Bones vary widely in their shape but can be broadly divided into two categories: flat bones (skull bones, scapula, mandible etc.) and long bones (tibia, femur, humerus etc.). These two categories are based largely upon the method of bone formation by which these bones develop. The bones of the appendicular skeleton, as well as the bones of the vertebral column and base of the skull, are formed by endochondral ossification. In this process, bone forms through a cartilage intermediate that is produced by chondrocytes, providing a template upon which osteoblasts can form new bone. By contrast, flat bones, including most of the bones of the face, the vault of the skull and the pelvis, are formed by intramembranous ossification. In intramembranous ossification, osteoblasts form bone matrix de novo, without a cartilage anlage (Olsen et al., 2000). These two methods of bone formation are present, not only during development, but in adult life as well. For example, a fracture heals via endochondral bone formation, where a cartilage callus is first formed, followed by bone formation in the callus, and finally, remodeling to repair the fracture site to its original anatomic state. Intramembranous bone formation is less common in adult life, but it can be observed in such clinical settings as distraction osteogenesis for limb lengthening. In this procedure, an osteotomy is performed on a long bone and the two ends of bone are separated by a defined distance and externally fixed. This distance is then increased at regular intervals by turning a screw on the external fixator, stimulating bone formation between the bone ends and, thus, lengthening the limb. In the space between the two cut bone ends, known as the distraction gap, osteoblasts form new bone directly, without a cartilage template.

Gross inspection of the skeleton reveals that there are two types of bone tissue found in all bones: cortical (compact) bone and trabecular (cancellous) bone. Cortical and trabecular bone have the same matrix composition (predominantly collagen with hydroxyapatite mineral), but the mass of the cortical bone matrix per unit volume is considerably greater due to higher mineral content. Much of the difference between cortical and trabecular bone is secondary to the dual function of bone as both a structural element and a reservoir for calcium in the body. Cortical bone forms the dense outer shell (cortex) of long bones, such as the femur, and bears the majority of mechanical force exerted on the skeleton. This dense (generally 90% by volume calcified) cortical tissue is the predominant type of bone in the diaphysis (midshaft) of long bones, where little or no trabecular bone is present. Moving toward the end of the femur, the thick cortical walls of the diaphysis become thinner and increase in diameter. This region, the metaphysis, is where spicules of trabecular bone emerge, formed from the cartilage template produced by chondrocytes in the epiphyseal growth plate. Still further toward the end of the femur and nearing the knee, atop the epiphysis, is a thin shell of subchondral bone that underlies articular cartilage. As well as occupying the ends of long bones as described above, trabecular bone forms the greater part of each vertebral body and is present at other sites such as the iliac crest. Interestingly, despite accounting for nearly 60% of the surface area of bone in the body, trabecular bone represents only 25% of the total skeletal mass (Fernandez-Tresguerres-Hernandez-Gil et al., 2006). This allows a large surface area for osteoclasts to resorb bone mineral and release calcium rapidly when necessary, while the dense cortical bone remains relatively unaffected and capable of bearing the mechanical loads applied to the skeleton. Trabecular bone is the most metabolically active compartment of the skeleton, with a high rate of turnover and a blood supply that is much greater than that of cortical bone (Banse, 2002).

Osteoclasts are large, multinucleated cells found on bone surfaces that are responsible for bone resorption. Specific hormones and growth factors produced by osteoblasts and osteocytes (as well as other cell types in pathological conditions) influence their development from monocyte/macrophage precursors. These precursors differentiate and fuse together to form osteoclasts on the surface of bone, where they are very efficient at destroying bone matrix. They begin by binding to the surface of the bone and creating a sealed space between the cell membrane and the bone matrix. Osteoclasts then use membrane bound proton pumps to transport protons into, and acidify, the sealed space, decreasing the pH from ~7 to 4. This acidic environment solubilizes the hydroxyapatite mineral found in bone, releases calcium and phosphate, and allows access to the organic matrix, which is degraded by osteoclast-secreted acid proteases. Growth factors bound in the organic matrix are also released during this process, which stimulates osteoblast formation and, thus, couples the two processes to ensure proper maintenance of bone mass (Fernandez-Tresguerres-Hernandez-Gil et al., 2006).

Osteocytes, as mentioned previously, differentiate from a subset of mature osteoblasts and become entombed within lacunae in the newly formed, mineralizing bone matrix. During this process, they form an extensive network of neuron-like cell projections, connecting them to other osteocytes, osteoblasts, bone-lining cells, blood vessels and nerves through a vast canalicular network in bone. Unlike the relatively short-lived osteoclasts (~3 weeks) and osteoblasts (~3 months), osteocytes have an estimated life span of 10–20 years in humans and comprise 90–95% of bone cells. Although their precise function has yet to be clearly established, osteocytes are widely assumed to play a role in transducing mechanical forces into anabolic signals within bone, allowing bone to adapt to increased or decreased activity. More recently, they have been demonstrated to produce factors that can regulate both osteoblast and osteoclast development, implicating them as a possible ‘conductor’ in orchestrating bone remodeling. In addition, osteocytes secrete a growth factor known as fibroblast growth factor 23 (FGF23), which regulates phosphate homeostasis through endocrine actions in the kidney (Bonewald, 2011). Despite their populous nature and obvious importance in bone physiology, many aspects of osteocyte function remain undefined due to their highly specialized microenvironment in bone and the inherent technical difficulty in generating faithful model systems.

