Alterations of Musculoskeletal Function PDF

CHAPTER 45 Alterations of Musculoskeletal...

CHAPTER 45 Alterations of Musculoskeletal Function Leslie W. Hopkins, Benjamin A. Smallheer, Kathryn L. McCance http://evolve.elsevier.com/McCance/ Content Updates Chapter Summary Review Review Questions Case Studies Animations CHAPTER OUTLINE Musculoskeletal Injuries, 1423 Disorders of Skeletal Muscle, 1458 Skeletal Trauma, 1423 Secondary Muscular Dysfunction, 1458 Support Structure Trauma, 1427 Muscle Membrane Abnormalities, 1461 Disorders of Bones, 1432 Metabolic Muscle Diseases, 1462 Metabolic Bone Diseases, 1432 Inflammatory Muscle Diseases: Myositis, 1463 Infectious Bone Disease: Osteomyelitis, 1440 Myopathy, 1464 Bone Tumors, 1441 Muscle Tumors, 1464 Disorders of Joints, 1445 Osteoarthritis, 1445 Classic Inflammatory Joint Disease, 1450 The musculoskeletal system is comprised of the bones, muscles, cartilage, associated with diagnosis and treatment; indirect care costs are related tendons, ligaments, and other connective tissues. This system provides to time away from work, loss of employment, and decreased productivity. structure, support, stability, and movement to the body. Injuries to the Several national organizations in the United States are collaborating to musculoskeletal system include fractures (traumatic and nontraumatic), develop a centralized national resource for injury prevention.4 dislocations, sprains, and strains. Additionally, alterations in bones, joints, and muscles may be caused by metabolic disorders, infections, inlammatory or noninlammatory diseases, or tumors. The most Skeletal Trauma common disease affecting bones is osteoporosis and the incidence Fractures increases with age.1 A fracture is a break in the continuity of a bone. A break occurs when force is applied that exceeds the tensile or compressive strength of the bone. Fracture incidence varies depending on the bone involved, age, MUSCULOSKELETAL INJURIES and gender. The highest incidence of fractures occurs in young males Trauma has been termed “the neglected disease of modern society.”2 ages 15 to 24 and in adults 65 years and older. Rates of hip and wrist Unintentional traumatic injuries are the number one cause of death fractures tended to be higher in women. An estimated 158 million hip for people ages 1 to 44.3 Fractures are most commonly caused by falls, fractures occurred worldwide in 2015; this number is expected to increase car accidents, and athletic injuries. For those who survive traumatic to 316 million by 2040.5 injuries, the impact is signiicant. Injury affects their families, and impacts Classification. Fractures are classiied as complete or incomplete society because of related loss or limitation of daily activities and mobility, and open or closed (Fig. 45.1). In a complete fracture, the integrity of pain, and a decreased quality of life. Signiicant direct care costs are the bone is broken into two pieces, whereas in an incomplete fracture 1423 1424 UNIT XIII The Musculoskeletal System TABLE 45.1 TYPES OF FRACTURES TYPE DEFINITION Typical Complete Fractures Closed fracture Skin overlying the bone is intact Open fracture Communicating wound between bone and skin Comminuted Multiple bone fragments fracture A B C Linear fracture Fracture line parallel to long axis of bone Oblique Occult Open Oblique fracture Fracture line at an angle to long axis of bone Spiral fracture Fracture line encircling bone (as in a spiral staircase) Transverse fracture Fracture line perpendicular to long axis of bone Impacted Fracture fragments are pushed into each other Pathologic Fracture occurs at a point in the bone weakened by disease (e.g., bones with tumors or osteoporosis) Avulsion A fragment of bone connected to a ligament or tendon breaks off from the main bone Compression Fracture is wedged or squeezed together on one D E F side of bone Displaced Fracture with one, both, or all fragments out of Pathologic Segmented Spiral normal alignment Extracapsular Fragment is close to the joint but remains outside the joint capsule Intracapsular Fragment extends into or is within the joint capsule Fragility Fracture caused by low-level trauma Typical Incomplete Fractures Greenstick fracture Break on one cortex of bone with splintering of inner bone surface (commonly occurs in children and G H I older adults) Transverse Greenstick Impacted Torus fracture Buckling of cortex FIGURE 45.1 Examples of Types of Bone Fractures. A, Oblique: fracture Bowing fracture Bending of the bone at oblique angle across both cortices. Cause: direct or indirect energy, with angulation Stress fracture Microfracture and some compression. B, Occult: fracture that is hidden or not readily discernible. Transchondral Separation of cartilaginous joint surface (articular Cause: minor force or energy. C, Open: skin broken over fracture; possible soft fracture cartilage) from main shaft of bone tissue trauma. Cause: moderate to severe energy that is continuous and exceeds tissue tolerances. D, Pathologic: transverse, oblique, or spiral fracture of bone weakened by tumor pressure or presence. Cause: minor energy or force, which may be direct or indirect. E, Segmented: fracture with two or more pieces or The three main types of incomplete fractures are greenstick, buckle segments. Cause: direct or indirect moderate to severe force. F, Spiral: fracture or torus, and bowing. A greenstick fracture perforates one cortex and that curves around cortices and may become displaced by twist. Cause: direct or splinters the spongy bone and is relatively unstable. The term greenstick indirect twisting energy or force with distal part held or unable to move. G, Transverse: is derived from the damage sustained by a young tree branch (a green horizontal break through bone. Cause: direct or indirect energy toward bone. stick) when it is bent sharply. The outer surface of the bone (or tree H, Greenstick: break in only one cortex of bone. Cause: minor direct or indirect branch) is disrupted, but the inner surface remains intact. Greenstick energy. I, Impacted: fracture with one end wedged into opposite end of inside fractures typically occur in the metaphysis or diaphysis of the tibia, fractured fragment. Cause: compressive axial energy or force directly to distal radius, and ulna. In a buckle or torus fracture, the cortex of the bone fragment. (Redrawn from Mourad L: Musculoskeletal system. In Thompson JM buckles but does not break, thus making it a relatively stable fracture. et al, editors: Mosby’s clinical nursing, ed 7, St Louis, 2002, Mosby.) Bowing fractures usually occur when longitudinal force is applied to bone. This type of fracture is common in children and usually involves the paired radius-ulna or ibula-tibia. A complete diaphyseal fracture occurs in one bone of the pair, which disperses the stress suficiently the bone is damaged but still in one piece. Complete or incomplete to prevent a complete fracture of the second bone, which bows. Treatment fractures are further classiied as open or closed. An open fracture, of a bowing fracture is dificult because the bowed bone interferes with formerly referred to as a compound fracture, is characterized by a concur- the reduction of the fractured bone. In addition, a bowing fracture rent break in the skin in the area of the fracture. A closed fracture, resists correction (reduction) because the force necessary to reduce it formerly referred to as a simple fracture, has no break in the surrounding must be equal to the force that caused the initial injury. A fracture that skin. Fractures are classiied according to the direction of the fracture results from a trauma that would not normally cause a fracture (a line. A linear fracture runs parallel to the long axis of the bone. An low-level trauma) is termed a fragility fracture. Fragility fractures are oblique fracture is a slanted fracture of the shaft of the bone. A spiral often a sequela of osteoporosis. Types of fractures are summarized in fracture encircles the bone, and a transverse fracture occurs straight Table 45.1. across the bone. A fracture in which a bone breaks into more than two Fractures may be further classiied by cause as pathologic, stress, or fragments is termed a comminuted fracture. transchondral fracture. A pathologic fracture is a break at the site of  CHAPTER 45 Alterations of Musculoskeletal Function 1425 a preexisting abnormality (such as a tumor), usually by force that would phases. The initial inlammatory phase of healing lasts 3 to 4 days. not fracture a healthy bone. Any disease process that weakens a bone During the next few days, the repair phase begins and capillary ingrowth, (especially the cortex) predisposes the bone to pathologic fracture. This together with mononuclear cells and ibroblasts, begins the transforma- type of fracture is most commonly