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 Bone and Soft-Tissue Disorders

= uncontrolled production of parathyroid hormone

Age: 3rd–5th decade; M÷F = 1÷3

Histo: decreased bone mass ← increased number of osteoclasts + increased osteoid volume (defect in mineralization) + slightly increased number of osteoblasts

  1. BONE RESORPTION
    1. subperiosteal (most constant + specific finding; virtually PATHOGNOMONIC of hyperparathyroidism):
      • lacelike irregularity of cortical margin; may progress to scalloping / spiculation (pseudoperiostitis)

      Site: phalangeal tufts (earliest involvement), radial aspect of middle phalanx of 2nd + 3rd finger beginning in proximal metaphyseal region (early involvement), bandlike zone of resorption in middle / base of terminal tuft, distal end of clavicles, medial tibia plateau, medial humeral neck, medial femoral neck, distal ulna, superior + inferior margins of ribs in midclavicular line, lamina dura of skull and teeth
      DDx: acroosteolysis
    2. subchondral:
      • pseudowidening of joint space
      • collapse of cortical bone + overlying cartilage with development of erosion, cyst, joint narrowing (similar to rheumatoid arthritis)

      Site: DIP joint (most commonly 4th + 5th digit), MCP joint, PIP joint, distal clavicle, acromioclavicular joint (clavicular side), “pseudowidening” of sacroiliac joint (iliac side), sternoclavicular joint, temporomandibular joint, symphysis pubis, “scalloping” of posterior surface of patella, Schmorl nodes; typically polyarticular
    3. cortical (← osteoclastic activity within haversian canal):
      • intracortical tunneling
      • scalloping along inner cortical surface (= endosteal resorption)
    4. trabecular:
      • spotty deossification with indistinct + coarse trabecular pattern
      • granular salt and pepper skull
      • loss of distinction between inner and outer table
      • ground-glass appearance
    5. subligamentous / subtendinous:
      • bone resorption with smooth scalloped / irregular ill-defined margins

      Site: inferior surface of calcaneus (long plantar tendons + aponeurosis), Achilles tendon, inferior aspect of distal clavicle (coracoclavicular ligament), greater trochanter (hip abductors), lesser trochanter (iliopsoas), anterior inferior iliac spine (rectus femoris), humeral tuberosity (rotator cuff), ischial tuberosity (hamstrings), proximal extensor surface of ulna (anconeus), posterior olecranon (triceps)
  2. BONE SOFTENING
    • basilar impression of skull
    • wedged vertebrae, kyphoscoliosis, biconcave vertebral deformities
    • bowing of long bones
    • slipped capital femoral epiphysis
  3. BROWN TUMOR
    = OSTEOCLASTOMA = CENTRAL GIANT CELL LESION
    = focal osteolytic area with bone swelling
    Cause: PTH-stimulated osteoclastic activity (more frequent in 1° HPT; in 1.5% of 2° HPT)
    Path: localized replacement of bone by hypervascularized reactive fibrous stroma containing proliferating osteoclasts, osteoblasts and multinucleated giant cells; may become cystic following hemorrhage + necrosis + liquefaction (= osteitis fibrosa cystica)
    Histo: differentiation from giant cell tumor not possible
    • in patients with long-standing HPT
    • hypercalcemia, hypophosphatemia
    • elevated levels of parathyroid hormone

