Disorders of bone remodeling

Abstract

The skeleton provides mechanical support for stature and locomotion, protects vital organs, and controls mineral homeostasis. A healthy skeleton must be maintained by constant bone modeling to carry out these crucial functions throughout life. Bone remodeling involves the removal of old or damaged bone by osteoclasts (bone resorption) and the subsequent replacement of new bone formed by osteoblasts (bone formation). Normal bone remodeling requires a tight coupling of bone resorption to bone formation to guarantee no alteration in bone mass or quality after each remodeling cycle. However, this important physiological process can be derailed by a variety of factors, including menopause-associated hormonal changes, age-related factors, changes in physical activity, drugs, and secondary diseases, which lead to the development of various bone disorders in both women and men. We review the major diseases of bone remodeling, emphasizing our current understanding of the underlying pathophysiological mechanisms.

Figure 1

Current model for bone remodeling. The remodeling process consists of four major distinct but overlapping phases: Phase 1: initiation/activation of bone remodeling at a specific site. Phase 2: bone resorption and concurrent recruitment of mesenchymal stem cells (MSCs) and osteoprogenitors. Phase 3: osteoblast differentiation and function (osteoid synthesis). Phase 4: mineralization of osteoid and completion of bone remodeling. In normal bone remodeling, there is no net change in bone mass and strength after each remodeling cycle. However, abnormal bone remodeling in certain pathological conditions, such as osteoporosis, causes reduced bone mass and strength. Abbreviation: BRC: bone-remodeling compartment.

Figure 2

Current understanding of the pathological mechanisms of postmenopausal osteoporosis. Dates indicate the time of the discovery of the functions. Abbreviations: FSH, follicle-stimulating hormone; IL, interleukin; M-CSF, monocyte/macrophage colony–stimulating factor; OPG, osteoprotegerin; RANK, receptor activator of nuclear factor κB; RANKL, RANK ligand; TNF, tumor necrosis factor.

Figure 3

Current understanding of the pathological mechanisms of age-related osteoporosis. (a) Pathological mechanisms of osteoporosis in women. (b) Pathological mechanisms of osteoporosis in men. Up and down arrows represent increases and decreases, respectively. Abbreviations: A, androgen; b, bioavailable; E, estrogen; FSH, follicle-stimulating hormone; IGF, insulin-like growth factor; PTH, parathyroid hormone; ROS, reactive oxygen species.

Figure 4

Current understanding of the pathological mechanisms of glucocorticoid (GC)-induced osteoporosis. (a) Inhibition of differentiation of mesenchymal stem cells (MSCs) and osteoprogenitors into osteoblasts. (b) Impairment of osteoblast function and enhancement of osteoblast apoptosis. (c) Induction of apoptosis of osteocytes. (d) Enhancement of receptor activator of nuclear factor κB ligand and reduction of osteoprotegerin expression in osteoblasts. (e) Prolonging of the life span of osteoclasts. (f) Inhibition of osteoclast function. (g) Suppression of osteoclast-generated osteogenic factors. Abbreviation: BRC, bone-remodeling compartment.

Figure 5

Radiographic changes in the left tibia of an untreated woman with Paget’s disease over 23 years (from age 45 to age 68). The arrows indicate the area of marked cortical thickening. The distal tibia appeared normal in 1964, but sclerotic changes progressively increased by 1987. Anterior bowing, which was mild in 1964, became progressively worse by 1987 (150). Reprinted with permission from Reference 151.

Figure 6

Defects in osteoclast function in osteopetrosis. The sites of the four main genetic defects in osteoporosis—CAII (carbonic anhydrase), V-ATPase (proton pump), CLCN7 (chloride channel), and CTSK (cathespin K)—are highlighted in blue.