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 Bone and Soft-Tissue Disorders

= constellation of musculoskeletal abnormalities that occur with chronic renal failure as a combination of

  1. osteomalacia (adults) / rickets (children)
  2. 2° HPT with osteitis cystica fibrosa + soft-tissue calcifications
  3. osteosclerosis
  4. soft-tissue + vascular calcifications

Classification:

  1. Glomerular form = acquired renal disease: chronic glomerulonephritis (common)
  2. Tubular form = congenital renal osteodystrophy:
    1. Vitamin D–resistant rickets = hypophosphatemic rickets
    2. Fanconi syndrome = impaired resorption of glucose, phosphate, amino acids, bicarbonate, uric acid, sodium, water
    3. Renal tubular acidosis

Pathogenesis:

  1. Renal insufficiency → decrease in vitamin D conversion into the active 1,25(OH)2D3 (done by 25-OH D-1-α hydroxylase, which is exclusive to renal tissue mitochondria); vitamin D deficiency slows intestinal calcium absorption; vitamin D resistance predominates and calcium levels stay low (Ca x P product remains almost normal ← hyperphosphatemia); low calcium levels lead to OSTEOMALACIA; additional factors responsible for osteomalacia are (a) inhibitors to calcification produced in the uremic state, (b) aluminum toxicity, (c) dysfunction of hepatic enzyme system
  2. Renal insufficiency with diminished filtration → phosphate retention; maintenance of Ca x P product lowers serum calcium directly, which in turn increases PTH production (2° HPT); 2° HPT predominates associated with mild vitamin D resistance → increase in Ca x P product with SOFT-TISSUE CALCIFICATION in kidney, lung, joints, bursae, blood vessels, heart as well as increase in osteoclastic activity = OSTEITIS FIBROSA
  3. Mixture of (a) and (b): increased serum phosphate inhibits vitamin D activation via feedback regulation
  1. OSTEOPENIA (in 0–25–83%)
    = diminution in number of trabeculae + thickening of stressed trabeculae = increased trabecular pattern
    Cause: combined effect of
    1. Osteomalacia (= reduced bone mineralization ← acquired insensitivity to vitamin D / antivitamin D factor)
    2. Osteitis fibrosa cystica ← increase in bone resorption
    3. Osteoporosis ← decrease in bone quantity

    Contributing factors:
    chronic metabolic acidosis, poor nutritional status, pre- and posttransplantation azotemia, use of steroids, hyperparathyroidism, low vitamin D levels
    Cx: fracture predisposition ← lessened structural strength with minor trauma / spontaneously; fracture prevalence increases with duration of hemodialysis + remains unchanged after renal transplantation
    Site: vertebral body (3–25%), pubic ramus, rib (5–25%)
    • Milkman fracture / Looser zones (in 1%)
    • metaphyseal fractures

    Prognosis: osteopenia may remain unchanged / worsen after renal transplantation + during hemodialysis
  2. RICKETS (children)
    Cause: in CRF normal vessels fail to develop in an orderly way along cartilage columns in zone of provisional calcification; this results in disorganized proliferation of the zone of maturing + hypertrophying cartilage and disturbed endochondral calcification
    Location: most apparent in areas of rapid growth such as knee joints
    • diffuse bone demineralization
    • widening of growth plate
    • irregular zone of provisional calcification
    • metaphyseal cupping + fraying
    • bowing of long bones, scoliosis
    • diffuse concave impression at multiple vertebral end plates
    • basilar invagination
    • slipped epiphysis (10%): capital femoral, proximal humerus, distal femur, distal radius, heads of metacarpals + metatarsals
    • general delay in bone age
  3. SECONDARY HPT (in 6–66%)
    Cause: inability of kidneys to adequately excrete phosphate leads to hyperplasia of parathyroid chief cells (2° HPT); excess PTH affects the development of osteoclasts, osteoblasts, osteocytes
    • hyperphosphatemia; hypocalcemia; ↑ PTH levels
    • subperiosteal, cortical, subchondral, trabecular, endosteal, subligamentous bone resorption:
      • replacement of trabeculation by ground-glass attenuation (early phase)
      • loss of definition of cortex, lamina dura, wall of inferior alveolar nerve canal
    • osteitis fibrosa (advanced pattern) = mixture of osteolysis + sclerosis + heterogeneous pattern of bone resorption with osteoid production and increased bone remodeling
    • osteoclastoma = brown tumor = osteitis fibrosa cystica in 1.5–1.7% ← PTH-stimulated osteoclastic activity (more common in 1° HPT)
    • periosteal new-bone formation (8–25%)
    • chondrocalcinosis (more common in 1° HPT)
    • Face
      • macrognathia + cortical thickening
      • protrusion + splaying of teeth
    • OSTEOSCLEROSIS (9–34%)
      • One of the most common radiologic manifestations; most commonly with chronic glomerulonephritis; may be the sole manifestation of renal osteodystrophy
      • diffuse chalky density: thoracolumbar spine in 60% (rugger jersey spine); also in pelvis, ribs, long bones, facial bones, base of skull (children)

