Porth's Essentials of Pathophysiology, 4e

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Disorders of the Skeletal System: Metabolic and Rheumatic Disorders

C h a p t e r 4 4

bone resorption by inhibiting osteoclast activity. The most dramatic impact has been in the reduction of multiple spine fractures, showing that treatment can decrease progression of the disease. These drugs are effective in men as well women and for various causes of osteoporosis. 24 Raloxifene, a selective estrogen receptor modula- tor (SERM) that acts only on specific estrogen recep- tors, has been approved for prevention and treatment of osteoporosis in postmenopausal women. Although hormone therapy (i.e., estrogen with or without proges- terone) has been shown to slightly reduce the risk of hip and vertebral fractures in postmenopausal women, the use of hormone therapy has come under scrutiny after the release of data from the Women’s Health Initiative, which linked hormone replacement therapy to an increased risk of stroke, venous thromboembolism, coronary heart disease, and breast cancer. 25 Raloxifene does not prevent hot flashes associated with menopause and it imposes the same risk of venous thrombosis as estrogen. 24 Calcitonin is an endogenous peptide that partially inhibits osteoclastic activity. Nasal calcitonin has been approved for the treatment of postmenopausal osteo- porosis. It has been shown to decrease the occurrence of vertebral fractures, but not nonvertebral or hip frac- tures. Because more effective drugs are available, it is not usually considered first-line treatment for osteoporosis. Teriparatide, a recombinant human parathyroid hor- mone, stimulates bone remodeling by increasing osteo- blast-mediated bone formation. Unlike the fluoride, this bone appears structurally normal and is associated with substantial reduction in the incidence of fractures. Teriparatide is given by injection and is approved for only 2 years of use. 24 Denosumab, the RANKL inhibitor, has recently been approved for treatment of postmenopausal osteoporo- sis. 24 It is given subcutaneously every 6 months. Like the biphosphonates it suppresses bone resorption and sec- ondary bone formation. Denosumab reduces the risk of both vertebral and nonvertebral fractures with compa- rable effectiveness to the potent biphosphonates. 24 To reduce their fracture risk, persons with osteopo- rosis should correct conditions in their homes that pre- dispose them to falls. They should follow their health care provider’s prescribed diet and program of physical activity. In treating fractures, it is important to minimize immobility. Surgical interventions are used to provide stable fixation of lower extremity fractures and allow for early weight bearing and restoration of mobility and function. Vertebral fractures are treated symptomati- cally. Conservative treatment with bracing is most often seen, especially in fractures of the thoracic vertebra. Osteomalacia and Rickets In contrast to osteoporosis, which causes a loss of total bone mass and results in brittle bones, osteomalacia and rickets produce a softening of the bones resulting from an inadequate mineralization of newly formed bone

matrix. 4 The term rickets refers to the disorder in chil- dren in which changes in bone growth produce charac- teristic skeletal abnormalities, and osteomalacia is used in adults because the bone that forms during the remod- eling process is undermineralized. 4 Osteomalacia Osteomalacia is a generalized bone condition in which there is inadequate mineralization of bone. 3,4,15 There are two main causes of osteomalacia: (1) insufficient calcium absorption from the intestine because of a lack of dietary calcium or a deficiency of or resistance to the action of vitamin D and (2) phosphate deficiency caused by increased renal losses or decreased intestinal absorp- tion. Vitamin D is ingested in the diet and synthesized in the skin from 7-dehydrocholesterol under the influ- ence of ultraviolet B (UVB) sunlight. The vitamin is first hydroxylated in the liver to form its major metabolite, 25-hydroxyvitamin D. It is then hydroxylated in the kidney to produce the active hormone 1,25(OH) 2 D (see Chapter 42). There are many causes of vitamin D deficiency including reduced skin synthesis, inadequate dietary intake, diminished intestinal absorption, and heritable and acquired disorders of vitamin D metabo- lism and responsiveness. 26,27 The incidence of osteomalacia is high among the elderly because of diets deficient in calcium and vita- min D, a problem often compounded by the intestinal malabsorption that accompanies aging. Melanin is extremely efficient in absorbing UVB radiation; thus, decreased skin pigmentation markedly reduces vitamin D synthesis, as does the use of sunscreens. Osteomalacia also may occur in persons on long-term treatment with medications such as anticonvulsants (e.g., phenytoin, carbamazepine, valproate) that decrease the activation of vitamin D in the liver. There also is a greater inci- dence of osteomalacia in the colder regions of the world, particularly during the winter months when UVB radia- tion is inadequate to allow skin synthesis of vitamin D. A form of osteomalacia called renal rickets occurs in persons with chronic renal failure. It is caused by the inability of the kidney to activate vitamin D and excrete phosphate and is accompanied by hyperparathyroidism, increased bone turnover, and increased bone resorption (see Chapter 26). Another form of osteomalacia results from renal tubular defects that cause excessive phos- phate losses. This form of osteomalacia is commonly referred to as vitamin D–resistant rickets, and often is a familial disorder. 4 It is inherited as an X-linked domi- nant gene passed by mothers to one half of their chil- dren and by fathers to their daughters only. This form of osteomalacia affects boys more severely than girls. Long-standing primary hyperparathyroidism causes increased calcium resorption from bone and hypophos- phatemia, which can lead to rickets in children and osteomalacia in adults. The clinical manifestations of osteomalacia are bone pain, tenderness, and fractures as the disease progresses. In severe cases, muscle weakness often is an early sign. Osteomalacia predisposes a person to pathologic