AAOS Comprehensive Orthopaedic Review

Section 4 - Orthopaedic Oncology and Systemic Disease

Chapter 44. Metabolic Bone and Inflammatory Joint Disease

I. Osteopetrosis (Albers-Schonberg Disease)

A. Definition and demographics


1. Osteopetrosis is a rare disorder characterized by a failure of osteoclastic resorption with resultant dense bone with no medullary cavity (prone to fracture).


2. Autosomal recessive forms are discovered in children; the delayed type often is not discovered until adulthood.


B. Genetics/etiology


1. Lethal form is autosomal recessive (malignant).


2. Delayed type is autosomal dominant.


3. When osteopetrosis occurs with renal tubular acidosis and cerebral calcification, there is an associated carbonic anhydrase II deficiency.


4. Deactivating mutations in three genes have been found (inability to cause acidification in the clear zone). The sites of the defects are as follows:


a. Carbonic anhydrase II (CA II)


b. Alpha 3 subunit of vacuolar proton pump


c. Chloride channel 7


C. Clinical presentation—Often discovered following:


1. Fracture


2. Complications following tooth extraction


3. Anemia


4. Cranial nerve palsy (hearing loss)


D. Radiographic appearance (

Figure 1)


1. Symmetric increase in bone mass


2. Thickened cortical and trabecular bone


3. Often alternating sclerotic and lucent bands


   *Frank J. Frassica, MD, is a consultant or employee for SLACK Inc.


[Figure 1. Osteopetrosis. A, AP radiograph of the hip in a patient with osteopetrosis. The medullary cavity is intensely sclerotic. There is no medullary cavity in the periacetabular region. B, AP view of the spine of a patient with osteopetrosis demonstrates the dense sclerosis at the superior and inferior end plates of the vertebral bodies.]

4. Widened metaphyses (Erlenmeyer flask deformity)


E. Pathology


1. Islands or bars of calcified cartilage within mature trabeculae


2. Osteoclasts without ruffled borders


F. Treatment


1. Bone marrow transplantation for infantile form


2. Interferon gamma-1β for delayed type

II. Oncologic Osteomalacia (Tumor-Induced Osteomalacia)

A. Definition and demographics


1. Paraneoplastic syndrome of renal phosphate wasting caused by a bone tumor or soft-tissue tumor that secretes a substance that leads to osteomalacia


2. Putative factor is "phosphatonin"; possible gene is fibroblast growth factor-23.


3. Often a long delay in detecting the tumor


B. Genetics/etiology—Four types of tumors cause oncologic osteomalacia.


1. Phosphaturic mesenchymal tumor, mixed connective tissue type


2. Osteoblastoma-like tumors


3. Ossifying fibrous tumors


4. Nonossifying fibrous tumors


C. Clinical presentation


1. Progressive bone and muscle pain


2. Weakness and fatigue


3. Fractures of the long bones, ribs, and vertebrae


D. Imaging appearance


1. Diffuse osteopenia, pseudofractures on radiographs


2. Tumors detected on octreotide scan (indium-111-pentetreotide scintigraphy, radiolabeled somatostatin analog)


E. Laboratory features


1. Hypophosphatemia


2. Phosphaturia due to low proximal tubular reabsorption


3. Low serum 1,25-dihydroxyvitamin D


F. Treatment


1. Removal of the tumor


2. Phosphate supplementation with 1,25-dihydroxyvitamin D

III. Hypercalcemia and Malignancy

A. Definition and demographics


1. Hypercalcemia may develop in patients with cancer.


2. Two types: with diffuse lytic metastases (20%) and without (80%)


a. Hypercalcemia with diffuse lytic metastases is commonly associated with the following types of cancers:


i. Breast cancer


ii. Hematologic malignancies: multiple myeloma, lymphoma, leukemia


b. Hypercalcemia without diffuse lytic metastases is commonly associated with the following types of cancers:


i. Squamous cell carcinoma


ii. Renal or bladder carcinoma


iii. Ovarian or endometrial cancer


iv. Breast cancer


B. Genetics/etiology—Local or circulating factor that causes bone resorption and release of calcium ions.


C. Clinical presentation


1. Neurologic: difficulty concentrating, sleepiness, depression, confusion, coma


2. Gastrointestinal: constipation, anorexia, nausea, vomiting


3. Genitourinary: polyuria, dehydration


4. Cardiac: shortening of QT interval, bradycardia, first-degree block


D. Radiographic appearance—Diffuse lytic metastases may or may not be present.


E. Laboratory features


1. Hypercalcemia


2. Normal or high serum phosphorus level


3. Low parathyroid hormone level


F. Pathology—Osteoclastic bone resorption.


G. Treatment


1. Bisphosphonate therapy to halt osteoclastic bone resorption


2. Combination therapy (chemotherapy and radiation) to kill the cancer cells

IV. Paget Disease

A. Definition and demographics


1. Remodeling disease characterized initially by osteoclast-mediated bone resorption and then disordered bone formation


2. Common in patients older than 50 years


B. Genetics/etiology


1. Possibly caused by a slow virus infection (paramyxovirus, respiratory syncytial virus)


2. Most common in Caucasians of Anglo-Saxon descent


3. Strong genetic tendency (autosomal dominant)


a. Candidate genes



Figure 2. Paget disease. A, AP view of the pelvis in a patient with Paget disease. Note the coarsened trabeculae from the pubis to the supra-acetabular area and marked thickening of the iliopectineal line. B, Technetium Tc 99m bone scan in a patient with Paget disease. Note the intense uptake in the scapula, lumbar vertebral body, right ilium, and right ulna. C and D, Hematoxylin and eosin stain of pagetic bone. Note the disordered appearance of the bone and the multiple cement lines (curved blue lines).]

b. 5q35-QTER (ubiquitin binding protein sequestosome-1)


C. Clinical presentation


1. No sex predilection


2. Generally found in patients older than 50 years


3. May be monostotic or polyostotic; the number of sites remains constant.


4. Common sites: femur, pelvis, tibia, skull, spine (Figure 2)


5. Often asymptomatic and found incidentally on a bone scan, chest radiograph, or in patients with elevated alkaline phosphatase levels


6. Progresses through three phases


a. Lytic phase


i. Profound resorption of the bone


ii. Purely lucent on radiographs, with expansion and thinned but intact cortices


b. Mixed phase: combination of lysis and bone formation with coarsened trabeculae


c. Sclerotic phase: enlargement of the bone with thickened cortices and with sclerotic and lucent areas


7. Bone pain may also be present, which may be caused by increased vascularity and warmth or by stress fractures.


8. Bowing of the femur or tibia


9. Fractures, most commonly femoral neck


10. Arthritis of the hip and knee


11. Lumbar spinal stenosis


12. Malignant degeneration


a. Occurs in 1% of patients


b. Most common locations: pelvis, femur, humerus


c. Patients often note a marked increase in pain, and the pain is usually constant.


D. Laboratory features


1. Increased alkaline phosphatase level


2. Increased urinary markers of bone turnover


a. Collagen cross-links


b. N-telopeptide, hydroxylproline, deoxypyridinoline


3. Normal calcium level


E. Radiographic appearance


1. Plain radiographs (Figure 2, A)


a. Coarsened trabeculae


b. Cortical thickening


c. Lucent advancing edge ("blade of grass" or "flame-shaped") in active disease


d. Loss of distinction between the cortices and medullary cavity


e. Enlargement of the bone


2. Technetium Tc 99m bone scans—Increased up-take accurately marks sites of disease (Figure 2, B).


a. Intense activity, which often outlines the shape of the bone during the active phase


b. Mild to moderate activity in the sclerotic phases


3. CT scans


a. Cortical thickening


b. Coarsened trabeculae


F. Pathology


1. Profound osteoclastic bone resorption


2. Abnormal bone formation—mosaic pattern


a. Woven bone and irregular sections of thickened trabecular bone


b. Numerous cement lines


G. Treatment


1. Therapy is aimed to stop the osteoclasts from resorbing bone and halt the pagetic bone changes.


2. Bisphosphonates


a. Oral agents: alendronate and risedronate


b. Intravenous agents: pamidronate and zoledronic acid


3. Calcitonin—Salmon calcitonin is administered subcutaneously or intramuscularly.

V. Osteonecrosis

A. Definition—Death of bone cells and bone marrow secondary to a loss of blood supply.


B. Genetics/etiology


1. Four mechanisms have been proposed.


a. Mechanical disruption of the blood vessels (trauma, such as a hip dislocation)