      Prognosis: may increase / regress after renal transplantation
    • SOFT-TISSUE CALCIFICATIONS
      = UREMIC TUMORAL CALCINOSIS = SECONDARY TUMORAL CALCINOSIS = PSEUDOTUMOR CALCINOSIS
      ◊Most frequent cause of a periarticular calcified mass!
      Cause: ?
      1. metastatic
        ?← hyperphosphatemia (= solubility product for calcium + phosphate [Ca2+ • PO4-2] exceeds 60–75 mg/dL in extracellular fluid), hypercalcemia, alkalosis with precipitation of calcium salts
      2. dystrophic ← local tissue injury

      Location:
      • arterial (27–83%): in medial + intimal elastic tissue
        Site: dorsalis pedis a., forearm, hand, wrist, leg
        • pipestem appearance without prominent luminal involvement
      • periarticular (0.5–1.2%): multifocal, frequently symmetric, may extend into adjacent joint
        • chalky fluid / pastelike material
        • inflammatory response in surrounding tenosynovial tissue
        • discrete cloudlike dense areas
        • fluid-fluid level in tumoral calcinosis

        Prognosis: often regresses with treatment
      • visceral (79%): heart, lung, stomach, kidney
        • fluffy amorphous “tumoral” calcification

Rx:

  1. Decrease of phosphorus absorption in bowel (in hyperphosphatemia)
  2. Vitamin D3 administration (if vitamin D resistance predominates)
  3. Parathyroidectomy for 3° HPT (= autonomous HPT)

Dialysis-associated Disorders  !!navigator!!

  1. Osteomyelitis
  2. Pyogenic spondylodiskitis
  3. Osteonecrosis
  4. Destructive spondyloarthropathy
  5. Crystal deposition
  6. Dialysis cysts
  7. Amyloidosis

Congenital Renal Osteodystrophy  !!navigator!!

Vitamin D–Resistant Rickets

= PHOSPHATE DIABETES = PRIMARY HYPOPHOSPHATEMIA = FAMILIAL HYPOPHOSPHATEMIC RICKETS

= rare X-linked dominant disorder of renal tubular reabsorption characterized by

  1. impaired resorption of phosphate in proximal renal tubule ← defect in renal brush-border membrane
  2. inappropriately low synthesis of 1,25-dihydroxy-vitamin D3 [1,25(OH)2D3] in renal tubules → decreased intestinal resorption of calcium + phosphate

Age:<1 year

  • hypophosphatemia + hyperphosphaturia
  • elevated serum alkaline phosphatase
  • normal plasma + urine calcium
  • normal / low serum 1,25(OH)2D3
  • classic rachitic changes
  • skeletal deformity, particularly bowed legs
  • retarded bone age; dwarfism if untreated
  • osteosclerosis / bone thickening ← overabundance of incompletely calcified matrix

Rx: phosphate infusion + large doses of vitamin D

DDx: vitamin-D–deficient and –dependent rickets (absence of muscle weakness + seizures + tetany)

Fanconi Syndrome

Triad of

  1. Hyperphosphaturia
  2. Aminoaciduria
  3. Renal glucosuria (normal blood glucose)

Etiology: renal tubular defect

  • rickets, osteomalacia, osteitis fibrosa, osteosclerosis

Prognosis: functional renal impairment likely when bone changes occur

Rx: large doses of vitamin D + alkalinization

Renal Tubular Acidosis

  • systemic acidosis, bone lesions
  • rickets, osteomalacia, pseudofractures, nephrocalcinosis, osteitis fibrosa (rare)
    1. Lightwood syndrome = salt-losing nephritis (transient self-limited form)
      • NO nephrocalcinosis
    2. Butler-Albright syndrome (severe form)
      • nephrocalcinosis

      RHEUMATOID ARTHRITIS

= chronic systemic connective tissue disease

= type III (delayed) hypersensitivity

= immune complex disease (= formation of antigen-antibody complexes with complement fixation) with T-cell–mediated autoreactivity against synovium