The peak bone mass attained in adult life is governed by a combination of genetic, hormonal (predominantly estrogen, GH and IGF-1), nutritional and mechanical factors (Bonjour et al., 1994). In humans, this peak bone mass is attained in the third decade of life and is a large determinant of one’s susceptibility to fractures later in life regardless of sex, race etc. This is because a slow loss of bone mass (~0.5% per year) begins around age 40 in both sexes and continues for the rest of life (Mazess, 1982; Clarke & Khosla, 2010). Thus, the greater the peak bone mass, the longer it will take to reach the threshold of bone density at which fracture risk begins to rise. At all ages, however, women have a lower bone mass than men and, with increasing age, this gap widens. This widening gap is largely the result of an accelerated period of bone loss in women around the time of menopause, when bone loss rates of 5–6% per year for up to 10 years are not unusual. This accelerated loss is associated with the withdrawal of estrogen (Dempster, 2003; Downey & Siegel, 2006; Clarke & Khosla, 2010), which results in a dramatic increase in bone resorption – as much as 90% as indicated by biochemical markers. Bone formation markers are also increased during menopause (although formation decreases later), but only by 45%, thus favoring the high turnover bone loss that decimates bone density in postmenopausal women.

Men do not suffer the sudden drop in sex steroid levels and concomitant rapid bone loss observed in women, and they are, therefore, less susceptible to fracture than females with age because they retain a greater percentage of their bone mass. The slow bone loss that is observed in men was long assumed to result from reduced serum testosterone, as it predominates in many other aspects of male physiology. In recent years, however, numerous studies have proved this not to be the case. In fact, reduced estrogen – converted by aromatase from testosterone – is responsible for age-related bone loss in men. Further, estrogen actually appears to be critical for proper bone growth in men earlier in life. Thus, throughout life in both genders (even into the eighth and ninth decades), estrogen has significant anabolic effects on bone, and its reduction accounts for a large portion of age-related bone loss (Raisz, 2005; Clarke & Khosla, 2010).

In both genders, levels of parathyroid hormone (PTH) tend to gradually increase with age (Ledger et al., 1995). Parathyroid hormone is responsible for maintaining calcium balance in the body, in concert with vitamin D, by regulating bone resorption, calcium reabsorption in the kidney and calcium absorption in the small intestine (Quarles, 2008). Although this gradual rise in PTH level is certainly multifactorial, vitamin D deficiency is common among the elderly and likely contributes to bone loss by disturbing this PTH–vitamin D endocrine loop. Thus, as blood calcium would drop from reduced vitamin D (thereby less intestinal calcium absorption and renal reabsorption of calcium), PTH would stimulate additional bone resorption to maintain healthy blood calcium levels, thereby further contributing to age-related bone loss. Although the cause of vitamin D deficiency with age remains unclear, recent studies have identified an inverse correlation between BMI and vitamin D levels (Wortsman et al., 2000; Vimaleswaran et al., 2013). It has been suggested that the reduction in vitamin D may result from the increased fat mass capable of storing vitamin D and thus sequestering it from the circulation, providing a possible explanation for reduced vitamin D levels in the elderly since body fat, much to our chagrin, unavoidably increases with age.

As mentioned previously, bone formation rates decline in both sexes with increasing age. This drop in osteoblast function and bone formation parallels the reduction in GH and IGF-1 levels observed in aging (Perrini et al., 2010). These two factors have been demonstrated, in numerous studies, to be critical for osteoblast proliferation, survival and function, particularly mineralization. The GH/IGF-1 axis is also intimately linked to the positive effects exerted by sex steroids on bone, particularly during pubertal growth (Olson et al., 2011). Thus, it is likely that the decline of GH and IGF-1 levels also contributes significantly to age-related bone loss by failing to sufficiently stimulate bone formation.

Immobility (Fox et al., 2000), systemic acidosis (as might be seen with poor kidney function) (Arnett, 2003) and some pharmaceutical agents (e.g. glucocorticoids and corticosteroids) (Weinstein, 2012) can also impact on bone mass in a negative fashion. Unfortunately, it is not uncommon for an individual to encounter one or more of these negative modifiers with increasing age. In this regard, reduced activity and/or immobility due to injury pose an especially significant risk for exacerbating frailty and increasing fracture risk in an elderly population. Muscle mass and function also suffer significant loss with disuse and aging (Jang & Van Remmen, 2011; Marimuthu et al., 2011), leading to an increased propensity for falls and, with concomitant bone loss, even greater risk of fracture. Other factors that can impair osteoblast function and stimulate osteoclast formation/activity include chronic inflammation – possibly associated with cellular senescence (Freund et al., 2010) – and accumulated oxidative damage (Almeida et al., 2007), as might be observed with long-term obesity. Finally, nutrition also contributes to bone loss with age, beyond simply vitamin D and calcium intake, since appetite decreases. This decrease in appetite results in a reduction of both macro- and micronutrients across the board. For example, reduced protein intake has been linked to poorer bone mass in the elderly (Bonjour, 2011). This observation is not surprising when one considers that the vast majority of bone is organic collagen matrix, which requires adequate protein building blocks to produce and maintain.