b. Arterial vessel occlusion


i. Nitrogen bubbles (bends), sickle cell disease


ii. Fat emboli


c. Injury or pressure on the blood vessel wall


i. Marrow diseases (such as Gaucher)


ii. Vasculitis, radiation injury


d. Venous outflow obstruction


2. Hypercoagulable states


a. Decreased anticoagulants—proteins C, S


b. Increased procoagulants


C. Clinical presentation—The patient may present with a dull pain in the joint, severe arthritic pain with collapse of the joint, or may be asymptomatic.


D. Imaging appearance


1. Initially normal radiographs


2. Sclerosis and cyst formation


3. Subchondral fracture (crescent sign), subchondral collapse


4. Arthritic changes: osteophytes, loss of joint space


5. MRI: characteristic marrow changes in the metaphyseal marrow and subchondral locations (

Figure 3)


E. Pathology


1. Osteocyte death (no cells in the bone lacunae)


2. Marrow necrosis


3. Loss of the vascular supply


F. Treatment


1. Core decompression if the joint surfaces remain intact (no collapse)


2. Arthroplasty for joint collapse


[Figure 3. Osteonecrosis. A, T1-weighted coronal MRI in a patient with osteonecrosis showing a large metaphyseal lesion and a wedge-shaped area of necrosis at the subchondral region of the lateral femoral condyle. B, T2-weighted coronal MRI in a patient with osteonecrosis demonstrates a large metaphyseal lesion with a large subchondral wedge-shaped lesion in the lateral femur. C, Hematoxylin and eosin stain demonstrates the complete loss of the bone marrow and an absence of osteocytes in the trabecular lacunae.]

VI. Rheumatoid Arthritis

A. Definition and demographics


1. Systemic inflammatory disease of the synovium


2. Twice as common in females compared with males


3. According to the American College of Rheumatology revised criteria, the patient must have four of the seven symptoms and have had symptoms 1 through 4 for at least 6 weeks (

Table 1).


B. Genetics/etiology


1. Genetic marker human leukocyte antigen (HLA)-DR4 (patients of northern European descent)


2. Monozygotic twins have a concordance rate of 12% to 15%.


C. Clinical presentation


1. Morning stiffness, pain


2. Joint swelling (most prominent in small joints of the hands and feet)


a. Effusions


b. Synovial proliferation


3. Hand deformities: subluxation, ulnar drift, swan-neck deformity


D. Imaging appearance (

Figure 4)


1. Periarticular osteopenia


2. Juxta-articular erosions


3. Joint space narrowing


[Table 1. American College of Rheumatology Revised Criteria for Rheumatoid Arthritis]

E. Laboratory features


1. Approximately 90% of patients are positive for rheumatoid factor.


2. Acute-phase reactants: erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) elevated level


F. Pathology—Inflammatory agents destroy cartilage, ligaments, and bone.


G. Treatment


1. Nonsteroidal anti-inflammatory drugs


2. Aspirin


3. Disease-modifying antirheumatic drugs


a. Methotrexate (current treatment of choice)


b. Others (D-penicillamine, sulfasalazine, gold, antimalarials)


[Figure 4. Rheumatoid arthritis. A, AP radiograph of the knee showing a subchondral cyst in the proximal tibia with narrowing of the medial compartment of the knee. B, T1-weighted sagittal MRI of the knee shows a large subchondral lesion in the distal femur and proximal tibia and an erosion on the tibial condylar surface. C, T2-weighted sagittal MRI of the knee demonstrates a large erosion on the distal femur and proximal tibia, an effusion, and diffuse synovial thickening.]

4. Cytokine-neutralizing


a. Etanercept (soluble p75 tumor necrosis factor [TNF] receptor immunoglobulin G fusion protein)


b. Infliximab (chimeric monoclonal antibody to TNF-α)


c. Rituximab (monoclonal antibody to CD20 antigen; inhibits B-cells)


5. Physical therapy

VII. Ankylosing Spondylitis (Marie-Strumpell Disease)

A. Definition and demographics


1. Inflammatory disorder that affects the spine and sacroiliac joints and large joints such as the hip in young adults


2. Male to female ratio = 3:1


B. Genetics/etiology


1. 90% of patients with ankylosing spondylitis have HLA-B27 antigen.


