Bone remodeling (Fig. 36-3) consists of a sequence of events involving the dynamic interaction of osteoclasts (bone-resorbing cells) and osteoblasts (bone-forming cells). The recruitment and activation of osteoclasts are mediated by compounds released from osteoblasts and peripheral leukocytes called bone cell cytokines. The cytokines include interleukins, tumor necrosis factor, colony-stimulating factors, and other factors that alter gene expression. After the osteoclasts are activated, they adhere to the bone surface and release hydrogen ions and proteases to break down the bone. The destroyed bone releases growth factors that increase osteoblast production and decrease osteoclast activity. The osteoblasts then lay down new bone in the cavity created by osteoclasts. The entire remodeling process takes about 100 days on average. Trabecular bone (internal, spongy, cancellous bone) undergoes more remodeling than cortical (hard compact outer layer) bone (25% versus 3% annually).

FIGURE 36-3 Effects of drugs and hormones on bone remodeling. Bone remodeling consists of two phases: bone resorption followed by bone formation. In the first phase, growth factors induce circulating preosteoclasts to differentiate to osteoclasts and attach to bone. Osteoclasts erode the mineral and matrix of bone surfaces, creating small cavities. In phase two, bone morphogenetic protein *(BMP)* and other factors induce mesenchymal cells to differentiate into preosteoblasts. Under the influence of PTH, preosteoblasts become osteoblasts and are further stimulated by insulin-like growth factor *(IGF)* to fill the cavities with new bone matrix that is subsequently mineralized. Short-term intermittent administration of teriparatide mimics the effect of PTH on bone formation and increases bone mass, but continuous long-term administration of these hormones increases bone resorption.

The balance between bone resorption and bone formation is usually maintained until the third or fourth decade of life, when a slow, age-related imbalance begins and favors resorption over formation. Hormonal and nutritional deficiencies can contribute to this imbalance.

Bone Disorders

Osteoporosis, the most common bone disorder, is characterized by a gradual reduction in bone mass that weakens bones and leads to the occurrence of fractures after minimal trauma, such as falls. Vertebral fractures are the most frequent type of fracture in patients with postmenopausal osteoporosis, a disorder partly caused by decreased estrogen secretion in this population; hip, humerus, and pelvis fractures are also major causes of immobility, morbidity, and mortality in older persons. In the United States the annual cost of osteoporotic hip fractures is currently about $11 billion, and the cost is projected to rise to $240 billion by the year 2040 if more effective methods of prevention and treatment are not developed and implemented (Box 36-1).

Box 36-1 A Case of Low Bone Density

Case Presentation

A healthy 50-year-old woman has returned to her physician to assess hormone replacement therapy. She recently entered menopause and for the past 3 months has been taking a low dose of oral estrogen and a vaginal estrogen cream along with cyclic medroxyprogesterone to relieve menopausal symptoms. The treatment has reduced hot flashes and sleep disruption, but she still has an occasional episode. Because her mother had osteoporosis and fractured her hip, the woman asks about preventive therapy. She has been taking an adequate amount of calcium and has increased her intake of vitamin D. Her physician arranges for a bone mineral density (BMD) test, which reveals that her BMD T-score is −2 (normal is greater than −1). Based on her T-score and family history of osteoporosis, her physician suggests that she begin therapy with alendronate. She will be scheduled for a follow-up BMD test in 6 months.

Case Discussion

BMD typically increases until about age 35 and then levels off until menopause. After menopause, BMD usually undergoes a sharp decline, and the risk of fractures increases with age. BMD is often determined using dual energy x-ray absorptiometry. The T-score compares a woman’s BMD in grams per square centimeter with that of healthy young adults. The T-score is calculated as the patient’s BMD minus the average young adult BMD, divided by 1 standard deviation of young adult BMDs. A normal T-score is greater than −1, whereas scores of −1 to −2.5 indicate low bone mass (osteopenia) and a risk of developing osteoporosis. Scores less than −2.5 indicate osteoporosis. Treatment guidelines recommend that women with risk factors receive preventive therapy if their T-score is less than −1.5. The risk factors include a previous fragility fracture, a family history of fracture, cigarette smoking, and low body weight (<127 pounds). Hence, the woman meets the criteria for preventive treatment, and a bisphosphonate drug is usually selected for this purpose. If this treatment does not improve her BMD, calcitonin therapy might be considered.

Paget disease of bone, or osteitis deformans, is the second most common bone disorder. Characterized by excessive bone turnover, it causes bone deformities, pain, and fractures. Its cause is unknown.

Osteomalacia is characterized by abnormal mineralization of new bone matrix. The condition has numerous causes, the most common of which include vitamin D deficiency, abnormal vitamin D metabolism, phosphate deficiency, and osteoblast dysfunction. In children, osteomalacia usually results from vitamin D deficiency and is called rickets. This disorder is uncommon today because of vitamin D–supplemented foods and sun exposure. In adults, factors such as aging, malabsorption, chronic renal impairment, and use of phenytoin or other anticonvulsant drugs can interfere with vitamin D absorption, metabolism, or target organ response and result in osteomalacia.

Calcium and Vitamin D

An adequate intake of calcium and vitamin D is essential for optimal bone formation in children and to prevent osteoporosis in adults. All persons should be encouraged by health professionals to meet the recommendations of the Institute of Medicine of the National Academies of the United States, or similar agencies in other countries, for daily calcium and vitamin D intake (Table 36-1). These recommendations can be met by ingesting calcium-rich foods, which are primarily dairy products, and by taking oral calcium and vitamin D supplements if dietary intake is inadequate. Studies have shown that adequate calcium and vitamin D intake prevents loss of bone mass and osteoporosis. For example, nursing-home residents who were given 800 International Units (IU) of vitamin D₃ and 1200 mg of calcium were found to have an increased bone density and a decreased incidence of hip and nonvertebral fractures in comparison with those who were given placebos. In another study, administration of vitamin D₃ was found to decrease the incidence of vertebral and nonvertebral fractures in women with previous fractures.

TABLE 36-1

AGE GROUP	DAILY ELEMENTAL CALCIUM (mg)	DAILY VITAMIN D₃ OR EQUIVALENT (IU)
Infants
0-6 months	400	400
7-12 months	600	400
Children, Adolescents
1-3 years	700	600
4-8 years	1000	600
9-18 years	1300	600
Men
19-70 years	1000	600
>70 years	1200	800
Women
25-50 years	1000	600
>50 years	1200	600
>70 years	1200	800
Pregnant and nursing	1000-1300	600