associated with tumors, infections, tion of a hematoma into granulation tissue. Next, osteoblasts within osteoporosis, and other metabolic bone disorders. the procallus synthesize collagen and matrix, which becomes mineralized A stress fracture is caused by the cumulative effects of repeated to form callus. As the repair process continues, remodeling occurs, forces over time, such as occurs during athletics. Fatigue and insuficiency during which unnecessary callus is resorbed and trabeculae are formed fractures are subtypes of stress fractures. Fatigue fractures are caused along lines of stress; at the end of this stage, bone can withstand normal by abnormal stress or torque applied to a bone with normal ability to stresses. The last phase, remodeling, lasts for months to years. Except deform and recover (e.g., joggers, dancers, military recruits). Insufficiency for the liver, bone is unique among all body tissues in that after a fractures include fragility fractures of osteoporosis and osteomalacia, fracture it will heal with normal, not scar, tissue. and occur in bones lacking normal ability to deform and recover (i.e., CLINICAL MANIFESTATIONS. Clinical manifestations of a fracture normal weightbearing or activity fractures the bone). can vary according to the type of fracture, site of the fracture, and A transchondral fracture consists of fragmentation and separation associated soft tissue injury. In general, the signs and symptoms of a of a portion of the articular cartilage that covers the end of a bone at fracture include impaired function, unnatural alignment (deformity), a joint. (Joint structures are deined in Chapter 44.) The fragments swelling, muscle spasm, tenderness, pain, and impaired sensation. The may consist of cartilage alone or cartilage and bone. Typical sites of position of the bone segments is determined by the pull of attached transchondral fractures are the distal femur, the ankle, the kneecap, the muscles, gravity, and the direction and magnitude of the force that elbow, and the wrist. Transchondral fractures are most prevalent in caused the fracture. One or both segments of the fractured bone may adolescents. be rotated inward or outward on the bone’s long axis (rotation), PATHOPHYSIOLOGY. When a bone is broken the periosteum and misaligned at an angle (angulation), or slide over the other segment blood vessels in the cortex, marrow, and surrounding soft tissues are (overriding) or out of normal position (displaced). disrupted. Bleeding occurs from the damaged ends of the bone and Fractures are usually caused by trauma and immediate, often severe from the neighboring soft tissue. A hematoma forms within the medullary pain at the site of injury occurs. Subsequent pain is produced by muscle canal, between the fractured ends of the bone, and beneath the peri- spasm, overriding of the fracture segments, or damage to adjacent soft osteum. Bone tissue immediately adjacent to the fracture dies. This tissues. Numbness also is common and caused by swelling, pinching, necrotic tissue and any debris in the fracture area stimulate an intense or severing of a nerve caused by the trauma or bone fragments. Pathologic inlammatory response characterized by vasodilation, exudation of fractures can cause angular deformity, painless swelling, or generalized plasma and leukocytes, and iniltration by inlammatory leukocytes bone pain. Stress fractures usually occur in weightbearing bones. Stress and mast cells. Cytokines, including transforming growth factor-beta fracture symptoms can vary, but the most common is pain. The pain (TGF-β), platelet-derived growth factor (PDGF), prostaglandins, and of a stress fracture is often gradual in onset and can be relieved with other factors that promote healing, are released. Within 48 hours after rest. Other symptoms of stress fractures include local tenderness and the injury, vascular tissue invades the fracture area from the surrounding soft tissue swelling. Transchondral fractures may be entirely asymptomatic soft tissue and marrow cavity, and blood low to the entire bone is or painful during movement. Range of motion in the joint is limited increased. Osteoblasts and osteoclasts (or bone-forming cells) in the and movement may evoke crepitation, a crunching sensation felt when periosteum, endosteum, and marrow are activated to produce subperi- bones rub against each other. osteal procallus along the outer surface of the shaft and over the broken EVALUATION AND TREATMENT. Treatment of a displaced fracture ends of the bone (Fig. 45.2). Healing generally occurs in three overlapping involves manipulating the bone to realign bone fragments (reduction) to the correct anatomic position and holding the fragments in place (immobilization) so bone healing can occur. Many fractures heal without manipulation and require only adequate immobilization. Several methods of manipulation are available to reduce a fracture that will not heal with simple immobilization, including closed manipulation, traction, and open reduction. Maligned fractures require the most aggressive treatment of all types of fractures. Fractures can be reduced by closed manipulation if the skin is not opened and the bone is able to be moved or manipulated into place. Appropriate use of closed manipulation occurs when the contour of the bone is well aligned and the alignment can be maintained with immobilization. Traction is another option used to accomplish or maintain reduction of a fracture. When bone fragments are displaced (not in their anatomic position), weights are used to apply irm, steady traction (pull) and countertraction to the long axis of the bone. Traction stretches and fatigues muscles that pull the bone fragments out of place, allowing the distal fragment to align with the proximal fragment. Traction can be applied to the skin (skin traction), directly to the involved bone, or distal to the involved bone (skeletal traction). Skin traction is used when only a few pounds of pulling force are needed to realign the fragments or when the traction will be used for only a brief time, such FIGURE 45.2 Exuberant Callus Formation Following Fracture. (From Rosai as before surgery or for a few days before applying a cast. In skeletal J: Ackerman’s surgical pathology, ed 8, St Louis, 1996, Mosby.) traction, a pin or wire is drilled through the bone below the fracture 1426 UNIT XIII The Musculoskeletal System site, and a traction bow, rope, and weights are attached to the pin or luid-illed space that resembles a joint, termed a false joint, or pseud- wire to apply tension by providing the pulling force needed to overcome arthrosis. Delayed union is union that does not occur until approximately the muscle spasm and helping realign the fracture fragments. 8 to 9 months after a fracture. Malunion is the healing of a bone in a Open reduction is a surgical procedure that exposes the fracture nonanatomic position. Treatment of delayed union and nonunion site; the fragments are brought into alignment under direct visualization. includes use of various modalities designed to stimulate new bone Some form of hardware, such as a screw, plate, nail, or wire, is used to formation. Physical modalities, such as implantable or external electric maintain the reduction (internal ixation). External ixation is a procedure current devices, electromagnetic ield generations, and low-density used to reduce and immobilize signiicantly displaced open fractures. ultrasound, have been effective in stimulating bone formation.6 Stem Pins are placed in the bone proximal and distal to the break and then cells and gene therapy also show promise in promoting formation of stabilized by an external frame of clamps and rods (Fig. 45.3). Bone new bone.7,8 Large defects in bone can be illed with bone graft or grafts also are used to repair fractures and illing voids in the bone. synthetic materials, such as calcium phosphate cement. These grafts are from the injured individual (autograph), a cadaver (allograft), or a bone substitute (ceramic composites, bioactive cement). Dislocation and Subluxation Improper reduction or immobilization of a fractured bone may Dislocation and subluxation are caused by trauma, but also can be result in nonunion, delayed union, or malunion. Nonunion is failure caused by ligamentous laxity, nerve injury, rheumatoid disease, or genetic of the bone ends to grow together (Fig. 45.4). The gap between the problems. Dislocation is the temporary displacement of a bone from broken ends of the bone ills with dense ibrous and ibrocartilaginous its normal position in a joint. If a dislocation does not involve a fracture, tissue instead of new bone. Occasionally, the ibrous tissue contains a it is a simple dislocation; if there is an associated fracture, it becomes a complex dislocation. If the contact between the two joint surfaces