This chapter presents current available data on the epidemiology of bone and mineral diseases including osteoporosis, low bone mass (osteopenia), vitamin D deficiency, primary hyperparathyroidism, primary hypoparathyroidism, hypercalcemia, hypocalcemia, Paget’s disease of the bone, and phosphate disorders.
According to the World Health Organization (WHO), in 1994 osteoporosis affected more than 75 million people in the United States (US), Europe, and Japan. 1
In 2010, Watts et al. reported that of Americans with osteoporosis and low bone mass, 80% were women (mostly postmenopausal), and that at age 50, the projected lifetime risk of fractures was 39% in Caucasian women and 13% in Caucasian men.2 The National Health and Nutrition Examination Survey (NHANES) III (1988-94) estimated that by age 60 years, half of Caucasian US women have osteopenia or osteoporosis. Based on male bone density comparison values, 1-2 million men were estimated to have osteoporosis, and 8-13 million were estimated to have osteopenia.3 Table 1 shows data on the incidence of osteoporotic fractures as compared to other disorders in women.4-6
|US Census Bureau; US Nationwide Inpatient Sample Database||US Population||Fractures||1.4 million||Burge et al. 20074|
|American Heart Association||Total new and recurrent strokes among all US women||New strokes||373,000||Rosamond et al. 20075|
|American Heart Association||Total new and recurrent myocardial infarction among all US women||Heart attacks||345,000||Rosamond et al. 20075|
|National Cancer Institute||New cases in the US||Invasive breast cancer||213,000||American Cancer Society. 20066|
Abbreviations: US, United States
In 2005, there were over 2 million fractures associated with osteoporosis in the US. This number translated to a cost of approximately $17 billion, with men accounting for 29% of the fractures and 25% of the costs.4 In addition, in Europe and the Americas osteoporotic fractures accounted for 2.8 million disability-adjusted life years (more than those caused by hypertension and rheumatoid arthritis but less than those caused by diabetes mellitus or chronic obstructive pulmonary diseases).7 Table 2 presents data on the cost breakdown of osteoporotic fractures in the US.
|Total Number Of Fractures||Direct Costs *||Cost Breakdown|
|2 million (71% in women)||$17 billion||Inpatient care: 57%|
|Long-term care: 30%|
|Outpatient care: 13%|
Source: Burge et al. 20074
By 2025, it is estimated that both the incidence and costs associated with osteoporosis will rise by 50%, with over 87% of the increase expected among those age 65-74 years.4 Table 3 summarizes the cost of osteoporotic fractures in the US, by sex, age, and race/ethnicity.
|Cost In US Dollars (Billions)|
Source: Burge et al. 20074
1.3.1 From Mechanisms of Bone Metabolism to Therapeutic Applications
Table 4 summarizes the many recent and emerging therapies targeting bone metabolism.
|RANKL||RANKL is a cytokine that regulates skeletal metabolism.||Denosumab, a RANKL inhibitor, was first approved by the US FDA in 2010 for postmenopausal osteoporosis; now it has additional approved indications.||Takayanagi. 20098|
|Sclerostin||Sclerostin is a negative regulator of bone mass; inhibiting sclerostin increases bone formation.||An antibody that targets sclerostin (decreasing endogenous levels of sclerostin while increasing BMD) is currently in phase-III clinical trials.||Compton and Lee. 20149|
|Cathepsin K||Cathepsin K is produced by activated osteoclasts; it degrades type 1 collagen and, thus, helps to initiate the bone resorption process.||Cathepsin K inhibitor phase 3 clinical trials have been completed.10||Costa et al. 201111|
|PTHrP||PTHrP regulates endochondral bone development and can simulate some of the actions of parathyroid hormone.||Abaloparatide, a synthetic PTHrP analog, phase 3 clinical trial has been completed.||Leder et al. 201412|
Abbreviations: RANKL, receptor activator of nuclear factor Κb ligand; US, United States; FDA, Food and Drug Administration; PTHrP, parathyroid hormone-related protein; BMD, bone mineral density
1.3.2 The Hormonal Interface Between Bone and Other Organ Systems
Besides its mechanical function, bone is itself an endocrine organ.13 For example, undercarboxylated osteocalcin is secreted by osteoblasts and has been implicated in the regulation of insulin secretion, insulin intolerance, and glucose homeostasis in patients with type 2 diabetes mellitus or on a high-fat diet.14 Bone has also been associated with a lipotoxicity-associated loss of insulin receptors, resulting in insulin resistance.15 Similarly, others have shown that osteocalcin enhances the synthesis of adiponectin, which is involved in glucose regulation and the breakdown of fatty acids in animals fed a normal diet.16
In addition to its effects on metabolism, osteocalcin appears to act also via the testis to regulate reproductive functions in male mice through its effects on testosterone production.17
1.3.3 Intercellular Communication Systems Among Bone Cells (Osteoblasts, Osteoclasts, and Osteocytes)
Research has indicated that the continuous modeling and remodeling of bone is controlled by signals exchanged between effector cells. Specifically, osteoblast-lineage cells—including osteoblast progenitors, matrix-producing osteoblasts, bone-lining cells, and matrix-embedded osteocytes—stimulate osteoclast differentiation by producing inhibitory and stimulatory factors.18
Until recently, osteocytes have been considered passive and metabolically inactive cells. However, current evidence indicates that osteocytes are multifunctional cells that play important roles in the homeostasis and/or regulation of bone mineral, phosphate, and calcium metabolism. Osteocytes also coordinate the skeleton’s response to mechanical loading. They survive for decades within the bone matrix, which makes them among the body’s longest-living cells.19 These processes require tight control of the bone remodeling process, which involves ensuring the availability of mesenchymal precursors and local signaling molecules that promote differentiation in the osteoblast lineage.20 Furthermore, during their development from pluripotent precursors to matrix-embedded osteocytes, osteoblast-lineage cells produce regulatory signals that control the differentiation and activity of bone-forming osteoblasts and bone-resorbing osteoclasts.21
1.3.4 New Skeletal Imaging Modalities and their Clinical Applicability
In addition to probing the signaling pathways by which bone is modeled or remodeled, advancements in skeletal imaging are also noteworthy. These are summarized in Table 5.
|Skeletal Imaging Modality||Potential Therapeutic Application||Reference|
|HR-Pqct||HR-Pqct helps to identify microstructural deterioration and reduced bone strength.||Nishiyama and Shane, 201322|
|TBS||TBS is a texture analysis of lumbar spine DXA images. It infers bone microarchitecture not shown by DXA; TBS has been used in cross-sectional and longitudinal studies to predict fractures in combination with DXA.||Silva et al., 201423|
|μCT||Total area ratios derived from μCT 2-dimensional measurements of bone area may predict bone porosity. In humans, mCT can only be used on ex vivo specimens due to the radiation exposure.||Sandino et al., 201424|
|Hand-held reference point indentation instrument||Results are reported as an index of bone material strength and have been helpful in assessing this element of bone quality in diseases such as diabetes mellitus.||Farr et al., 201425 and Randall et al., 201326|
Abbreviations: μCT, micro-computed tomography; HR-pQCT, high-resolution peripheral quantitative computed tomography; DXA, dual-energy x-ray absorptiometry; TBS, trabecular bone score