2. Autoimmune disorder


a. High levels of TNF


b. CD4+, CD8+ T-cells


C. Clinical presentation


1. Young adults


2. Low back and pelvic pain


3. Morning stiffness


4. Hip arthritis in approximately one third of patients


5. Uveitis: pain, light sensitivity


6. Heart involvement


a. Aortic valve insufficiency


b. Third-degree heart block


D. Radiographic appearance


1. Sacroiliac joint inflammation


a. Blurring of subchondral margins


b. Erosions


c. Bony bridging


2. Lumbar spine involvement (

Figure 5)


a. Loss of lumbar lordosis


b. Squaring of the vertebrae


c. Osteophytes bridging the vertebrae


E. Pathology


1. Laboratory findings


a. HLA-B27 in 90% of patients


b. Elevated ESR and CRP level


2. Inflammation of ligamentous attachment sites


a. Erosions, subchondral inflammation


b. Ossification of joints such as the sacroiliac joint


[Figure 5. Lateral radiograph of the spine in a patient with ankylosing spondylitis. Note the anterior osteophytes bridging all the lumbar vertebrae.]

3. Arthritis—pannus formation with lymphoid infiltration


F. Treatment: anti-TNF therapy


1. Infliximab (chimeric monoclonal antibody to TNF-α)


2. Etanercept (soluble p75 TNF receptor immunoglobulin G fusion protein)

VIII. Reactive Arthritis

A. Overview—Reactive arthritis (formerly called Reiter syndrome) occurs after an infection at another site in the body.


B. Genetics/etiology—Affected individuals are genetically predisposed (high incidence of HLA-B27).


C. Clinical presentation


1. An infection occurs 1 to 8 weeks before the onset of the arthritis.


2. Common extraskeletal involvement


a. Urethritis, prostatitis


b. Uveitis


c. Mucocutaneous involvement


3. Systemic symptoms are usually present: fatigue, malaise, fever, weight loss.


4. Arthritis is asymmetric.


5. Common sites include the knee, ankle, subtalar joint, and metatarsophalangeal and interphalangeal joints.


6. Tendinitis/fasciitis common


a. Achilles tendon insertion


b. Plantar fascia


D. Radiographic appearance


1. Juxta-articular erosions


2. Joint destruction


E. Pathology


1. Synovial inflammation


2. Enthesitis


F. Treatment


1. Indomethacin


2. Recurrent joint symptoms and tendinitis are common.

IX. Systemic Lupus Erythematosus

A. Definition—Autoimmune disorder in which autoimmune complexes damage joints, skin, kidneys, lungs, heart, blood vessels, and nervous system.


B. Genetics/etiology


1. Multiple genes


2. HLA class II, HLA class III, HLA-DR, HLA-DQ


C. Clinical presentation


1. Multiple joint involvement


2. Osteonecrosis of the hips is common, especially in patients taking glucocorticoids.


D. Radiographic appearance


1. Unusual to have erosions or joint destruction


2. Osteonecrosis may be seen as a result of corticosteroid treatment.


E. Pathology—Anti-nuclear antibodies are present in 95% of patients.


F. Treatment


1. Analgesics


2. Antimalarials

X. Gout

A. Definition and demographics


1. Gout is a metabolic disorder caused by uric acid crystals in the synovium.


2. Affects older men and postmenopausal women



Figure 6. Gout. A, AP radiograph of the hand in a patient with gout showing a lucent lesion in the distal radius and erosive changes in the carpal bones. B, Hematoxylin and eosin stain of a patient with gout. Note the tophaceous areas are amorphous and white and are bordered by inflammatory cells.]