is only partially lost, the injury is called a subluxation. Dislocation and subluxation are most common in persons younger than 20 years and are generally associated with fractures. Dislocation and subluxation, however, may result from congenital or acquired disorders that cause (1) muscular imbalance, as occurs with congenital hip dislocation or neurologic disorders; (2) incongruities in the articulat- ing surfaces of the bones, such as with rheumatoid arthritis (see Classic Inlammatory Joint Disease); or (3) joint instability. Most often dislocated or subluxated are the joints of the shoulder, elbow, wrist, inger, hip, and knee (Fig. 45.5). The shoulder’s glenohumeral joint is a relatively unstable joint because the articular surface of the glenoid cavity is only one-third as large as the surface of the humeral head. As a result, the glenohumeral joint is often injured. Physical trauma to the shoulder can cause anterior, posterior, superior, or inferior disloca- tion. Anterior dislocation is the most common and is usually the result of an indirect force that places the shoulder in extreme external rotation. FIGURE 45.3 Example of an External Fixation Device on the Right Leg. The left leg is in a splint. FIGURE 45.4 Nonunion of Old Fracture of Tibia and Fibula in a 53-Year-Old Man. Multiple fractures had occurred in 2 years previously and necessitated bone FIGURE 45.5 Displaced Fracture. An x-ray showing a displaced fracture of grafting. (From Rosai J: Ackerman’s surgical pathology, ed 8, St Louis, 1996, Mosby.) the base of the first metacarpal, also known as a Bennett fracture.  CHAPTER 45 Alterations of Musculoskeletal Function 1427 Posterior dislocations usually occur because of trauma. A superior Attempts to lift the arm aggravate the pain. In most shoulder dislocations, dislocation is rare and usually the result of an extreme forward and the ability to elevate the arm is minimal and the individual supports upward force on an adducted arm. Inferior displacement is seen the injured arm with the opposite hand. Pain and an abnormal gait or in persons with neurologic injuries of the brachial plexus and is limp or inability to bear full weight usually accompanies traumatic believed to be caused by stretching of the supporting muscles or by dislocation of the hip. The pain is constant and severe and is felt in the joint effusion. inguinal region or thigh. The thigh and leg may assume a position of Traumatic dislocation of the elbow joint is common in the immature inward rotation, adduction, or lexion and appear shortened. In a rare skeleton. In adults, however, an elbow dislocation is usually associated anterior dislocation, the limb is not shortened and the joint is ixed in with a fracture of the ulna or head of the radius. Posterior dislocations abduction, outward rotation, and lexion. occur when the individual falls on an outstretched hand with the elbow EVALUATION AND TREATMENT. Evaluation of dislocations and extended. Anterior dislocations are usually the result of a direct blow subluxations is based on clinical manifestations and roentgenograms. to the lexed elbow. Treatment consists of reduction and immobilization for 2 to 6 weeks Traumatic dislocation of the wrist usually involves the distal and exercises to maintain normal range of motion in the joint. Depending ulna and carpal bones. Any one of the eight carpal bones can be on the joint, healing is usually complete within months to years. dislocated after an injury. The most common cause is a fall on the hyperextended hand. Dislocation in the hand usually involves the metacarpophalangeal Support Structure Trauma and interphalangeal joints. Dislocation of the metacarpophalangeal joint Sprains and Strains of Tendons and Ligaments is often the result of a fall on the outstretched hand that forces the joint Tendon and ligament injuries can accompany fractures and dislocations. into hyperextension. Dislocation of the interphalangeal joint occurs A tendon is ibrous connective tissue that attaches skeletal muscle because of injury to the ingers in a hyperextended position. to bone. A ligament is a band of ibrous connective tissue that connects Considerable trauma is needed to dislocate the hip. Anterior hip bones where they meet at a joint. Tendons and ligaments support the dislocation is rather rare and caused by forced abduction, for example, bones and joints and either facilitate or limit motion. Tendons and when an individual lands on the feet from a high fall. Posterior dislocation ligaments can be torn, ruptured, or completely separated from bone at of the hip can occur in an automobile accident in which the lexed their points of attachment. knee strikes the dashboard. A tear in a tendon is known as a strain. Major trauma can tear or The knee is a relatively unstable joint that depends heavily on the rupture a tendon at any site in the body. Most often injured are the soft tissue structures around it for support. Because the knee is an tendons of the hands and feet, the knee (patellar), the upper arm (biceps unstable weightbearing joint exposed to many different types of motion and triceps), the thigh (quadriceps), the ankle, and the heel (Achilles). (lexion, extension, rotation), it is one of the most commonly injured Lifting excessive weight with the arms can cause traumatic rupture of joints. A knee dislocation can be anterior, posterior, lateral, medial, or the biceps tendon. Rupture of the Achilles tendon occurs when forced rotary. It is often the result of a hyperextension injury that occurs during dorsilexion is applied to the foot when it is in plantar lexion. Spontane- sports activities. ous tendon ruptures can occur in individuals receiving local corticosteroid PATHOPHYSIOLOGY. Dislocations and subluxations are often injections or luoroquinolones and in persons with rheumatoid arthritis accompanied by fracture because stress is placed on areas of bone not or systemic lupus erythematosus. normally subjected to stress. In addition, as the bone separates from Ligament tears are known as sprains. Ligament tears and ruptures the joint, it may bruise or tear adjacent nerves, blood vessels, ligaments, can occur at any joint, but are most common in the wrist, ankle, elbow, supporting structures, and soft tissue. Dislocation of the shoulder may and knee joints. A complete separation of a tendon or ligament from damage the shoulder capsule and the axillary nerve. Damage to the its bony attachment site is known as an avulsion. An avulsion is the axillary nerve causes anesthesia in the sensory distribution of the nerve result of abnormal stress on the ligament or tendon and is commonly and paralysis of the deltoid muscle. Torn periosteum, ligaments, and seen in young athletes, especially sprinters, hurdlers, and runners. muscle frequently accompany elbow dislocations. Bleeding from the Strains and sprains are classiied as irst degree (least severe), damaged periosteum and muscle puts pressure on adjacent arteries second degree, and third degree (most severe). that stops circulation to and from the forearm and hand. If the pressure PATHOPHYSIOLOGY. When a tendon or ligament is torn, an is not promptly relieved, ischemic paralysis develops. Dislocations of extensive inlammatory cascade process begins. Inlammatory mediators the hand often result in permanent disability because of damage to the include cytokines, nitric oxide, prostaglandins, and lipoxins. An inlam- tendons and intricate mechanisms that allow smooth gliding in the matory exudate develops between the torn ends. Later, granulation joints. In the hip, avascular necrosis of the femoral head is a complication tissue containing macrophages, ibroblasts, and capillary buds grows seen with dislocations. Knee dislocation usually tears both the collateral inward from the surrounding soft tissue and cartilage to begin the and the cruciate ligaments. repair process. Within 3 to 4 days after the injury, collagen formation CLINICAL MANIFESTATIONS. Signs and symptoms of dislocations begins. At irst, collagen formation is random and disorganized. As the or subluxations include pain, swelling, limitation of motion, and joint collagen ibers interweave and connect with preexisting tendon ibers, deformity. Pain is caused by effusion of inlammatory exudate into the they organize parallel to the lines of stress. Eventually, vascular ibrous joint or associated tendon and injury to the ligament. Joint deformity tissue fuses the new and surrounding tissues into a single mass. As is caused by muscle contractions that exert pull on the dislocated or reorganization takes place, the healing tendon or ligament separates subluxated joint or luid within the joint. Limitation of motion may from the surrounding soft tissue. Usually, a healing tendon or ligament be a result of effusion into the joint or the displacement of