the bone mineral by secreting acid H+ ions originating from H2CO3 , whereas proteolytic enzyme Cathespin K digest the collagen and other proteins of bone matrix to complete the process of resorption. Osteoblasts then move into the resorption space and starts to produce osteoid. Osteoblasts and osteoclasts interact via transcription factors. Osteoclast precursors express RANK, that recognises RANKL (expressed by osteoblasts) through cell-cell interaction with osteoblast cells. Osteoprotegerin (OPG) is a secreted transcription receptor which then recognises RANKL and block the interaction between RANK and RANKL, leading to inhibiton of osteoclast differentiation and activation (Cowin, 2001).
Skeletal development begins as mesenchymal condensations early in the fetal period. These condensations ossify to form membrane bones through intramembranous ossification and cartilage bones through endochondral ossification. Cartilage bones later become chondrified and form hyaline cartilage in the shape of future bones. Bone formation begins with increase in the number of cells and fibres. The cells differentiate into osteoblasts, which lay down on unmineralized matrix and osteoid then mineralises (Cowin, 2001). The osteoblasts that become engulfed within the matrix become osteocytes. The first bone deposited in fetal period is woven bone with loosely packed collagen fibres, varying size and no special arrangements. Mechanical behaviour of woven bone is the same regardless of orientation of forces (Clarke, 2008). The lamellar bone which then replaces woven bone is not formed until after birth (Cowin, 2001).
Bone tissue is continuously remodelled through the coordinated actions of bone cells. This include bone resorption by osteoclasts and bone formation by osteoblasts. Osteocytes act as a mechanosensors and regulators of the bone remodelling process. Through the process of modelling bone is able to adapt to changing biomechanical forces, whereas remodelling has an important role in removing old, micro damaged bone and replacing it with new, mechanically stronger bone. This helps to preserve bone strength. (Clarke, 2008). As positive, remodelling also have negative effects on bone quality on the tissue level. Remodelling of cortical bone increases porosity and decreases cortical width, whereas remodelling of trabecular bone may perforate and remove trabeculae (Cowin, 2001). Bone remodelling process consists of three phases: initiation of bone resorption by osteoclasts, the transition from resorption to new bone formation and the bone formation by osteoblasts (Florencio-Silva et al., 2015).
How does bone respond to loading?
The physical forces acting on bone during daily activities induce tissue-level strains, which are directly affecting skeletal growth, the development of trabecular architecture, peak bone mass, cross-sectional shape, matrix architecture and the anatomical relationship within skeletal elements (Jepsen, 2009). This process ensures that, for example, long bones are stiff enough to support loading demands and sufficiently strong to resist fracturing (Ruff et al., 2006). Julius Wolff’s law describes the observation that bone will adapt accordingly to imposed load, therefore, bone cells are constantly adopting, reinforcing, remodelling and realigning (Ruff et al., 2006). “Input determines output” (Jepsen, 2009). Lot of research has been carried out on animal model of the rat for better understanding of the principles of responses to increased loading (Cowin, 2001). In this particular experiment, the axial load has been applied to the rat ulna (Figure 1). The rat was subjected to forelimb loading 3 times a week for 16 weeks. The duration of each loading session was 3 minutes. This short loading program substantially changed the shape of the bone section. Ulna is curved and when exposed to loading it bows. This bowing causes a predictable pattern of strain within the bone tissue. Compressive strain is the highest and it is located on the medial surface, followed by tensile strain on the lateral surface. Bone exposed to mechanical loading undergoes formation following a pattern consistent with the distribution of strain energy. This pattern is found to dramatically improve function in rat ulna. With change of bone size, there is an increase in bone mineral content for 7% which improves bone strength by 64%. After 16 weeks of loading the rat ulna will sustain 100-fold more loading cycles before failure or the actual energy required to fracture is 94% higher than prior to this experiment. These results suggest that bone tissue contains sensors of strain energy which are mostly contained in the osteocytes. Osteocytes are not able to form new bone, so it is believed that they send signals to osteoblasts that enhances their bone forming activity. It is believed this is an osteocyte-specific secreted protein known as sclerostin (Robling and Turner, 2009).
Figure 1 Red = the highest strain energy, white = the lowest strain energy. A cross-section from a rat ulna is shown in the right panel. The red line is showing the outline of the bone at the beginning of the experiment. One can clearly see where the bone was formed and these locations correspond with the red and orange regions in the middle panel (Robling et al., 2002, Robling et al., 2006, Robling and Turner, 2009)
Bone adaptation to exercise
Exercise has generally been considered to have a positive influence on bone health. The popular treadmill exercise model has been used in several studies to review the effects on bone in young and adult rats. The purpose was to test effects on bone mass, metabolism and strength in rats. Considering that rat is a tetrapedal animal, appendicular bones are exposed to a greater mechanical loading compared to axial, whereas in bipedal humans the loading would be equally split between these two. Therefore, the effect of running exercises on lumbar spine in rats cannot be applied to humans. It has been found that treadmill exercise enhances cortical and cancellous bone mass of the tibia as a result of a positive bone turnover, meaning that increased formation and decreased bone resorption were observed in young and adult rats. Positive effect on lumbar bone mass appears to be significant only in long-term exercise, where increase in mas has been observed. Furthermore, treadmill exercise increases bone strength of femur, again, as a result of a positive bone turnover (Iwamoto et al., 2005). Several studies demonstrate that treadmill exercise stimulates bone formation and supresses bone resorption in rats, therefore they may increase bone mass, prevent bone loss and increase bone strength (Iwamoto et al., 2004).
Bone ageing and disease
Bone undergoes different changes throughout life, and its properties do not remain constant with age. Function can either improve or deteriorate. Changes are observed in bone mechanical behaviour, bone morphology, bone tissue and composition. Bone is composed and structured in a balance to resist fractures. Its stiffness and strength enable to respond to large loads, whereas ductility is required to absorb the energy from the impact loads. Studies has shown that strength of bone is defined by the amount of mineral that is there (Boskey and Coleman, 2010). During development bone shape changes in respond to load, as observed within Wolff’s law and demonstrated through exercise experiments in various animals. This happens through a process known as “cortical drift”. Cortical drift occurs when bone formation is decreased and resorption increased, resulting in cortical thinning. In the healthy individual, bone formation and resorption are balanced. Studies has shown that in humans, as well as in animals, bone gets stiffer with age, and the trabecular surface responsible for distribution of mechanical load, decreases. This results in increased stress and bone deformation, which may lead to fractures. Furthermore, studies had shown that bone mineral density (BMD) is reduced with later aging. The mineral content of bone (also referred to as “ash content”) increases with age and as observed in studies, breaking stress of bone increases exponentially with ash content, while bone resistance to fracture (toughness of bone) declines as the ash content increases (Boskey and Coleman, 2010).
Is osteoporosis disease of aging?
Osteoporosis (“silent disease”), is a disease that occurs in both women and men and is associated with loss of bone mass and increased risk of fracture. Osteoporosis is not necessarily the disease of aging but its incidence increase with age, therefore it is age-associated (Boskey and Coleman, 2010).
Bone is a composite material and heterogeneity refers to the spatial variation of structure and properties in materials. Heterogeneity of bone plays a key role in determining their mechanical performance. One can clearly see that the mechanical properties of bone are somehow dependant upon the properties of its constituents. Different variations in bone size, and its composition are observed across species, between populations, types of bones and sexes.It is necessary to look at the bone at its different structural levels to be able to understand its function.
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