Prevalence: 1–2% of world's population

Cause: genetic predisposition; ? reaction to antigen from Epstein-Barr virus / certain strains of E. coli

Peak age: 45–65 years; M÷F = 1÷3 if <40 years; M÷F = 1÷1 if >40 years

Pathogenesis:

  • injury to synovial endothelial cells → proliferative hyperplastic hypervascular synovitis (= pannus) mediated by TNF-α (tumor necrosis factor α) and IL-1 (interleukin 1) leads to invasion by local macrophages, fibroblasts, and activated lymphocytes; invasion of articular cartilage + bone ← secretion of degrading enzymes (metalloproteinases)

Diagnostic criteria of American Rheumatism Association (at least 4 criteria should be present):

  1. morning stiffness for ≥1 hour before improvement
  2. swelling of ≥3 joints, particularly of wrist / metacarpo-phalangeal / proximal interphalangeal joints for >6 weeks
  3. symmetric swelling
  4. typical radiographic changes on PA views of hand & wrist
  5. subcutaneous rheumatoid nodules
  6. positive test for rheumatoid factor
  • morning stiffness; fatigue, weight loss, anemia
  • carpal tunnel syndrome
  • rheumatoid factor (positive in 85–94%) = IgM-antibody
    = agglutination of sensitized sheep RBCs closely correlating with disease severity
    False positive: normal (5%), asbestos workers with fibrosing alveolitis (25%), viral / bacterial / parasitic infection, other inflammatory diseases
  • human leukocyte antigen (HLA)–DR4 (positive in 70%)
  • antinuclear antibodies (positive in many)
  • LE cells (positive in some); positive latex flocculation test
  • hormonal influence:
    1. decrease in activity during pregnancy
    2. men with RA have low testosterone levels

Location: bilateral symmetric involvement of >3 diarthrodial joints (polyarthritis), commonly of hand, wrist, foot

  • Symmetric arthritis of multiple small hand joints in >60% of patients at initial presentation

Early signs:

MR and high-resolution US (methods of choice): ← greater sensitivity for detection of synovitis and articular erosions than either clinical examination / conventional radiography.

  • synovitis = abnormal hypo- / anechoic / (rarely) iso- / hyperechoic (relative to subdermal fat) nondisplaceable poorly compressible intra-articular material ± Doppler signals:
    • positive Doppler signals = synovial hyperemia (in acute disease + exacerbation of chronic disease)
    • synovial swelling (edema + cellular infiltrates)
    • intermediate to low SI of pannus on T1WI + T2WI (= synovial hyperplasia = tumorlike focal proliferation of inflammatory tissue with destruction of cartilage and bone)

    Synovitis occurs early in RA and is considered a strong predictor of developing bone erosion.
  • tenosynovitis = abnormal an- / hypoechoic (relative to tendon fibers) tendon sheath widening / distention ← abnormal tenosynovial fluid ± synovial hypertrophy
  • joint effusion = abnormal hypo- / anechoic / (rarely) iso- / hyperechoic (relative to subdermal fat) displaceable compressible intra-articular material without Doppler signals
  • bursal effusion
  • marginal bone erosion = intra-articular discontinuity of bone surface at “bare area” (= site of attachment of internal synovial layer of joint capsule to bone) ← lack of protective cartilage layer:
    • pre-erosive subcortical cysts
    • bone marrow edema at site of erosion (by MRI only)
      Time of onset: within first 6 symptomatic months
      Prognosis: poor prognostic indicator in early disease

Radiography (indirect & nonspecific):

  • fusiform periarticular swelling ← joint effusion
  • periarticular osteoporosis ← inactivity due to pain + local inflammatory hyperthermia
  • translucent subchondral end plate
  • widened joint space ← synovial swelling + joint fluid
  • effacement of fat pads
  • subcortical synovial cyst
  • marginal erosion (up to 47% within 1st year after onset) initially at “bare area”
    • Radiographically detectable 1–2 years after US / MR

Late signs:

  • concentric joint space narrowing ← destruction of cartilage, formation of scar tissue, fibrosis
  • subluxation ← laxity of capsule + ligaments ← inflammatory destruction + capsular shrinkage ← fibrosis + scar formation:
    • mallet finger = droopy distal phalanx due to disrupted extensor tendon insertion site
    • swan-neck deformity = hyperextension at PIP + flexion at DIP
    • boutonnière deformity = flexion at PIP + hyperextension at DIP
    • hitchhiker deformity = flexion at MCP + hyperextension at DIP
  • dislocation
  • marked destruction + fractures of bone ends:
    • intraarticular loose bodies
    • (polished) rice bodies = subset of loose bodies
  • soft-tissue rheumatoid nodule of heterogeneous echogenicity

