Bones, Joints, and Soft Tissues
The skeletal system provides structural support and protection to the human body and its internal organs, serves as primary home for blood-forming tissues, and stores several vital minerals, above all, calcium. This chapter focuses on alterations of the bony (structural support) part of the skeletal system. Calcium metabolism is also discussed with the endocrine system (chapter 12), and blood-forming tissues are treated separately in the chapter about hematopoietic and lymphatic tissues (chapter 10).
Metabolic Bone Diseases
Metabolic bone diseases include diseases of increased bone resorption, such as osteoporosis, and of calcium metabolism, such as rickets, osteomalacia, hyperparathyroidism, and renal osteodystrophy. Primary osteoporosis is an age-related disorder preferentially affecting women that ultimately may cause a loss of 35% to 50% of cortical or trabecular bone mass. It is related to hormonal influences (e.g., estrogen deficiency), reduced physical activity, and nutritional and genetic factors. Secondary osteoporosis follows a large variety of diseases, including malabsorption or malnutrition, endocrine disorders (e.g., hyperparathyroidism or hypoparathyroidism, hypogonadism, and type 1 diabetes) and neoplastic diseases, such as multiple myeloma and bony metastases. Disorders in calcium homeostasis cause reduced matrix mineralization with osteopenia. Primary and secondary hyperparathyroidism (with the latter related to renal insufficiency) are characterized by increased osteoclastic bone resorption with features of dissecting osteitis and osteitis fibrosa cystica (von Recklinghausen disease of the bone).
Infectious Diseases
Osteomyelitis (OM), an acute or chronic inflammation of the bone marrow cavity and bone, usually has an infectious cause. OM may originate from hematogenous spread of infectious organisms (i.e., secondary to pyemia or septicemia) or from their direct invasion through penetrating wounds (including from orthopaedic procedures) or open fractures. Despite readily available antibiotic drugs, infectious OM still constitutes a serious clinical problem for several reasons: First, OM is rarely a primary disease but more often a complication of an undiagnosed or inadequately treated infection. Second, OM responds poorly to antibiotic treatment (causative organisms may be drug resistant) and may run a chronic course with complications such as amyloidosis. Third, OM may be the source of additional hematogenous spread causing septic shock, hemorrhage, or abscesses in vital organs (brain, myocardium). Therefore, treatment must be radical, combining antibiotic and surgical intervention.
Noninfectious Arthritic Diseases
Osteoarthritis (OA) is an extremely common cause of disability, especially in people aged older than 75 years, 85% of whom show clinical evidence of the disorder. Despite its ubiquity, primary OA is of unknown etiology, although it is thought to result from intrinsic defects of cartilage. Abnormal mechanical forces on the cartilage, decreased water bonding of cartilage, increased stiffness of subcartilaginous bone, and biochemical abnormalities such as decrease in proteoglycans and shortening of glucosaminoglycans have been implicated. The latter decreases cartilaginous water binding in favor of its binding by collagen fibers. Mutations of the collagen type II gene may be involved. Secondary OA occurs in patients with such underlying causes as malformations, trauma, and metabolic diseases with or without crystalline deposits.
Paget Disease
Excessive osteoblastic bone formation with abnormal structure and impaired stability characterize Paget disease (PD; osteitis deformans). After the age of 40 years, the disease increases in incidence to affect 4% to 10% of the population, primarily in white populations of Northern Europe, North America, Australia, and New Zealand, more often in men than women. It may occur in a monostotic form (in only one bony site) or in polyostotic forms (i.e., systemically). Head bones become enlarged; patients report headache, back pain, deafness, and visual disturbances; long bones (especially of the lower extremities) become tender; and deformities and fractures occur. The disease course is complicated by osteosarcoma (OS) in approximately 1% of patients.
Tumors of the Skeletal System
Tumors of the skeletal system comprise a large variety of benign and malignant lesions, including bone cysts. They are classified according to their tissue of origin and are further identified by the age of the patient and the site. Primary tumors of bone are less common than metastatic lesions to the skeletal system, which always should be considered in differential diagnosis (usually, radiographic findings of primary and metastatic lesions are quite characteristic). The extraskeletal malignant neoplasms most likely to metastasize to the skeleton are carcinomas of the prostate, the breast, the lungs, the gastrointestinal tract, the kidneys, and the thyroid. Such metastases may be osteoblastic (e.g., prostate) or osteolytic. Other primary tumors with secondary involvement of the bony skeleton are those of the hematopoietic bone marrow or lymphatic tissues (e.g., plasmacytoma, Hodgkin disease). They are discussed in chapter 10.
