Bone microarchitecture describes the structure of the cortical and trabecular compartments and can be assessed invasively by histomorphometric examination of bone biopsies or noninvasively using high-resolution peripheral quantitative computed tomography (HR-pQCT ) . Within the trabecular compartment, greater trabecular number confers higher resistance to compressive forces. Trabecular thickness is also an important determinant of deformation. While both trabecular number and trabecular thickness are important determinants of fracture risk, bone loss through trabecular number confers greater structural compromise than bone loss through trabecular thinning [7, 8]. Interconnections between individual trabeculae are important to maintaining the overall structure of the compartment. Greater trabecular separation compromises the integrity and strength of the bone. Sex differences are observed in trabecular arrangement which additionally contribute to the greater fracture risk in women: young women have fewer and thinner trabeculae with higher trabecular separation than young men [4, 9]. With aging, there is greater reduction in trabecular number in women than men [4, 9].

The outer cortex provides a dense outer shell, but increasing porosity and “trabecularization” reduce bone strength. At PBM, females have lower cortical porosity than males; however, this is offset by the greater CSA and cortical thickness in the males, such that strength is not compromised [4]. However, porosity increases with aging in both sexes, and this occurs at a faster rate in women than men, such that at age 80 years, cortical porosity is greater in women [4, 10].

At the cellular level, there are three main types of bone cells: osteoblasts, osteocytes, and osteoclasts. In simple terms, osteoblasts are responsible for bone formation and may become embedded within bone mineral as mature osteocytes or remain on the surface of the bone as bone-lining cells. In contrast, multinucleated osteoclasts resorb bone. Osteoblasts and osteoclasts act in a coordinated fashion at specific sites on the surface of trabecular or cortical bone, forming “bone multicellular units” (Fig. 1.2).

After new osteoid collagen matrix is laid down by osteoblasts, crystals of calcium hydroxyapatite form on the collagen fibrils, thus achieving mineralization of the bone tissue over succeeding weeks and months. Modeling is defined as the process by which bone mass is acquired during growth, repair, and adaptation to mechanical loading. In contrast, remodeling involves a cycle of resorption and formation of existing bone. Thus the balance between bone formation and resorption has a critical influence on overall bone mass and strength. During growth, formation clearly exceeds resorption, and after the achievement of PBM, the two opposing forces are in relative balance. However, as age increases into later adulthood, resorption begins to outstrip formation, and often the remodeling rate increases, reducing the opportunity for resorption cavities to be filled with new osteoid and for them to undergo a secondary mineralization. Over recent years, it has been recognized that osteocytes, which comprise 90–95 % of the cells within bone, play a key role in the regulation of these processes. The arrangement of the osteocytes within the lacunocanalicular system acts as a mechanosensory system and allows communication both directly and through the release of endocrine, paracrine, and autocrine signaling molecules to the other bone cells. There are a number of pathways which are important to the regulation of osteoblast and osteoclast activity. These are becoming increasingly recognized as targets for anti-osteoporosis agents.

Osteoblasts are the primary source of receptor activator of nuclear factor κB ligand (RANK-L) , which binds to RANK on osteoprogenitor cells, stimulating the differentiation of osteoclasts and activating bone resorption [13, 14]. The production of RANK-L by osteoblasts is increased in response to disuse, estrogen deficiency, and some medications including glucocorticoids and chemotherapeutic agents [15]. The activity of RANK-L is antagonized by osteoprotegerin (OPG), which competitively binds to RANK. This prevents the binding of RANK-L to RANK, and therefore the balance of OPG and RANK-L will determine the extent of bone resorption.

The Wnt signaling pathway has a key role in osteoblast differentiation, proliferation, and bone mineralization. The activation of this pathway in osteoblasts occurs through the binding of Wnt to a membrane receptor complex comprising Frizzled (Fzd) and either low-density lipoprotein-related protein 5 (LRP5) or 6 (LRP6). This leads to cytoplasmic accumulation of β-catenin, which can subsequently increase osteoblast differentiation. There is simultaneous repression of osteoclast function through increased secretion of OPG by osteoblast and osteocytes in response to Wnt signaling. However, in remodeling, osteoclasts appear to release Wnt ligands to stimulate local differentiation of osteoblasts [16]. The importance of this pathway to bone mineralization is demonstrated clinically by the osteoporosis-pseudoglioma syndrome, which results from loss of function mutations in LRP5. Conversely, gain-of-function mutations in LRP5 can result in a high bone mass phenotype [16]. Osteocytes regulate osteoblast differentiation through secretion of sclerostin (SOST) , an antagonist of Wnt signaling which competitively binds to LRP5/6. Thus, lack of sclerostin also results in high bone mass, as observed in van Buchem disease and sclerosteosis [16]. Furthermore, osteocytes also express Dickkopf-1 (DKK1) , but to a lesser extent than sclerostin. DKK1 also antagonizes Wnt signaling and thus reduces bone mineralization. No single gene defects in DKK1 associated with alterations in bone mass have been identified, but single nucleotide polymorphism (SNP) in DKK1, in addition to other genes in the Wnt signaling pathway, has been associated with BMD in genome-wide association studies (GWAS ) [17].