B. Clinical presentation


1. Severe pain in a single joint is common; joint is intensely painful, swollen, and erythematous.


2. Often polyarticular in men with hypertension and alcohol abuse


C. Radiographic appearance (Figure 6, A)


1. Periarticular erosions


2. Peripheral margin of the erosion often has a thin overlying rim of bone (cliff sign).


D. Pathology


1. Joint aspiration is the only definitive diagnostic procedure.


2. Needle- and rod-shaped crystals with negative birefringence


3. Joint white blood cell count usually <50,000 to 60,000/μL


4. Serum uric acid often elevated (but not always)


5. Hematoxylin and eosin staining shows amorphous material and inflammatory cells (Figure 6, B).


E. Treatment/outcome


1. Nonsteroidal anti-inflammatory drugs


2. Colchicine


3. Hypouricemic therapy: allopurinol, probenecid

XI. Osteoporosis

A. Definition and demographics


1. Characteristics


a. Low bone mass


b. Microarchitectural deterioration


c. Fractures


2. Peak bone mass is attained between 2 and 30 years of age, and failure to attain adequate bone mass at this time is one of the main determinants in the development of osteoporosis.


3. World Health Organization definition


a. Normal: within 1 SD of peak bone mass (T-score = 0 to -1.0)


b. Low bone mass (osteopenia): 1.0 to 2.5 SDs below peak bone mass (T-score = -1.0 to -2.5)


c. Osteoporosis: >2.5 SDs below peak bone mass (T-score = < -2.5)


B. Genetics/etiology


1. Causes are multifactorial.


2. Genetic predisposition is important.


3. Genes that have been associated with the development of osteoporosis


a. COL1A1 (collagen 1α1): main bone collagen


b. Vitamin D receptor


c. LRP5: (low-density lipoprotein receptor-related protein)


C. Clinical presentation


1. Patient usually presents with a fracture following minor trauma.


2. Found on routine screening (bone mineral density)


3. Most important risk factors


a. Increasing age (geriatric patient)


b. Female sex


c. Early menopause


d. Fair-skinned


e. Maternal/paternal history of hip fracture


f. Low body weight


g. Cigarette smoking


h. Glucocorticoid use


i. Excessive alcohol use


j. Low protein intake


k. Anticonvulsant or antidepressant use


D. Radiographic appearance


1. Osteopenia


2. Thinning of the cortices


3. Loss of trabecular bone


E. Pathology


1. Loss of trabecular bone


2. Loss of continuity of the trabecular bone


F. Treatment


1. Adequate calcium and vitamin D intake


2. Antiresorptive therapy for patients with osteoporosis


3. Parathyroid hormone therapy for patients with osteoporosis resistant to bisphosphonates

Top Testing Facts

1. Osteopetrosis is a rare disorder characterized by a failure of osteoclastic resorption with resultant dense bone with no medullary cavity (prone to fracture).


2. Oncologic osteomalacia is a paraneoplastic syndrome characterized by renal phosphate wasting and can be caused by a variety of bone and soft-tissue tumors (osteoblastoma, nonossifying fibroma, and phosphaturic mesenchymal tumor).


3. Hypercalcemia may occur as a complication of breast cancer, multiple myeloma, and lymphoma.


4. Paget disease is a remodeling disease characterized by disordered bone formation; it is treated with bisphosphonates.


5. Rheumatoid arthritis is a systemic inflammatory disorder characterized by morning stiffness and joint pain; 90% of patients are positive for rheumatoid factor.


6. Ankylosing spondylitis is an inflammatory disorder of the spine and sacroiliac joints characterized by HLA-B27 positivity; it is treated with anti-TNF therapy.


7. Gout is a metabolic disorder caused by uric acid crystals in the synovium resulting in periarticular erosions.


8. Osteoporosis is characterized by low bone mass (>2.5 SDs below the mean) and an increased risk of fracture.


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McAlister WH, Herman TE: Osteochondrodysplasias, dysostoses, chromosomal aberrations, mucopolysaccharidoses, and mucolipodoses, in Resnik D, Kransdorf, M (eds): Diagnosis of Bone and Joint Disorders, ed 3. Philadelphia, PA, WB Saunders, 1995, pp 4200-4204.

Miclau T, Bozic KJ, Tay B, et al: Bone injury, regeneration, and repair, in Orthopaedic Basic Science: Foundations of Clinical Practice, ed 3. Rosemont, IL, American Academy of Orthopaedic Surgeons, 2007, pp 331-333.

Siris ES, Roodman GD: Paget's Disease of Bone, ed 6. Washington, DC, American Society for Bone and Mineral Research, 2006, pp 320-329.