Neoplasia Miscellaneous

••Multiple myeloma ••Osteogenesis imperfecta

••Carcinomatosis ••Immobilization

Gastrointestinal••Pulmonary disease

••Malnutrition ••Homocystinuria

••Malabsorption ••Anemia

••Hepatic insufficiency

••Vitamin C, D deficiencies

new hypotheses in the pathogenesis of osteoporosis ( Fig. 26-11 ):

• Age-related changes in bone cells and matrix have a strong impact on bone metabolism. Osteoblasts from elderly individuals have reduced replicative and biosynthetic

potential when compared with osteoblasts from younger individuals.[22] Also, proteins bound to the extracellular matrix (such as growth factors, which are mitogenic to

osteoprogenitor cells and stimulate osteoblastic synthetic activity) lose their biologic potency over time. The end result is a skeleton populated by bone-forming cells that have a

diminished capacity to make bone. This form of osteoporosis, also known as senile osteoporosis, is categorized as a low turnover variant.

• Reduced physical activity increases the rate of bone loss in experimental animals and humans because mechanical forces are important stimuli for normal bone remodeling. The

bone loss seen in an immobilized or paralyzed extremity, the reduction of skeletal mass observed in astronauts subjected to a gravity-free environment for prolonged periods, and

the higher bone density in athletes as compared with nonathletes all support a role for physical activity in preventing bone loss. The type of exercise is important because load

magnitude influences bone density more than the number of load cycles. Because muscle contraction is the dominant source of skeletal loading, it is logical that resistance

exercises such as weight training are more effective stimuli for increasing bone mass than repetitive endurance activities such as jogging. Certainly the decreased physical

activity that is associated with aging contributes to senile osteoporosis.

• Genetic factors are also important, as noted previously. The type of vitamin D receptor molecule that is inherited accounts for approximately 75% of the maximal peak mass

achieved. Polymorphism in the vitamin D receptor molecule is associated with either a higher or lower maximal bone mass. Calcium deficiency, increased PTH levels, and

reduced levels of vitamin D also may play a role in the development of senile osteoporosis.

• The body's calcium nutritional state is important. It has been shown that adolescent girls (but not boys) have insufficient calcium intake in the diet. This calcium deficiency

occurs during a period of rapid bone growth, stunting the peak bone mass ultimately achieved; thus, these individuals are at greater risk of developing osteoporosis.

• Hormonal influences. In the decade after menopause, yearly reductions in bone mass may reach up to 2% of cortical bone and 9% of cancellous bone. Women may lose as

much as 35% of their cortical bone and 50% of their trabecular bone within the 30 to 40 years after menopause. It is thus no surprise that 1 out of every 2 women suffers an

osteoporotic fracture, in contrast to 1 in 40 men. Postmenopausal osteoporosis is characterized by a hormone-dependent acceleration of bone loss that occurs during the decade

after menopause. Estrogen deficiency plays the major role in this phenomenon, and estrogen replacement at menopause is protective against bone loss. The effects of estrogen

on bone mass are mediated by cytokines. Decreased estrogen levels result in increased secretion of IL-1, IL-6, and TNF by blood monocytes and bone marrow cells.[23] These

cytokines are potent stimulators of osteoclast recruitment and activity; they act, in part, by increasing the levels of RANK and RANKL and diminishing the quantity of OPG.

Compensatory osteoblastic activity occurs, but it does not keep pace, leading to what is classified as a high turnover form of osteoporosis.

Figure 26-11Pathophysiology of postmenopausal and senile osteoporosis (see text).

Figure 26-12Osteoporotic vertebral body (right) shortened by compression fractures, compared with a normal vertebral body. Note that the osteoporotic vertebra has a characteristic

loss of horizontal trabeculae and thickened vertical trabeculae.

Figure 26-13Diagrammatic representation of Paget disease of bone, demonstrating the three phases in the evolution of the disease.

Figure 26-14Mosaic pattern of lamellar bone pathognomonic of Paget disease.

Figure 26-15Paget disease of the humerus. A, The three sequential stages: (1) lytic, (2) mixed, and (3) sclerotic. B, Area 1, the lytic stage, is seen in close-up. Area 2, the mixed stage

(upper portion of B) reveals central and endosteal cortical resorption and replacement by less compact new bone. C, Area 3, the sclerotic stage, with irregular thickening of both cortical

and trabecular bone. (From Maldague B, Malghem J: Dynamic radiologic pattern of Paget's disease of bone. Clin Orthop 217:127, 1987.)

Figure 26-16Hyperparathyroidism with osteoclasts boring into the center of the trabeculum (dissecting osteitis).

Figure 26-17Resected rib, harboring an expansile brown tumor adjacent to the costal cartilage.

Figure 26-18A, Recent fracture of the fibula. B, Marked callus formation 6 weeks later. (Courtesy of Dr. Barbara Weissman, Brigham and Women's Hospital, Boston, MA.)

TABLE 26-5-- Disorders Associated with Osteonecrosis

Idiopathic Pregnancy

Trauma Gaucher disease

Corticosteroid administration Sickle cell and other anemias

Infection Alcohol abuse

Dysbarism Chronic pancreatitis

Radiation therapy Tumors

Connective tissue disorders Epiphyseal disorders

pathophysiology underlying steroid-induced bone infarcts is obscure. The infarcts follow high-dose steroid therapy for short periods, long-term administration of smaller doses, and even

intra-articular injections.

Morphology.

The pathologic features of bone necrosis are the same regardless of the cause. In medullary infarcts, the necrosis is geographic and involves the cancellous bone and marrow. The cortex

is usually not affected because of its collateral blood flow. In subchondral infarcts, necrosis involves a triangular or wedge-shaped segment of tissue that has the subchondral bone plate

as its base and the center of the epiphysis as its apex. The overlying articular cartilage remains viable because it receives nutrition from the synovial fluid. The dead bone, recognized by

its empty lacunae, is surrounded by necrotic adipocytes that frequently rupture, releasing their fatty acids, which bind calcium and form insoluble calcium soaps that may remain for life.

In the healing response, osteoclasts resorb the necrotic trabeculae; however, those that remain act as scaffolding for the deposition of new living bone in a process known as creeping

substitution. In subchondral infarcts, the pace of creeping substitution is too slow to be effective so there is eventual collapse of the necrotic cancellous bone and distortion, fracture, and

even sloughing of the articular cartilage ( Fig. 26-19 ).

Clinical Course.

The symptoms depend on the location and extent of infarction. Typically, subchondral infarcts cause chronic pain that is initially associated only with physical activity but then becomes

progressively more constant as secondary changes supervene. In contrast, medullary infarcts are clinically silent except for large ones occurring in Gaucher disease, dysbarism, and

hemoglobinopathies. Medullary infarcts usually remain stable over time and rarely are the site of malignant transformation. Subchondral infarcts, however, often collapse and may

predispose to severe, secondary

Figure 26-19Femoral head with a subchondral, wedge-shaped pale yellow area of osteonecrosis. The space between the overlying articular cartilage and bone is caused by trabecular

compression fractures without repair.

Figure 26-20Resected femur in a patient with draining osteomyelitis. The drainage tract in the subperiosteal shell of viable new bone (involucrum) reveals the inner native necrotic

cortex (sequestrum).

TABLE 26-6-- Classification of Primary Tumors Involving Bones

Date: 2016-04-22; view: 765