bones. lacks suficient strength to withstand strong pull for 4 to 5 weeks after Tenderness and deformity are prominent in dislocations of the ingers. the injury. If strong muscle pull does occur during this time, the tendon Unusual muscle pull and pain often result in abnormal posturing of or ligament ends may separate again, which causes the tendon or ligament the ingers; for example, the ingers or thumb may be abnormally lexed. to heal in a lengthened shape with an excessive amount of scar tissue A dislocated elbow is often held in a lexed position, and the joint resists that renders the tendon or ligament functionless. Scar remodeling may active or passive movement. Pain is the key symptom of shoulder injuries. take months to years before it is complete.9 1428 UNIT XIII The Musculoskeletal System CLINICAL MANIFESTATIONS. Tendon and ligament injuries are the result of tissue degeneration or irritation of the extensor carpi painful and cause functional limitation. These injuries are usually radialis brevis tendon at its origin. Medial epicondylopathy, referred accompanied by soft tissue swelling, changes in tendon or ligament to as golfer’s elbow, is a degenerative process of the pronator teres, contour, and dislocation or subluxation of bones. The pain is generally flexor carpi radialis, and palmaris longus tendons at the medial humeral sharp and localized, and tenderness persists over the distribution of the condyle (Fig. 45.6). Epicondylopathy is also related to smoking, obesity, tendon or ligament. Painful joint swelling usually can be seen in inger and work activities that involve forceful or repetitive cyclic lexion and and elbow sprains. Flexion deformities of the ingers and thumb occur extension of the elbow, or cyclic pronation, supination, extension, and in injuries to the extensor tendons. Crepitus may accompany tendon lexion of the wrist that generates loads to the elbow and forearm region. injury in the wrist. Tendon or ligament pain in the elbow is accentuated by lexion, supination, and extension of the elbow or by extension of the wrist. Lifting small objects requires extension of the wrist and Humerus therefore aggravates the pain. Tendon injuries in the upper arm cause weakness when the individual tries to lex the forearm. Pain is often the key symptom of shoulder injuries with pain radiating to the deltoid muscle or extending down the arm and is aggravated by attempts to Olecranon bursa actively raise the arms. Depending on the ligament or tendon involved, Lateral epicondyle Medial epicondyle Olecranon injuries to the knee may produce pronounced immobility, absence of Annular ligament Coronoid process lateral movement, instability when walking down stairs, lexion deformity, crepitus, or an upward or downward shift of the patella. Radius Ulna EVALUATION AND TREATMENT. Evaluation is based on clinical manifestations, stress radiography, arthroscopy, or arthrography. When A possible, treatment consists of protection of the involved structures (splinting), promotion of early motion, and rehabilitation. Surgical intervention that sutures the tendon or ligament ends in close approxima- tion may be necessary to treat complete rupture. If this is not possible because of the extent of damage, tendon or ligament grafting may be necessary. Prolonged rehabilitation exercises help ensure that the individual regains nearly normal functions. Gastrocnemius muscle Tendinopathy and Bursitis (Lateral head) Trauma and overuse injuries can cause painful degradation of collagen (Medial head) ibers (tendinosis), inflammation of tendons (tendinitis), or inflam- mation in bursal sacs (bursitis). The term tendinopathy includes ten- dinitis, tendinosis, and paratendinitis. Studies have shown that vascular Soleus muscle ingrowth in tendinopathy (neovascularization) is accompanied with Achilles tendon nerve ingrowth, facilitating pain transmission in Achilles and patellar tendinopathies.10 Other causes of tendinopathy include crystal deposits, postural misalignment, and hypermobility in a joint. Table 45.2 sum- marizes classes of tendinopathies. Calcaneus Epicondylitis is inlammation of a tendon where it attaches to a bone (at its origin). Most tendon pathology, however, is caused by tissue B degeneration rather than inlammation.11 Epicondylar areas of the FIGURE 45.6 Tendinitis and Epicondylitis. A, Medial or lateral epicondyles humerus, radius, or ulna and the area around the knee are most often of humerus, site of epicondylitis. B, Achilles tendon, site of commonly occurring involved. Lateral epicondylopathy, commonly called tennis elbow, is tendinitis. TABLE 45.2 HISTOPATHOLOGIC CLASSIFICATION OF TENDON DISORDERS PATHOLOGIC DIAGNOSIS MACROSCOPIC PATHOLOGY HISTOPATHOLOGIC FINDINGS Tendinosis Intratendinous degeneration (commonly Collagen disorientation, disorganization, and fiber separation by an increase in due to aging, microtrauma, muscular mucoid ground substance, increased preponderance of cells and vascular spaces compromise) with or without neovascularization and focal necrosis or calcification Tendinitis Symptomatic degeneration of the tendon Degenerative changes as noted above with superimposed evidence of tear, with vascular disruption and including fibroblastic and myofibroblastic proliferation, hemorrhage, and inflammatory repair response organizing granulation tissue Paratenonitis “Inflammation” of the outer layer of the Mucoid degeneration if the areolar tissue is seen; a scattered mild mononuclear tendon (paratenon) alone, whether or infiltrate with or without focal fibrin deposition and fibrinous exudate not the paratenon is lined by synovium Paratenonitis with tendinosis Paratenonitis associated with Degenerative changes as noted in tendinosis with mucoid degeneration with or intratendinous degeneration without fibrous and scattered inflammatory cells in the paratenon alveolar tissue From Maffulli N, Wong J, Almekinders LC: Clin Sports Med 22(4):675–692, 2003.  CHAPTER 45 Alterations of Musculoskeletal Function 1429 Bursae are small sacs lined with synovial membrane and illed with 45.3 summarizes common sites of bursitis. Signs of infectious bursitis synovial luid; they are located between tendons, muscles, and bony may include the presence of a puncture site, prior corticosteroid injection, prominences. Their primary function is to separate, lubricate, and severe inlammation, or an adjacent source of infection. cushion these structures. When irritated or injured, these sacs become EVALUATION AND TREATMENT. Evaluation of tendinopathy, epi- inlamed and swell. Because most bursae lie outside joints, joint move- condylopathy, and bursitis is based on clinical manifestations, physical ment is rarely compromised with bursitis. Acute bursitis occurs primarily examination, arthroscopy, arthrography, ultrasound, and possibly in the middle years and is often caused by trauma; repetitive irritation magnetic resonance imaging (MRI). Treatment includes administration can cause chronic bursitis. Septic bursitis is caused by wound infection of systemic analgesics, application of ice or heat, or local injection of or bacterial infection of the skin overlying the bursae. Bursitis commonly an anesthetic and a corticosteroid to reduce inlammation. Bursitis may occurs in the shoulder, hip, knee, and elbow. require aspiration to drain excess luid. Physical therapy to prevent loss PATHOPHYSIOLOGY. In tendinitis, inflammatory fluid accumulates, of function begins after acute symptoms subside. causing swelling of the tendon and its enclosing sheath. Inlammatory changes cause thickening of the sheath, which limits movements and Muscle Strains causes pain. Microtears cause bleeding, edema, and pain in the involved Mild injury such as muscle strain is usually seen after traumatic or tendons or surrounding structures. At times, after repeated inlammations, sports injuries. Muscle strain is a general term for local muscle damage. calcium may be deposited in the tendon origin area, causing a calciic It is often the result of sudden, forced motion causing the muscle to tendinitis. become stretched beyond normal capacity. Strains often involve the The typical bursitis is an inlammation that is reactive to overuse tendon as well. Muscles are ruptured more often than tendons in young or excessive pressure. The inlamed bursal sac becomes engorged, and people; the opposite is true in older adults. Muscle strain may be chronic the inlammation can spread to adjacent tissues (Fig. 45.7). The inlam- when the muscle is repeatedly stretched beyond its usual capacity. There mation may decrease with rest, heat, and aspiration of the luid. is evidence of tissue disruption with subsequent signs of muscle regenera- (Inlammation is discussed in Chapter 7.) tion and connective tissue repair when a biopsy is performed. Hemor- CLINICAL MANIFESTATIONS. Tendinopathy