    Location: rib, metaphysis of long bones (femur), facial bones, jaw, pelvis, axial skeleton
    Site: often eccentric / cortical; frequently solitary
    • expansile lytic cystlike lesion with variably defined margin (DDx: giant cell tumor)
    • cortical expansion + endosteal scalloping
    • generalized demineralization of medullary bones of jaw
    • loss of lamina dura around roots of teeth
    • NO adjacent reactive bone formation
    • destruction of midportions of distal phalanges with telescoping
    • osteolytic vertebra + tumor growth within spinal canal
    • remineralization after parathyroidectomy
  4. OSTEOSCLEROSIS
    More frequent in 2° HPT
    Cause: ? PTH-stimulated osteoblastic activity, ? role of calcitonin (poorly understood)
    Site: strong predilection for axial skeleton, pelvis, ribs, clavicles, metaphysis + epiphysis of appendicular skeleton
    • “rugger jersey spine”
  5. SOFT-TISSUE CALCIFICATION
    More frequent in 2° HPT
    • metastatic calcification when Ca x P product >70 mg/dL
    1. cornea, viscera (lung, stomach, kidney)
    2. periarticular in hip, knee, shoulder, wrist
    3. arterial tunica media (resembling diabetes mellitus)
    4. chondrocalcinosis (15–18%) = calcification of hyaline / fibrous cartilage in menisci, wrist, shoulder, hip, elbow
    5. bilateral basal ganglia, dentate nuclei, peripheral subcortical white matter

    Calciphylaxis = calcific uremic arteriolopathy
    = systemic medial calcification of arterioles
    • subcutaneous necrosis ← ischemia
    • ± chronic hemodialysis / recent renal transplantation
    • calcium deposits in kidney, stomach, heart, lung

    Prognosis: high mortality
  6. EROSIVE ARTHROPATHY
    • asymptomatic
    • simulates rheumatoid arthritis with preserved joint spaces
  7. PERIOSTEAL NEW-BONE FORMATION
    Cause: PTH-stimulation of osteoblasts
    Site: pubic ramus along iliopectineal line (most frequent), humerus, femur, tibia, radius, ulna, metacarpals, metatarsals, phalanges
    • linear new bone paralleling cortical surface; may be laminated; often separated from cortex by radiolucent zone
    • increase in cortical thickness (if periosteal reaction becomes incorporated into adjacent bone)

Sequelae:

  1. Renal stones / nephrocalcinosis (70%)
  2. Increased osteoblastic activity (25%)
    • increased alkaline phosphatase
    1. osteitis fibrosa cystica
      • subperiosteal bone resorption + cortical tunneling
      • brown tumors (primary HPT)
    2. bone softening
      • fractures
  3. Peptic ulcer disease ← increased gastric secretion from gastrinoma
  4. Calcific pancreatitis
  5. Soft-tissue calcifications (2° HPT)
  6. Marginal joint erosions + subarticular collapse (DIP, PIP, MCP)

Primary Hyperparathyroidism  !!navigator!!

= pHPT = 1° HPT = hypercalcemia due to autonomous hypersecretion of parathormone by one / more hyperfunctioning parathyroid glands featuring

  1. brown tumor
  2. chondrocalcinosis (20–30%)
  • requires surgical Rx

Prevalence: 2–3 ÷ 1000 (female) and 1 ÷ 1000 (male)

Incidence: 25 ÷ 100,000 per year; 25–40% incidence of bone lesions in HPT

Etiology: sporadic / familial

  1. Parathyroid adenoma (94%): solitary (90%); double adenomas (4%)
  2. Parathyroid hyperplasia of multiple glands(6%): chief cell (4%); clear cell (2%)
    • Hereditary disorders often involve multiple-gland hyperplasia
  3. Parathyroid carcinoma (<1%)

Age: 3rd–5th decade; M÷F = 1÷3

Associated with:

  1. Familial hyperparathyroidism
  2. Multiple endocrine neoplasia syndrome
    1. Wermer syndrome = MEA 1 (+ pituitary adenoma + pancreatic islet cell tumor)
    2. Sipple syndrome = MEA 2A (+ medullary thyroid carcinoma + pheochromocytoma)
  3. Hyperparathyroidism–jaw tumor syndrome
  • asymptomatic (75–80%): more common due to earlier detection ← widespread availability of laboratory screening for hypercalcemia
  • symptomatic (20–25%):
    • weakness, easy fatigability, mild depression, anorexia
    • dementia, depression, constipation
    • peptic ulcer disease, pancreatitis, renal calculi
    • diffuse bone + joint pain ← osteitis fibrosa cystica