  • Hand & wrist (typical)
    Target areas:
    • all five MCP, PIP, interphalangeal joint of thumb, all wrist compartments (especially radiocarpal, inferior radioulnar, pisiform-triquetral joints); earliest changes seen in MCP 2 + 3, PIP 3
    • marginal + central bone erosions (less common in large joints); site of first erosion is classically base of proximal phalanx of 4th finger
    • changes in ulnar styloid + distal radioulnar joint (early sign)
    • flexion + extension contractures with ulnar subluxation + dislocation
  • Cervical spine
    • erosions of odontoid process (1) between anterior arch of atlas + dens, (2) between transverse ligament of atlas + dens, (3) at tip of odontoid process
    • anterior atlantoaxial subluxation (in >6%): >2.5 mm in adults, >4.5 mm in children during neck flexion
    • “cranial settling” = odontoid process projects into skull base ← significant disease of atlanto-occipital and atlantoaxial joints
    • lateral head tilt = lateral subluxation = asymmetry between odontoid process + lateral masses of atlas
    • “stepladder appearance” of cervical spine ← subaxial subluxations + absence of osteophytosis:
      • destruction + narrowing of disk spaces
      • irregular vertebral body outlines
      • erosion + destruction of zygapophyseal joints
      • resorption of spinous processes
    • osteoporosis
      Cx: spinal cord compression
  • Cricoarytenoid arthritis (54–72%)
    • hoarseness, sense of pharyngeal fullness in throat (26%)
    • dyspnea, stridor, dysphagia, odynophagia
    • pain radiating into ears, pain with speech
    • cricoarytenoid erosion, luxation, prominence / mass at CT
    • abnormal position of the true vocal cord
  • Ribs
    • erosion of superior margins of posterior portions of ribs 3–5
  • Shoulder
    • symmetric loss of glenohumeral joint space:
      • marginal erosions at superolateral aspect of humeral head
      • osteoporosis
      • elevation of humeral heads = narrowing of acromiohumeral distance ← tear / atrophy of rotator cuff
    • widened acromioclavicular joint:
      • erosions at acromial + clavicular end
      • tapered margins of distal clavicle
    • scalloped erosion on undersurface of distal clavicle opposite coracoid process (= attachment of coracoclavicular ligament)
  • Sacroiliac joint (rarely affected)
    • typically asymmetric unilateral distribution
    • shallow erosions + mild sclerosis
    • rare ankylosis
  • Hip (rarely affected)
    • often appears normal during early disease process
    • pannus formation (MR imaging)
    • symmetric loss of joint space with axial migration of femoral head
    • marginal + central erosions, cysts, localized sclerosis
    • decompression of joint effusion into iliopsoas bursa through weak anterior capsule displacing muscle + vasculature
    • rupture of gluteal tendon
    • protrusio acetabuli (from osteoporosis)
  • Knee
    Location: medial + lateral femorotibial compartments; bilateral symmetric
    • diffuse loss of joint space
    • osteoporosis
    • superficial + deep marginal + central erosions
    • subchondral sclerosis (especially in tibia)
    • synovial herniation + cysts (eg, popliteal cyst)
    • varus / valgus angulation ← crumbling of osteoporotic bone of tibia + ligamentous abnormalities
  • Foot (typical)
    Target areas:
    • medial aspect of MT heads (2,3,4), medial + lateral aspect of MT5 (earliest sign); interphalangeal joints of foot (esp. great toe); midfoot joints; talonavicular, subtalar, tarsometatarsal joints; bilateral + symmetric
    • sinus tarsi syndrome = compression of tibial nerve
    • calcaneal plantar spur
    • retrocalcaneal bursitis

DDx:

  1. Acute viral polyarthritis: Parvovirus B19, Rubella, Hepatitis B
  2. Seronegative spondyloarthropathies: psoriasis, reactive arthritis, inflammatory bowel disease, ankylosing spondylitis
  3. Connective tissue disease: SLE, primary Sjögren syndrome, mixed connective tissue disease, scleroderma, dermatomyositis-polymyositis
  4. Crystal disease: gout, CPPD, osteoarthritis

EXTRA-ARTICULAR MANIFESTATIONS (50–76%)