may be asymptomatic, rhage into the surrounding tissue and signs of inflammation also may but generally there is localized pain that worsens with active more than be present. Knife and gunshot wounds also cause traumatic rupture. passive motion. With symptomatic tendinopathy, the pain is localized Regardless of the cause of trauma, muscle cells usually can regenerate. over the involved tendon and movement in the affected joint is limited. Regeneration may take up to 6 weeks, and the affected muscle should In bursitis, onset of pain may be gradual or sudden, but movement of the be protected during this time. Types of muscle strain, together with joint itself is normal. Shoulder bursitis impairs arm abduction because of their manifestations and treatment, are summarized in Table 45.4. pain and swelling of the bursa. Bursitis in the knee produces pain when climbing stairs, and crossing the legs is painful in bursitis of the hip. Lying on the side of an inlamed trochanteric bursa is also very painful. Table TABLE 45.3 COMMON SITES AND CAUSES OF BURSITIS SITE COMMON CAUSES Shoulder (subacromial) Repetitive overhead activities Elbow (olecranon) Rheumatoid arthritis (RA), gout, tuberculosis, leaning on elbow Hip (greater trochanter) Acute trauma, chronic stress Ischial (weaver’s bottom) Overuse (runner, ballet dancers), lumbosacral disease, RA, osteoarthritis (OA) Knee Prepatellar (housemaid knee) Trauma, frequent kneeling, infection Pes anserine (medial knee) Obesity, long-distance runner, OA, type 2 diabetes FIGURE 45.7 Olecranon Bursa. A case of olecranon bursitis in a patient with Heel (calcaneal) Poorly fitting footwear, Achilles rheumatoid arthritis. A rheumatoid nodule is also shown. (From Hochberg MC et al: tendinitis Rheumatology, ed 6, Philadelphia, 2015, Elsevier.) TABLE 45.4 MUSCLE STRAIN TYPE MANIFESTATIONS TREATMENT First degree (e.g., bench press in Muscle overstretched, painful Ice should be applied 5 or 6 times in the first 24–48 hr; complete rest for up to 2 untrained athlete) weeks, followed by weightbearing 3 times per week and range of motion daily Second degree (e.g., any muscle Muscle intact with some tearing pain, Treatment similar to that for first-degree strains, with added mild analgesia; strain with bruising and pain) mild bruising; fascia is intact cryokinetics (a treatment system of alternating applications of cold with progressive exercise) Third degree (e.g., traumatic injury) Caused by tearing of fascia; muscle Surgery to approximate ruptured edges; immobilization and rest for 6 weeks, rupture palpable, bleeding present followed by an individualized rehabilitation regimen of strengthening exercises 1430 UNIT XIII The Musculoskeletal System A late complication of localized muscle injury is abnormal bone of increased intracompartmental pressures of a muscle), or crush formation in soft tissue, often called myositis ossificans or heterotopic syndrome (the pathophysiologic events caused by rhabdomyolysis, ossification (HO). Its exact pathophysiology remains unknown, but primarily involving the kidneys and coagulation syndrome).13 Although the basic problem seems to be the inability of mesenchymal cells to relatively rare, rhabdomyolysis has many causes (Box 45.1) and can differentiate into osteoblastic stem cells and the improper development result in serious complications, including hyperkalemia (because of the of ibroblasts into bone-forming cells. Though uncommon, HO is release of intracellular potassium into the circulation), metabolic acidosis associated with burns, joint surgery, and trauma to the musculoskeletal (from liberation of intracellular phosphorus and sulfate), acute renal system or central nervous system. HO may involve muscle or tendons, failure (myoglobin precipitates in the tubules, obstructing low through ligaments, or bones near a muscle.12 Examples include “rider’s bone,” the nephron and producing injury), and even disseminated intravascular in which the adductor muscle of the thigh of equestrians becomes coagulation (DIC) (likely caused by activation of the clotting cascade calciied, as well as in football players after muscle injury to thigh muscles; by sarcolemma damage and release of intracellular components from and “drill bone,” in which the same complication is seen in the deltoid the damaged muscles). Even the weight of a limp extremity can generate and pectoral muscles of fencers and infantry soldiers. enough pressure to produce muscle ischemia (Fig. 45.8). Malignant hyperthermia (MH) is a potentially life-threatening Rhabdomyolysis hereditary disorder of skeletal muscle ryanodine receptors (RyR1), Once used interchangeably with the term myoglobinuria, rhabdomyolysis allowing large quantities of calcium to be released from the sarcoplasmic is the rapid breakdown of muscle that causes the release of intracellular reticulum (SR) after exposure to certain volatile anesthetics. The sustained contents, including protein pigment myoglobin, into the extracellular elevation of calcium concentration allows excessive stimulation of aerobic space and bloodstream. Physical interruptions in the sarcolemmal and anaerobic glycolytic metabolism, causing a hypermetabolic state membrane, called delta lesions, suggest that the sarcolemmal membrane resulting in respiratory and metabolic acidosis, muscle rigidity, altered is the route through which muscle constituents are released. Myoglo- cell permeability, and hyperkalemia.14 Dantrolene, a skeletal muscle binuria, irst described in victims of crush injuries in London during relaxant, inhibits calcium release from the SR and is used to reverse World War II, refers to the presence of the muscle protein myoglobin the effects of MH. in the urine. More recently, myoglobinuria has been reported in individu- Compartment syndromes occur when blood low to the affected als found unresponsive and immobile for long periods, such as drug area is compromised because of increased venous pressure, leading and alcohol overdoses. to decreased arterial inlow, ischemia, and edema. Emergency treat- PATHOPHYSIOLOGY. Rhabdomyolysis is sometimes incorrectly ment may be required to save an affected limb. Classic symptoms of used interchangeably with crush injury (a description of injuries resulting compartment syndrome are (1) pain out of proportion to the injury, from crushing of a body part), compartment syndrome (the consequences (2) paresthesia, (3) pallor, (4) pulselessness (uncommon), and (5) Limb compression Local pressure Local tamponade Muscle/capillary necrosis Edema Rising compartment pressure Muscle ischemia Compartment tamponade Neural injury Compartment syndrome Volkmann contracture Muscle infarction Myoglobinemia ECF shift Acidosis/hyperkalemia Crush syndrome Renal failure Shock Cardiac dysrhythmia FIGURE 45.8 Pathogenesis of Compartment Syndrome and Crush Syndrome Caused by Prolonged Muscle Compression. ECF, Extracellular fluid.  CHAPTER 45 Alterations of Musculoskeletal Function 1431 BOX 45.1 SELECTED CAUSES OF RHABDOMYOLYSIS Medications and Toxic Substances That Increase the Risk Ischemic Causes of Rhabdomyolysis Ischemic limb injury Direct Myotoxicity HMG-CoA reductase inhibitors (statins), especially in combination with Exertional Causes fibrate-derived lipid-lowering agents such as niacin (nicotinic acid; Marathon running Nicolar) Physical overexertion in untrained athletes Cyclosporine (Sandimmune) Pathologic muscle exertion Itraconazole (Sporanox) Severe dystonia Erythromycin Tetanus Colchicine Status epilepticus Zidovudine (Retrovir) Delirium tremens Corticosteroids Heat dissipation impairment Physical overexertion in persons with sickle cell disease Other Medications and Toxins Amphetamines Genetic Causes Anesthetic and paralytic agents (halothane, propofol, succinylcholine— Lipid Metabolism malignant hyperthermia syndrome) Carnitine palmitoyltransferase deficiency Antihistamines (diphenhydramine, doxylamine) Carnitine deficiency Anti-hyperlipidemic agents (statins, clofibrate, bezafibrate) Short-chain and long-chain acetyl-coenzyme A dehydrogenase deficiency Antipsychotics and antidepressants (amitriptyline, doxepin, fluoxetine, haloperidol, lithium, protriptyline, perphenazine, promethazine, Carbohydrate Metabolism chlorpromazine, trifluoperazine) Myophosphorylase deficiency (McArdle disease) Caffeine Phosphorylase kinase deficiency Cocaine Phosphofructokinase deficiency HIV integrase inhibitor (raltegravir) Phosphoglycerate mutase deficiency Hypnotics and sedatives (benzodiazepines, barbiturates) Lactate dehydrogenase deficiency (characteristic elevation of creatine kinase Heroin level with normal lactate dehydrogenase level) LSD Purine Metabolism Methamphetamine Myoadenylate deaminase deficiency Methadone Duchenne muscular dystrophy Methylenedioxymethamphetamine (MDMA; “ecstasy”) Miscellaneous medications (amphotericin B, azathioprine, ε-aminocaproic Infectious, Inflammatory, Metabolic, and Endocrinologic acid, quinidine, penicillamine, salicylates, theophylline, terbutaline, Causes thiazides, vasopressin) Infectious Causes Phencyclidine Viruses: influenza virus B, parainfluenza virus, adenovirus, coxsackievirus, Protease inhibitors echovirus, herpes simplex virus, cytomegalovirus, Epstein-Barr virus, human immunodeficiency virus Indirect Muscle Damage Bacteria: Streptococcus, Salmonella, Legionella, Staphylococcus, and Listeria Alcohol species Central nervous system depressants Cocaine Inflammatory Causes Amphetamines Polymyositis Ecstasy (MDMA) Dermatomyositis LSD Capillary leak syndrome Neuromuscular-blocking agents Snake bites (mostly in South America, Asia, and Africa) Traumatic, Heat-Related, Ischemic, and Exertional Causes Metabolic and Endocrinologic Causes Traumatic Causes Electrolyte imbalances: hyponatremia, hypernatremia, hypokalemia, Direct trauma hypophosphatemia, hypocalcemia Lightning strike Hypothyroidism Immobilization Thyrotoxicosis Extensive third-degree burn Diabetic ketoacidosis Crush injury Nonketotic hyperosmolar syndrome Heat-Related Causes Herbal Supplements Heat stroke Red yeast rice (Monascus purpureus) Malignant hyperthermia Compounds containing ma huang, guarana, and garcinia cambogia Neuroleptic malignant syndrome Ephedra-based compounds, especially weight-loss supplements HMG-CoA, 3-Hydroxy-3-methylglutaryl coenzyme A; LSD, lysergic acid diethylamide; MDMA, 3,4-methylenedioxymethamphetamine. Data from Acharya S et al: Ann Indian Acad Neurol 13(3):221–222, 2010; Cervelin G, Comelli I, Lippe G: Clin Chem Lab Med 48(6):749–756, 2010; Croce F et al Int J STD AIDS 21(11):783–785, 2010; Halpern P et al: Hum Exp Toxicol 29(5):259–266, 2010; Mammen AL, Amato AA: Curr Opin Rheumatol 22(6):644–650, 2010; Sauret JM, Narinides G, Wang GK: Am Fam Physician 65(3):907, 2002. 1432 UNIT XIII The Musculoskeletal System paralysis (a late inding). Of these symptoms, pain is the most sensitive BOX 45.2 RISK FACTORS FOR clinical sign.15 When clinical evaluation is inconclusive, the rising compart- OSTEOPOROSIS ment pressure can be directly measured by inserting a wick catheter, Genetic Lifestyle needle, or slit catheter into the muscle. Immediate fasciotomy and Family history of osteoporosis Sedentary débridement are advocated for reducing elevated intracompartmen- White/Asian race Smoker tal pressures.15 Those frequently affected are the compartments of Increased age Alcohol consumption (excessive) the leg, the volar compartment of the hand, the abdomen, and the Female gender gluteal compartments. Concurrent CLINICAL MANIFESTATIONS. A classic triad of muscle pain, weakness, Anthropometric Hyperparathyroidism and dark urine is considered typical of rhabdomyolysis, but those affected Small stature may have no complaint of pain or muscle weakness.13 Abnormally dark Fair or pale skinned Illness and Trauma urine caused by myoglobinuria may be the irst and only symptom. Thin build Renal insufficiency, hypocalciuria The renal threshold for myoglobin is low (approximately 0.5 mg/dL of Rheumatoid arthritis urine), so only 200 g of muscle needs to be damaged to cause visible Hormonal and Metabolic Spinal cord injury changes in the urine. Myoglobin is rapidly cleared and levels may return Early menopause (natural or Systemic lupus erythematosus to normal within 24 hours of injury. Along with the release of myoglobin, surgical) Late menarche Liver Disease creatine kinase (CK) and other serum enzymes are released in massive Nulliparity Marrow disease (myeloma, quantities. The eflux of proteins and enzymes also includes loss of Obesity mastocytosis, thalassemia) potassium, phosphate, nucleotides, creatinine, and creatine. Serum hypocalcemia is seen early in the course of myoglobinuria and is followed Hypogonadism Gaucher disease Drugs by late hypercalcemia. Corticosteroids EVALUATION AND TREATMENT. The most important and clinically Cushing syndrome Weight below healthy range Dilantin useful measurement in rhabdomyolysis is serum creatine kinase (CK) Gonadotropin-releasing hormone level. With normal CK serum levels of 5 to 25 units/L for women and Acidosis agonists 5 to 35 units/L for men, a level ive times the upper limit of normal Loop diuretics Dietary (about 1000 units/L) is used to identify rhabdomyolysis. Once CK Methotrexate Low dietary calcium and vitamin D levels exceed 5000 units/L, acute renal failure is likely. A recent study Thyroid Low endogenous magnesium evaluated the ultrasonographic appearance of rhabdomyolysis in damaged Heparin Excessive protein* muscle from earthquake victims and found abnormalities in muscle Cyclosporine Excessive sodium intake texture and subcutaneous tissue, as well as areas of liquid in the Depo-medroxyprogesterone acetate High caffeine intake damaged tissue.16 Retinoids Anorexia Maintaining adequate urinary low and prevention of kidney failure Malabsorption are goals of treatment. Rapid intravenous hydration maintains adequate kidney low. Other issues, such as hyperkalemia, may require temporary *Low levels of protein intake also have been reported. hemodialysis. Other treatments, such as using mannitol to cause an osmotic diuresis or bicarbonate to alkalinize the urine, have not been shown to consistently improve outcomes. DISORDERS OF BONES Metabolic Bone Diseases Metabolic bone disease is characterized by abnormal bone structure that is caused by altered or inadequate biochemical reactions resulting in disorders of bone strength. Abnormalities include genetic, mineral, vitamin, hormone, and structural abnormalities. Osteoporosis Osteoporosis, or porous bone, is the most common bone disease in FIGURE 45.9 Vertebral Body. Osteoporotic vertebra (right) shortened by humans. It is characterized by low bone mineral density (BMD), impaired compression fractures compared with normal vertebral body (left). Note that the structural integrity of the bone, decreased bone strength, and the risk osteoporotic vertebra has characteristic loss of horizontal trabeculae and thickened of fracture. Those with the lowest BMD are at most risk of fracture.17 vertebral trabeculae. (From Kumar V et al: Robbins & Cotran pathologic basis of There are two types of osteoporosis: primary or idiopathic osteoporosis, disease, ed 9, Philadelphia, 2015, Saunders.) which is the most common; and secondary osteoporosis. Secondary osteoporosis is caused by other conditions, including endocrine diseases (hormone imbalances, diabetes, hyperparathyroidism, hyperthyroidism), and prone to fractures (Fig. 45.9). The World Health Organization medications (such as heparin, corticosteroids, phenytoin, barbiturates, (WHO) has deined osteoporosis on the basis of bone density: lithium), and other substances (including tobacco and ethanol). Other 1. Normal bone mass is greater than 833 mg/cm2. conditions (including rheumatoid disease, human immunodeiciency 2. Osteopenia, or decreased bone mass, is 833 to 648 mg/cm2. virus [HIV], malignancies, malabsorption syndromes, liver or kidney 3. Osteoporosis is bone mass less than 648 mg/cm2. disease) also increase the risk for developing osteoporosis (Box 45.2). Osteoporosis is a complex, multifactorial chronic disease that often Cortical bone becomes more porous and thinner, making bone weaker progresses silently for decades until fractures occur. It is the most common  CHAPTER 45 Alterations of Musculoskeletal Function 1433 disease that affects bone. It is not necessarily a consequence of the aging addition to direct medical costs, studies have shown decreased quality process because some older adults retain strong, relatively dense bones. of life as well as excess loss of life-years for those experiencing hip or In osteoporosis, old bone is being reabsorbed faster than new bone is osteoporotic fractures.23,24 being made, causing the bones to lose density, becoming thinner and Vertebral fractures are the most common osteoporotic fracture but more porous. A progressive loss of bone mass may continue until the may be asymptomatic. Even if the fracture does not cause pain, vertebral skeleton is no longer strong enough to support itself. Eventually, bones fractures can cause deformity, reduced pulmonary function, and loss can fracture spontaneously. As bone becomes more fragile, fractures of height. The degree of compression necessary to deine a vertebral occur from falls or bumps that would not previously have caused fracture has not been standardized. fracture. Osteoporosis affects all races and both sexes. Recent data from the Severe or established osteoporosis is identiied when there has been National Health and Nutrition Examination Survey (NHANES) showed a fragility fracture. The disease can be (1) generalized, involving major that Mexican-Americans had higher risk for osteoporosis, whereas