X-RAY (skeletal involvement in 10–20%):

  • generalized osteopenia
  • thin cortices with lacy cortical pattern ← subperiosteal bone resorption
  • brown tumor (particularly in jaw + long bones)
  • osteitis cystica fibrosa (= intertrabecular fibrous connective tissue)

NUC:

  • bone scan: normal in 80%
    • foci of abnormal uptake: calvarium (especially periphery), mandible, sternum, acromioclavicular joint, lateral humeral epicondyles, hands
    • increased uptake in brown tumors
    • extraskeletal uptake: cornea, cartilage, joint capsules, tendons, periarticular areas, lungs, stomach
    • normal renal excretion [except in stone disease / calcium nephropathy (10%)]
  • 99mTc-sestamibi parathyroid scintigraphy

Rx: pathologic glands identified by experienced surgeons in 90–95% on initial neck exploration (ectopic + supernumerary glands often overlooked at operation; recurrent hypercalcemia in 3–10%)

Indications for surgery:

  1. serum calcium level 1.0 mg/dL above upper limit of normal
  2. 24-hour urinary calcium level >400 mg
  3. creatinine clearance reduced by 30%
  4. bone mineral density T-score of <−2.5 SD
  5. age <50 years
  6. undesirability / impossibility of surveillance

Surgical risk for repeat surgery:

  • 6.6% recurrent laryngeal nerve injury
  • 20.0% permanent hypoparathyroidism
  • <1.0% perioperative mortality

DDx of hypercalcemia:

  1. Malignancy (2nd most common cause): low / suppressed parathyroid hormone levels
  2. Benign familial hypocalciuric hypercalcemia:
    = autosomal dominant disorder characterized by hypercalcemia + relative hypocalciuria distinguished by calcium-creatinine clearance ratio <0.01

Secondary Hyperparathyroidism  !!navigator!!

= sHPT = 2° HPT = stimulation of all four parathyroid glands as a response to

  1. hypocalcemia → diffuse / adenomatous hyperplasia
  2. apparent insensitivity of parathyroid glands to ↑ serum calcium ← dysregulation of normal negative feedback loop (= pseudohyperparathyroidism)

◊requires medical Rx

Etiology:

  1. endstage renal disease (most common cause) → decreased renal production of 1,25(OH)2-vitamin D
  2. calcium deprivation, hypovitaminosis D, maternal hypoparathyroidism, pregnancy
  3. rise in serum phosphate → decrease in calcium by feedback mechanism
  • dementia, depression; peptic ulcer disease, constipation
  • diffuse joint pain
  • low (hypocalcemia) to normal calcium levels
  • phosphate retention (hyperphosphatemia) = Ca3(PO4)2 solubility product often exceeded
  • vitamin D deficiency = ⇓ vitamin D serum levels → compensatory ⇑ in PTH production
  • soft-tissue calcifications
  • “rugger jersey” spine = striped osteosclerotic appearance
  • periostitis
  • brown tumor

NUC:

  • “superscan” in 2° HPT:
    • “absent kidney” sign
    • increased ratio of bone-to-soft tissue uptake
    • increased uptake in calvarium, mandible, acromioclavicular region, sternum, vertebrae, distal third of long bones, ribs
  • diffuse 99mTc-MDP uptake in lungs (60%)

Tertiary Hyperparathyroidism  !!navigator!!

= tHPT = 3° HPT = development of autonomously functioning parathyroid glands despite correction of initial cause → hypersecretion of PTH in spite of normal calcium levels in patients with chronically overstimulated hyperplastic parathyroid glands

Cause: secondary HPT ← renal insufficiency + renal dialysis with prolonged hypocalcemia and hyperphosphatemia

◊requires surgical Rx

Clue:

  1. intractable hypercalcemia
  2. inability to control osteomalacia by vitamin D administration

Ectopic Parathormone Production  !!navigator!!

= pseudohyperparathyroidism as paraneoplastic syndrome in bronchogenic carcinoma + renal cell carcinoma

 Outline