Pathophysiology of osteoporosis

Key Points

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Osteoporosis is a systemic skeletal disease characterized by decreased bone strength and increased susceptibility to fractures. The reduction in bone strength is a function of reduced bone mass and abnormal bone quality. Determinants of bone quality include bone microarchitecture, geometry, turnover, mineralization, and osteocyte viability.
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Peak bone mass is highly heritable, with genes controlling 60% to 85% of the variance at different skeletal sites. Small contributions from more than 60 genes contribute to this heritability.
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Vitamin D deficiency plays an important role in osteoporosis by increasing rates of bone loss and by increasing fracture risk through contributing to muscle weakness, impaired balance, and increased risk for falling.
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Bone remodeling describes the process by which old bone is continuously replaced by new. Net gain or loss of bone at a particular skeletal site is determined by the balance between bone resorbed by osteoclasts and bone formed by osteoblasts.
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Osteoclasts are activated by membrane signaling through receptor activator of nuclear factor-κB (RANK), the cognate receptor for RANK ligand (RANKL), which is a member of the family of tumor necrosis factor ligands expressed on marrow stromal cells (including osteoclast precursors) and osteoblasts. The RANKL–RANK interaction promotes the differentiation of osteoclast precursors and increases the activity and life span of mature osteoclasts.
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Although aging and hypogonadism are universal risk factors for bone loss, many other factors play an important role, including chronic diseases, genes, medications, lifestyle, and environmental factors.

Introduction

Osteoporosis is a systemic skeletal disease characterized by decreased bone strength and increased susceptibility to fracture. The decline in bone strength is a function of both reduced bone mass and abnormal bone quality. Determinants of bone quality include bone microarchitecture, geometry, turnover, damage accumulation, mineralization, and osteocyte viability. Osteoporosis is generally asymptomatic until clinical sequelae (i.e., fractures) occur. Osteoporotic fractures are associated with increased mortality and morbidity, including pain, disability, and reduced health-related quality of life. The ability to measure bone mass with increasing precision by noninvasive means and progress in understanding the genes related to bone formation and fracture have shed significant light on the pathogenesis of osteoporosis. Osteoporosis is a complex disease with multiple genetic, hormonal, and environmental influences. This chapter briefly reviews the role of these factors in the development of osteoporosis.

Determinants of Peak Bone Mass

Bone mass at any time in life describes the amount of bone accrued during growth and consolidation (peak bone mass) and the inevitable loss of bone with aging. Both factors contribute to the risk for fractures.

Peak bone mass occurs by the third decade, early 20 s in women and mid-20s in men, and is primarily determined by genetic factors with an estimated heritability of 60%. That being said, lifestyle and environmental factors play important roles, as do gene–environment interactions. At skeletal maturity, men have 5% to 10% greater bone mass than women because of sexual dimorphism in periosteal bone apposition at puberty. In boys, higher androgen levels cause greater periosteal apposition; in girls, estrogen inhibits this process.

Genetic Factors Affecting Bone Mass

Genes play a role in peak bone mass and bone loss with aging. Genome-wide association studies (GWASs) using metaanalyses of population-based databases of up to 70,000 individuals have identified at least 60 genes related to bone health, greatly expanding our knowledge of bone physiology. Some genes identified include those related to (1) the Wnt signaling pathway, which is critical for bone formation; (2) the RANK-RANKL-OPG (receptor activator of nuclear factor κB and its ligand, osteoprotegerin) pathway, which is involved in bone resorption; and (3) endochondral ossification, which is important in the formation of long bones. In addition, GWASs have confirmed the contribution of genes related to vitamin D and parathyroid function. Each gene identified contributes no more than 3% of the total genetic influence on bone health. In aggregate, identified genes explain less than 30% of the total genetic influence on bone health. Identification of genes related to bone turnover has directly led to new drugs for osteoporosis, such as denosumab, a human monoclonal antibody to RANKL, and romosozumab, a monoclonal antibody that inhibits sclerostin; romosozumab increases bone formation and reduces bone resorption. Sclerostin, produced by osteocytes, inhibits the Wnt pathway; conversely, inhibition of sclerostin stimulates the Wnt pathway, thereby increasing bone formation. Odanacatib, an inhibitor of cathepsin K, which is produced by osteoclasts and dissolves bone matrix, was found to significantly reduce the incidence of vertebral and nonvertebral fractures, including hip fractures, but was withdrawn from development in 2016 because of an increased risk of cardiovascular events, including stroke, in older women.

Monogenic osteoporosis

Identification of genes causing monogenetic disorders of osteoporosis has given great insight into the pathogenesis of osteoporosis. In 2001, it was discovered that a rare syndrome of childhood osteoporosis and congenital blindness, known as osteoporosis pseudoglioma syndrome, was caused by inactivating mutations in LRP5 (protein product low-density lipoprotein receptor–like protein 5), a key regulator of the Wnt pathway. Activating mutations in LRP5 cause nonsyndromic high bone mass. In the general population, LRP5 has been shown to be important for mechanosensation of bone and mediates the response of bone to physical activity.

Ethnic differences

There are also racial differences in peak bone mass and fracture risk, with blacks having 5% to 10% greater bone mass than whites and thus a lower fracture risk. This is despite blacks having lower mean serum 25-hydroxyvitamin D (25[OH]D) levels, lower average calcium intake, and higher mean parathyroid hormone (PTH) levels compared to whites. This discrepancy may be explained by the resistance of the skeleton in blacks to the bone-resorbing effects of PTH, presumably an adaptive response to reduced cutaneous vitamin D production.

Nutrition Effects on Bone Mass

Several nutrients play a key role in skeletal development, including calcium, phosphorus, and vitamin D. Increased lifetime dietary calcium intake has been directly related to peak bone mass and indirectly to hip fracture rate. In 2011, the Institute of Medicine (IOM) set the recommended daily intake of calcium at 700 mg for children 1 to 3 years of age, 1000 mg for those 4 to 8 years of age, 1300 mg for those 9 to 18 years of age, 1000 mg for adults 19 to 50 years of age, 1000 mg for men 51 to 70 years of age, 1200 mg for women older than 50 years, and 1200 mg for men older than 70 years. The IOM report also recommended daily vitamin D intake of 600 IU for those aged 1 to 70 years and 800 IU for those older than 70 years. Although sunlight exposure allows skin to produce vitamin D endogenously, use of sunblock and increasing avoidance of sun exposure with sun-protective clothing are contributing factors to an epidemic of vitamin D deficiency in the young and old.

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