portions of the axial skeleton, or (2) regional, involving one segment non-Hispanic black persons had lower risk of osteopenia or osteoporosis of the appendicular skeleton. at the lumbar spine or femoral neck.19 Multiple genetic factors also Throughout a lifetime, old bone is removed (resorption) and new inluence development of osteoporosis.25 bone is added (formation) to the skeleton. During childhood and teenage Whites are more susceptible than other races to osteoporosis caused years, new bone is added faster than old bone is removed. Consequently, by loss of bone density with age. Blacks have only about half the fractures bones become larger, heavier, and denser. Bone formation continues found in whites, probably related to their higher peak bone mass, but at a pace faster than resorption until peak bone mass, or maximum black women remain at a high risk because of factors such as decreased bone density and strength, is reached, around age 30, after which bone dietary calcium intake, a high percentage of lactose intolerance, and resorption slowly exceeds bone formation. In women, bone loss begins increased prevalence of diseases, such as sickle cell disease and lupus, before menopause, and is most rapid in the irst years after menopause that increase the risk of developing osteoporosis.26 Both black women but persists throughout the postmenopausal years. Osteoporosis is most and black men have generally been undertreated for osteoporosis.26 common in women at a rate of one in two women.18 Men also are at Decreased bone strength with aging is partly due to lower bone mass, risk, with an estimated one in four men experiencing an osteoporosis- but other factors such as deterioration of type I collagen likely contribute related fracture at some point in one’s lifetime.18 In adults older than to increased fracture risk.27 age 50, the prevalence of osteoporosis at either the spine or the femoral Measuring bone mineral density (BMD) by using dual x-ray neck by age ranges from 3% to 10% in men and from 7% to 35% in absorptiometry (DXA) continues to be the most common method of women. One study showed that in men the prevalence of osteoporosis estimating bone mass. Bone quality relates not just to bone mass (as did not increase with age until age 80 years and older, but in women measured by bone density) but also to the microarchitecture of the it increased for each decade after age 50 years.19 bone. Other variables include crystal size and shape, brittleness, vitality Approximately 52 million people in the United States are affected of the bone cells, structure of the bone proteins, water volume, integrity by osteoporosis or low bone density.20 The major risks for persons with of the trabecular network, vascular supply, and the ability to repair osteoporosis are fractures. Men lose bone density with aging; but because tiny cracks.28 they begin with a higher bone density, they reach osteoporotic levels Because bone density relates to quantity of bone, bone quality is at an older age than do women.21 In 2011 the United States Preventive not accurately identiied by bone density testing. Therefore bone density Services Task Force (USPSTF) issued a recommendation that women testing may or may not accurately identify individuals with increased age 65 and older be routinely screened for osteoporosis.22 Hip fractures, fracture risk. An online tool called Fracture Risk Assessment (FRAX) in particular, can have devastating effects on an individual’s life. In (Fig. 45.10) incorporates clinical risk factors with BMD at the femoral Country: Canada Name/ ID: Questionnaire: 10. Secondary osteoporosis No Yes 1. Age (between 40 and 90 years) or Date of Birth 11. Alcohol 3 or more units/day No Yes Age: Date of Birth: 12. Femoral neck BMD (g/cm2) Y: M: D: 2. Sex Select BMD Male Female 3. Weight (kg) Clear Calculate 4. Height (cm) 5. Previous Fracture No Yes 6. Parent Fractured Hip No Yes 7. Current Smoking No Yes 8. Glucocorticoids No Yes 9. Rheumatoid arthritis No Yes FIGURE 45.10 Fracture Risk Assessment Tool: FRAX. (Available at: http://www.shef.ac.uk/FRAX/tool.aspx ?country=19.) 1434 UNIT XIII The Musculoskeletal System neck to predict an individual’s 10-year probability of fracture. This tool breakdown. Osteoporosis caused by heparin therapy usually resolves is available at http://www.shef.ac.uk/FRAX. when therapy ceases. Treatment with other medications may lead to Postmenopausal osteoporosis occurs in middle-aged and older the development of osteoporosis, such as the use of glucocorticoid women. It can occur because of estrogen deiciency as well as estrogen- treatment for many chronic disease processes. Other medications that independent age-related mechanisms (e.g., secondary causes such as increase the risk of osteoporosis include lithium, methotrexate, anti- hyperparathyroidism and decreased mechanical stimulation). Recent convulsants, cyclophosphamide, and cyclosporine. studies indicate that increased oxidative stress (OS) and increased One secondary cause, transient osteoporosis of the hip, is associated intracellular reactive oxygen species (ROS) play a signiicant role in the with the third trimester of pregnancy or the immediate postpartum development of age-related bone loss, as well as other age-related changes period. However, most transient osteoporosis is a typically self-limiting in the body.28 Hormonal deiciency also can increase with stress, excessive syndrome affecting the lower extremity joints of middle-aged men. exercise, and low body weight. Postmenopausal changes include a The etiology is unknown, and although most cases spontaneously substantial increase in bone turnover—that is, an imbalance between resolve, some occurrences of bone demineralization may be related to the remodeling activity of osteoclasts and osteoblasts. Increased formation osteonecrosis.32 and longevity of osteoclasts result in increased bone resorption and is Regional osteoporosis—osteoporosis conined to a region or segment associated with a cascade of proinlammatory cytokines. Increased of the appendicular skeleton—usually has a known cause. Transient cytokine activation, especially tumor necrosis factor (TNF), can occur regional osteoporosis has no known etiology, is characterized by bone with declining estrogen levels.28 In addition, estrogen helps protect marrow edema, and can cause severe pain. The lower extremity is most against the effects of OS and osteoclast apoptosis. Biologically, these often affected, but other areas also may be involved.33 Fortunately, it is processes involve the receptor activator of nuclear factor κβ ligand usually self-limited. It tends to occur in middle-aged men and women (RANKL), transcription factors such as Forkhead proteins, the Wnt in their late second or third trimester of pregnancy.33 It is characterized and osteoprotegerin (OPG) signaling pathways (see the following by bone marrow edema, seen on magnetic resonance imaging (MRI), Pathophysiology section), and insulin-like growth factor (IGF). Other and areas of localized bone demineralization are seen on plain causes may include a combination of inadequate dietary calcium intake radiographs. Treatment is primarily symptomatic and the condition and lack of vitamin D, possibly decreased magnesium level, lack of usually resolves spontaneously over 3 to 6 months, with no long-term exercise, low body mass, and family history. IGF is known to help in adverse effects. fracture healing and collagen synthesis and improves conditions for Classic regional osteoporosis is associated with disuse or immobiliza- bone mineralization. IGF levels signiicantly decline by age 60. tion of a limb because of fractures, motor paralysis, or bone or joint The levels of sex hormones, especially estradiol (estrogen) and inlammation (see Fig. 45.14). A negative calcium balance develops testosterone, are signiicant in premenopausal bone maintenance; early and continues throughout the period of immobilization. After 8 however, when estrogen levels drop after menopause, it appears that weeks of immobilization, signiicant osteoporosis is present, although circulating androgens become signiicant effectors on bone metabolism. it may develop earlier in persons younger than 20 years or older than In clinical studies of women, data have suggested that serum androgens 50 years. A uniform distribution of osteoporosis also has been observed inluence bone density in pre-, peri-, and postmenopausal women. in astronauts and in individuals treated with air suspension therapy as Androgens (i.e., testosterone and dihydrotestosterone) have long been a result of weightlessness and lack of mechanical strain. recognized to stimulate bone formation. Other risk factors are identiied PATHOPHYSIOLOGY. Whatever the cause, osteoporosis develops in Box 45.2. when the remodeling cycle—the