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

of Northern European heritage and is rare in Africans, people of the Indian subcontinent, and Asians. 32 Etiology and Pathogenesis Although the pathogenesis of Paget disease remains unclear, there is evidence of both genetic and environ- mental influences. It has been reported that 15% of per- sons with the disease have a positive family history 32 and numerous studies have described extended family mem- bers with the disease. 31 There is increasing evidence that Paget disease and some related diseases are caused by mutations in genes encoding proteins in the RANK sig- naling pathways. 3,4 Other evidence presents a probable association with a virus, possibly a paramyxovirus, sug- gesting that a viral infection may serve as a trigger for development of Paget disease in genetically predisposed individuals. 4,32 The incidence and severity of Paget dis- ease of bone have decreased in recent years, possibly as a result of improved nutrition, reduced exposure to infec- tions, and a more sedentary lifestyle, which has had the effect of reducing mechanical loading of the skeleton. 32 Paget disease is a focal process with considerable variation in its stage of development in separate skeletal sites. 33 At the onset, the disease is marked by regions of furious osteoclastic bone resorption, followed by a period of hectic bone formation with increased numbers of osteoblasts rapidly depositing bone in a chaotic fash- ion such that the newly formed bone is of poor quality and is disorganized rather than lamellar. The poor qual- ity of bone accounts for the bowing and fractures that occur in bones affected by the disease. The bone mar- row adjacent to the bone-forming surface is replaced by loose connective tissue that contains osteoprogeni- tor cells and numerous blood vessels, which transport blood to and from these metabolically active sites. The lesions of Paget disease may be solitary or may occur in multiple sites. They tend to localize to the bones of the axial skeleton, including the skull, spine, and pelvis. The proximal femur and tibia may be involved in more widespread forms of the disease. Histologically, Paget lesions show increased vascularity and bone marrow fibrosis with intense cellular activity. Numerous osteo- clasts, large active osteoblasts, and peritrabular fibrosis are encountered. The rapid remodeling leads to disrup- tion of bone architecture. The bone has a somewhat mosaic-like pattern resembling pieces of jigsaw puzzle, separated by prominent areas of density, called cement lines 4 (Fig. 44-4). Clinical Features The clinical manifestations of Paget disease are extremely variable and depend on the extent and site of the dis- ease (see Fig. 44-4). The disease is usually asymptomatic and discovered as an incidental radiograph finding. 32 Skeletal expansion and distortion may be obvious if the disease affects the skull, jaw, clavicle, or long bones of the leg. Involvement of the skull causes headaches, intermittent tinnitus, vertigo, and eventual hearing loss. The vertebrae of the spine may enlarge, weaken, and collapse, causing kyphosis of the thoracic spine and

FIGURE 44-3. A child suffering from nutritional rickets. Note the bowed legs, protruding abdomen, and enlarged left wrist. (From the Centers for Disease Control and Prevention Public Health Images Library. No. 2435.)

Nutritional rickets is treated with a balanced diet sufficient in calcium, phosphorus, and vitamin D. Exposure to sunlight also is important, especially for premature infants and those on artificial milk feedings. Supplemental vitamin D in excess of normal require- ments is given for several months. Children with vita- min D–dependent rickets caused by lack of the enzyme needed to convert vitamin D to its active form are treated with calcitriol, the active form of vitamin D. 29 Vitamin D–resistant forms of rickets are treated with oral phos- phorus or oral phosphorus and calcitriol. Maintenance of good posture, positioning, and bracing in older chil- dren are used to prevent deformities. After the disease is controlled, deformities may have to be surgically cor- rected as the child grows. Paget Disease Paget disease (i.e., osteitis deformans) is the second most common bone disease after osteoporosis. 3,4,32,33 The disease, which has been described as a “collage of matrix madness,” is characterized by focal areas of excessive osteoclast-mediated bone reabsorption pre- ceding disorganized osteoblast-mediated bone repair. Paget disease usually begins during mid-adulthood and becomes progressively more common with increasing age, affecting about 5% of women and 8% of men by the eighth decade of life. 32 It is more common in people