Soft Tissue Disorders
Soft tissue refers to the widely distributed interstitial tissue of mesodermal origin filling spaces between ectodermal, endodermal, and skeletal structures. It includes differentiated tissues such as fibrous tissue, fat, and skeletal muscle. Although all pathologic reaction patterns are represented in diseases of soft tissue, including necrosis and degeneration, infection and inflammation, and hyperplasia and neoplasia, only a few examples can be discussed here. We focus on such important disorders as compartment syndrome, collagen-vascular diseases (CVDs), and benign and malignant tumors.
TABLE 11-1
PATHOGENETIC FORMS OF OSTEOPOROSIS
| Category | Mechanism | Examples |
| Primary, type 1 | Increased osteoclast activity | Postmenopausal (estrogen withdrawal) |
| Primary, type 2 | Decreased osteoblast activity | “Old age” osteoporosis |
| Secondary | Endocrine disorders | Hyperparathyroidism, hyperthyroidism or hypothyroidism, hypogonadism, Cushing syndrome, Addison disease, acromegaly |
| Hematologic diseases | Multiple myeloma, systemic mastocytosis, some leukemias and lymphomas | |
| Malabsorptive | Malabsorption syndromes, malnutrition, gastrectomy, hepatic diseases, vitamin D and C deficiencies | |
| Others | Inactivity osteoporosis, chemotherapy and other drugs, chronic alcoholism, certain metabolic diseases |
TABLE 11-2
PATHOGENETIC MECHANISMS OF RICKETS AND OSTEOMALACIA*
| Category | Mechanism | Causes |
| Vitamin D deficiencies | Decreased synthesis in skin | Insufficient sun exposure from 7-dehydrocholesterol |
| Decreased intestinal absorption | Dietary lack, malabsorption syndromes (intestines, pancreas, bile) | |
| Decreased synthesis of 25(OH)-D | Liver diseases | |
| Enhanced degradation of 25(OH)-D | Various drugs inducing cytochrome and P450 enzymes | |
| Decreased synthesis of 1,25(OH)2-D | Advanced renal disease | |
| Phosphate deficiency | Increased excretion | Renal tubular disorders (e.g., Fanconi syndromes) |
| Decreased absorption | Phosphate-binding drugs (e.g., antacids) | |
| Disturbed reabsorption | Tumor associated (e.g., prostate cancer, neurofibromatosis) | |
| Mineralization defects | Target organ resistance | Congenital lack of receptors (type II rickets) |
*1,25(OH)-D indicates 1,25-dihydroxyvitamin-D, active form after second hydroxylation in renal tubule; 25(OH)-D, 25-hydroxyvitamin-D, major circulating metabolite hydroxylated in the liver.