process of bone resorption and bone Poor nutrition and insuficient intake or malabsorption of dietary formation—is disrupted, leading to an imbalance in the coupling process. minerals, particularly calcium, are factors in the development of The explosion of new information in the ield of bone biology has led osteoporosis. Calcium absorption from the intestine decreases with age, to new understanding of the roles of hormones, growth and signaling and studies of individuals with osteoporosis show that their calcium factors, and cellular biology in osteoporosis. Although hormonal inlu- intake is lower than that of age-matched controls. Deiciencies of vitamins, ences remain important in maintaining bone health, genetic factors and particularly vitamins C, D, E, and K, also contribute to bone loss.29 the role of oxidative stress are receiving increased attention as critical Skeletal homeostasis depends on a very narrow range of plasma determinants of bone homeostasis.25,28 Reactive oxygen species (ROSs) calcium and phosphate concentrations, which are maintained by the are normal byproducts of aerobic metabolism, and although they can endocrine system.30 Therefore endocrine dysfunction ultimately can cause cell damage, at levels below which they cause oxidative stress cause metabolic bone disease. In addition to declining levels of sex (OS), ROSs serve as signaling molecules for many cell types, including steroids, the hormones most commonly associated with osteoporosis osteocytes, osteoblasts, and osteoclasts. When excess ROSs accumulate, are parathyroid hormone, cortisol, thyroid hormone, and growth OS occurs and can result in loss of bone mass and bone strength.28 hormone. Excessive intakes of caffeine, alcohol, and nicotine along with The osteoclast differentiation pathway is directed by a series of low body fat have been considered risk factors. In addition, signiicant processes that include proliferation, differentiation, fusion, and activation. differences in the levels of trace elements (zinc, copper, manganese) These processes are controlled by hormones, cytokines, and paracrine were noted in the bones and hair of unaffected individuals compared stromal-cell microenvironment interactions. Thus the intercellular with those with osteoporosis. The development of selective estrogen communication in bone and the key molecular regulators are necessary receptor modulators (SERMs) for the treatment of postmenopausal for bone homeostasis. Certain transcription factors, known as Forkhead osteoporosis increases bone formation and builds more muscle mass. box (FoxO), help protect against the effects of OS by preventing excess In theory, selectively affecting bone, muscle mass, and other desired accumulation of ROS and regulating certain genes that affect DNA sites, while not affecting lipid or estrogen levels or blood pressure, side repair and cell life span. FoxOs help remove damaged and abnormal effects can be controlled but since the direct effects of SERMs on bone cells by inducing apoptosis.28 are not yet known, this remains a clinical challenge.31 Interleukins (IL-1, IL-4, IL-6, IL-7, IL-11, IL-17), tumor necrosis Secondary osteoporosis sometimes develops temporarily in individuals factor-alpha (TNF-α), transforming growth factor-beta (TGF-β), receiving large doses of heparin, perhaps because heparin promotes prostaglandin E2, and hormones interact to control osteoclasts34 (Fig. bone resorption by decreasing collagen synthesis or by increasing collagen 45.11). Normal bone homeostasis is dependent on the balance between  CHAPTER 45 Alterations of Musculoskeletal Function 1435 Skeletal system Stromal cell or osteoblast OPG production RANKL expression Increased by Decreased by Increased by IL-1, IL-13, IL-18 PTH IL-1, IL-11, IL-17 TNF-! Prostaglandin E2 TNF-! TGF-", BMP-2 Glucocorticoids PTH 17"-estradiol Cyclosporine A Prostaglandin E2 OPG Leptin Glucocorticoids Mechanical strain Decreased by RANKL Decoy IL-4 TGF-" 17"-estradiol RANK Mature osteoclast NF-!B pathway PKB/Akt pathway c-Jun N-terminal Kinase pathway Osteoclast A precursor Immune system Dendritic OPG production RANKL OPG cell Increased by RANKL expression CD40 ligand Increased by IL-1, IL-7, IL-17 TNF-! Decreased by RANK NF-!B pathway T cell 17"-estradiol c-Jun N-terminal Kinase pathway NF-!B T cell pathway B Vascular system OPG production Increased by Decreased by PDGF-BP Glucocorticoids OPG Cyclosporine A Troglitazone RANKL expression Endothelial RANKL Increased by cell IL-1 TNF-! RANK Smooth muscle OPG production cell PKB/Akt Increased by pathway IL-1 TNF-! C Endothelial cell FIGURE 45.11 OPG/RANKL/RANK System. Receptor activator of nuclear factor κβ ligand (RANKL, which is a cytokine and part of the tumor necrosis factor [TNF] family) and osteoprotegerin (OPG, which is a glycoprotein receptor antagonist) are modulated by various cytokines, hormones, drugs, and mechanical strains (see inserts). A, In bone, RANKL is expressed by both stromal cells and osteoblasts. RANKL stimulates the receptor RANK on osteoclast precursor cells and mature osteoclasts, and activates intracellular signaling pathways to promote osteoclast differentiation and activation and cytoskeletal reorganization and survival (PKB/Akt pathway) that increase resorption and bone loss. OPG, secreted by stromal cells and osteoblasts, acts as a “decoy” receptor and blocks RANKL binding to and activation of RANK. B, In the immune system, RANKL is expressed and secreted by T cells. T-cell–derived RANKL also can activate RANK on osteoclasts, T cells, and dendritic cells (antigen-presenting cells), which enhances bone loss that occurs in inflammatory bone diseases such as rheumatoid arthritis. Dendritic cells may regulate these processes by secreting OPG. C, In the vascular system, endothelial cells express RANKL and the RANK receptor. RANKL/RANK interactions contribute to endothelial and smooth muscle cells and can block RANKL binding. The physiologic significance of the OPG/RANKL/RANK system in endothelial and smooth muscle cells is being studied. BMP-2, Bone morphogenic protein 2; IL, interleukin; PDGF-BP, platelet-derived growth factor-beta polypeptide; PTH, parathyroid hormone; TGF-α, tumor necrosis factor-alpha; TGF-β, transforming growth factor-beta. (Adapted from Hofbauer LC, Schoppet M: JAMA 292:490–495, 2004.) 1436 UNIT XIII The Musculoskeletal System the cytokine receptor activator of nuclear factor κβ ligand (RANKL), ERKs converted the antiapoptotic effect of estradiol to proapoptotic. its receptor RANK, and its decoy receptor osteoprotegerin (OPG); In addition to ERKs, RANKL promotes the antiapoptotic effects on understanding this has led to a tremendously increased knowledge of osteoclasts, thus increasing their life span.40 Wnt signaling induces a osteoclast biology and pathogenesis of bone loss.35 biochemical series of events that increases osteoblast and bone formation. RANKL, a member of the TNF family, is expressed by osteoblasts Alterations in Wnt signaling account for critical pathophysiologic changes and their immature precursors and is necessary for osteoclast develop- in most acquired metabolic bone diseases including postmenopausal ment. RANKL activates the receptor RANK, which is expressed on osteoporosis, aging effects, and glucocorticoid (i.e., cortisone) excess. osteoclasts and their precursors and suppresses apoptosis, which leads Agents such as parathyroid hormone and bisphosphonates, used for to activation and prolongation of osteoclast survival.36 The effects of treatment of bone loss, exert their positive effects by altering the forma- RANKL are blocked by OPG, a glycoprotein that acts as a decoy receptor tion of osteoblasts or osteoclasts or by inducing osteoclast apoptosis. for RANKL that prevents it from binding and activating RANK (see Glucocorticoid- (e.g., cortisone-) induced osteoporosis is character- Fig. 45.11). Cytokines and hormones regulate the balance between ized by increased bone resorption and decreased bone formation. RANKL and OPG. Alterations of the RANKL/RANK/OPG system can Glucocorticoids increase RANKL expression and inhibit OPG production lead to dysregulation and pathologic conditions including osteoporosis, by osteoblasts (see Fig. 45.11). The use of immunosuppressive drugs immune-mediated bone diseases, malignant bone disorders, and inherited (e.g., cyclosporine A) to reduce rejection of transplanted organs also skeletal diseases (see Fig. 45.11). alters the OPG/RANKL/RANK system and can lead to posttransplantation Postmenopausal osteoporosis is characterized by increased bone osteoporosis. Other conditions affected by OPG/RANKL/RANK include resorption relative to the rate of bone formation, leading to sustained rheumatoid arthritis, myeloma, vascular diseases, and skeletal metastases bone loss resulting from estrogen deiciency. Bone los