  1. Felty syndrome (<1%)
    = rheumatoid arthritis (present for >10 years) + splenomegaly + neutropenia
    Age: 40–70 years; F >M; rare in Blacks
    • rapid weight loss; therapy refractory leg ulcers
    • brown pigmentation over exposed surfaces of extremities
  2. Sjögren syndrome (15%)
    = keratoconjunctivitis + xerostomia + rheumatoid arthritis
  3. Rheumatoid lung
  4. Subcutaneous nodules
    (in 5–35% with active arthritis) over extensor surfaces of forearm + other pressure points (eg, olecranon) without calcifications (DDx to gout)
  5. Cardiovascular involvement
    1. Pericarditis (20–50%)
    2. Myocarditis: arrhythmia, heart block
    3. Aortitis (5%) of ascending aorta → aneurysm (2%)
    4. Leaflet thickening of aortic valve → regurgitation
  6. Rheumatoid vasculitis
    = leukocytoclastic lesion of small venules mimicking periarteritis nodosa
    • polyneuropathy, cutaneous ulceration, gangrene, polymyopathy, myocardial / visceral infarction
  7. Neurologic sequelae
    1. Distal neuropathy (related to vasculitis)
    2. Nerve entrapment: atlantoaxial subluxation, carpal tunnel syndrome, Baker cyst
  8. Lymphadenopathy (up to 25%)
    • splenomegaly (1–5%)

Cystic Rheumatoid Arthritis  !!navigator!!

= intraosseous cystic lesions as dominant feature

Pathogenesis: increased pressure in synovial space from joint effusion → decompresses through microfractures of weakened marginal cortex into subarticular bone

◊Increase in size + extent of cysts correlates with increased level of activity + absence of synovial cysts

Age: as above; M÷F = 1÷1

  • seronegative in 50%
  • juxtaarticular subcortical lytic lesions with well-defined sclerotic margins
  • relative lack of cartilage loss, osteoporosis, joint disruption

DDx: gout (presence of urate crystals), pigmented villonodular synovitis (monoarticular)

Juvenile Rheumatoid Arthritis  !!navigator!!

= rheumatoid arthritis in patients <16 years of age; M <F

  • morning stiffness, arthralgia; subcutaneous nodules (10%)
  • skin rash (50%); fever, lymphadenopathy

Location: early involvement of large joints (hips, knees, ankles, wrists, elbows); later of hands + feet

  • radiologic signs similar to rheumatoid arthritis (except for involvement of large joints first, late onset of bony changes, more ankylosis, wide metaphyses)
  • periarticular soft-tissue swelling
  • thinning of joint cartilage
  • large cystlike lesions removed from articular surface (invasion of bone by inflammatory pannus); rare in children
  • articular erosions at ligamentous + tendinous insertion sites
  • joint destruction may resemble neuropathic joints
  • juxtaarticular osteoporosis
  • “balloon epiphyses” + “gracile bones” (epiphyseal overgrowth + early fusion with bone shortening ← hyperemia
  • Hand / foot
    • “rectangular” phalanges (periostitis + cortical thickening)
    • ankylosis in carpal joints
  • Axial skeleton
    Location: predominantly upper cervical spine
    • ankylosis of cervical spine (apophyseal joints), sacroiliac joints
    • decreased size of vertebral bodies + atrophic intervertebral disks
    • subluxation of atlantoaxial joint (66%)
    • thoracic spinal compression fractures
  • Chest
    • ribbon ribs
    • pleural + pericardial effusions
    • interstitial pulmonary lesions (simulating scleroderma, dermatomyositis)
    • solitary pulmonary nodules, may cavitate

Prognosis: complete recovery (30%); secondary amyloidosis

Clinical classification:

  1. Juvenile-onset adult type (10%)
    • IgM RA factor positive; age 8–9; poor prognosis
    • erosive changes; profuse periosteal reaction; hip disease with protrusio
  2. Polyarthritis of the ankylosing spondylitic type
    • iridocyclitis; boys age 9–11 years
    • peripheral arthritis; fusion of greater trochanter; complete fusion of both hips; heel spur
  3. Still disease
    1. systemic
    2. polyarticular
    3. pauciarticular + iridocyclitis (30%)
    • fever, rash, lymphadenopathy, hepatosplenomegaly; pericarditis, dwarfism
    • fatal kidney disease in 20%

    Age: 2–4 and 8–11 years of age; M <F
    Location: involvement of carpometacarpal joints (“squashed carpi” in adulthood), hind foot, hip (40–50%)
    • periosteal reaction of phalanges; broadening of bones; accelerated bone maturation + early fusion (stunting of growth)

 Outline