TABLE 11-3
BENIGN PRIMARY TUMOROUS LESIONS OF THE SKELETAL SYSTEM AND JOINTS
| Type of Lesion | Ages | Usual Location | Gross Features |
| Nonossifying fibroma (fibrous cortical defect) | Children | Metaphysis, long bones (tibia, fibula) | Eccentric cortical lesion with well-demarcated sclerotic margins |
| Solitary bone cyst | Children, adolescents | Humerus, femur (adjacent to growth plate) | Well-demarcated epidiaphyseal lesion |
| Aneurysmal bone cyst | Children, young adults | Long bones, vertebra (essentially everywhere) | Rapidly expanding cyst (previous trauma?) |
| Fibrous dysplasia (monostotic or polyostotic) | Adolescents, young adults | Long bones | Diaphyseal “soap bubble” translucencies |
| Osteoma (eburneum) (probably not a real neoplasm) | Adults | Skull, tibia | Exophytic solid mass |
| Osteoid osteoma | Children, young adults | Tubular bones, lower extremity | Diaphyseal cortex “nidus” |
| Osteoblastoma | Children, young adults | Vertebra, spinal, transverse process | Similar to osteoid osteoma (“nidus”) |
| Osteochondroma (exostosis) | Young adults | Long bones | Bony exostoses with cartilaginous cap |
| Chondroma (enchondroma) | Adults | Tubular bones metacarpi, phalanges | Intraosseous, solitary well-circumscribed lesion |
| Chondroblastoma | Children, young adults | Long bones femur, tibia, humerus | Epiphysis, paraarticular well-circumscribed lesion |
| Chondromyxoid fibroma | Children, young adults | Femur, tibia | Excentric lucent defect, delicate sclerotic border |
| Synovial chondromatosis (self-limited) | Young adults (men) | Large joints | Hyaline cartilage nodules and floating free bodies |
| Villonodular synovitis Pigmented | Young adults | Knee, hip, ankles, feet, fingers | Synovial lining cell proliferation with hemosiderin deposits |
TABLE 11-4
MALIGNANT PRIMARY TUMOROUS LESIONS OF THE SKELETAL SYSTEM AND JOINTS
| Type of Lesion | Ages | Usual Location | Gross Features |
| Osteogenic sarcoma (osteosarcoma) | Adolescents, children | Femur, tibia, fibula, and others | Irregular bone destruction, reactive periosteal new bone (see text for variants) |
| Chondrosarcoma | Adults (fourth to sixth decades of life) | Pelvis, shoulder, proximal femur, ribs | Often bulky destructive lesion with calcification or bone formation (see text for variants) |
| Giant cell tumor (locally aggressive, potentially malignant) | Adults | Long bones, epimetaphyseal junction | Slowly growing lytic lesion with periosteal reaction, circumscribed, painful |
| Ewing sarcoma | Children, adolescents | Long bones, mid shaft metaphyseal humerus, femur, tibia | Lytic lesion in medulla and inner cortex, periosteal reaction |
| Synovial sarcoma | Adolescents, young adults | In vicinity of joints, 10% intraarticular | Soft tissue tumor associated with tendons, bursae, joint capsule |
TABLE 11-5
FEATURES OF EXEMPLARY MEMBERS OF COLLAGEN-VASCULAR DISEASES
| Syndrome | Autoimmunity* | Features† |
| Systemic lupus erythematosus | Autoantibodies against native ds-DNA, denatured ss-DNA, histones, and histone complexes T-, NK-cell, and cytokine abnormalities, circulating immune complexes | Rashes, arthritis/arthralgia, glomerulonephritis, proteinuria, thrombocytopenia, hemolytic anemia, pleural effusions, pulmonary fibrosis, pericarditis, endocarditis, psychosis, seizuresVasculitis and thrombosis |
| Primary systemic sclerosis | Autoantibodies against small RNA protein (SS-A/Ro), topoisomerase I (Scl-70), 45K RNA protein (SS-B/La) | Hallmark: scleroderma, Raynaud syndrome, proliferative arteritis and fibrosis, capillary malformations such as telangiectasia and bleeding; esophagus and lower GI tract: fibrosis and muscular atrophy with motility problems and dysphagia, interstitial pneumonitis, “shrinking lung disease,” pulmonary hemorrhage; heart: conductive and ventricular dysfunction, renal vasculitis and hypertension |
| Polymyositis, dermatomyositis | tRNA synthetases: Jo-1, PL-7; protein complex (PM-Scl) | Muscle weakness: segmental myofiber necrosis with inflammatory infiltrate, fever, myoglobinuria, skin rash, erythema of hands (knuckles), interstitial pneumonitis, approximately 25% associated with malignancies |
| Rheumatoid arthritis | Denatured ss-DNARheumatoid factor, CIC, antikeratin, collagen antibody, T-cell “activation” | Chronic relapsing synovitis, arthritis, small joints of hands, symmetrical, tenosynovitis, soft tissue rheumatic nodules, pleuritis, pericarditis, vasculitis, interstitial pneumonitis, bronchiolitis obliterans, polyneuritis, mononeuritis, Felty syndrome |
CIC indicates circulating immune complexes; ds, double-stranded; GI, gastrointestinal; ss, single-stranded.
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