NUTRITIONAL-DEFICIENCY RICKETS AND OSTEOMALACIA

  • Definition & Distinction
    • Rickets: Occurs in children with deficient mineralization at the growth plate.
      • Leads to widened, irregular epiphyseal plates.
    • Osteomalacia: Deficient mineralization of bone matrix in adults.
      • Leads to uncalcified osteoid seams, soft bones with bowing, pseudofractures.
  • Key Nutrient Shortfalls
    • Calcium and/or phosphate deficiency.
    • Most commonly related to low calcium absorption or intake and/or low phosphate.

CALCIPENIC (CALCIUM-DEFICIENT) RICKETS/OSTEOMALACIA

  • Pathophysiology
    • Decreased intestinal absorption of calcium.
    • Vitamin D–related deficits in calcium absorption.
      • Ranges from vitamin D deficiency, 1α-hydroxylation defect, or receptor abnormalities.
    • Chronic hypocalcemiasecondary hyperparathyroidism → partial correction of calcium but excretes phosphate → hypophosphatemia.
  • Net Effect
    • Low/low-normal serum calcium, low serum phosphate.
    • Increased PTH → high bone turnover (osteoclast activity).
    • Bone matrix laid down but not mineralized (rickets in children, osteomalacia in adults).

VITAMIN D SYNTHESIS & DEFICIENCY

  • Vitamin D Sources
    • Skin synthesis (vitamin D3) from 7-dehydrocholesterol via sunlight UV.
    • Diet (ergocalciferol vitamin D2) from plants/fish/fortified products.
    • Both forms hydroxylated in liver → 25-hydroxyvitamin D (25[OH]D).
    • 25(OH)D further 1α-hydroxylated in kidney → 1,25-dihydroxyvitamin D (1,25[OH]2D).
  • Causes of Deficiency
    • Low sunlight exposure.
    • Low dietary intake.
    • Malabsorption (e.g., gastric surgery, celiac).
    • Less 25(OH)D production in liver disease or less 1α-hydroxylation in kidney disease.
    • P450-inducing drugs (e.g., anticonvulsants) accelerating vitamin D metabolism.
    • Nephrotic syndrome → urinary loss of vitamin D–binding protein.
    • End-organ resistance at vitamin D receptor.
  • Epidemiology & Risk
    • Vitamin D–deficient rickets typically appears in children <3 years.
    • Breastfed infants require extra vitamin D (400 IU/day).
  • Treatment
    • Vitamin D2 (ergocalciferol) often sufficient.
    • Calcium intake ≥1000 mg/day.
    • Monitor serum levels (Ca, phosphate, 25[OH]D, alkaline phosphatase) + urine calcium.
    • Bone healing confirmed by radiography.

PSEUDOVITAMIN D–DEFICIENCY RICKETS/OSTEOMALACIA

TYPE 1: Renal 1α-Hydroxylase Deficiency

  • Pathophysiology
    • Autosomal recessive.
    • No/minimal 1α-hydroxylation of 25(OH)D → low 1,25(OH)2D.
    • Presents in infancy (~1st year) with:
      • Hypocalcemia, hypophosphatemia, elevated PTH (secondary), low 1,25(OH)2D, high alkaline phosphatase.
      • Rickets/osteomalacia features (bone deformities, muscle weakness, growth failure).
  • Treatment
    • Calcitriol lifelong (1 μg/day typical).
    • Adequate calcium supplementation.
    • Avoid hypercalcemia/hypercalciuria (overtreatment) to prevent nephrocalcinosis.

TYPE 2: Hereditary Vitamin D–Resistant Rickets

  • Pathophysiology
    • Autosomal recessive vitamin D–receptor mutations.
    • Tissues unresponsive to 1,25(OH)2D.
    • Presents similarly in infancy/childhood:
      • Hypocalcemia, hypophosphatemia, ↑1,25(OH)2D (3–5× normal), high PTH, osteomalacic changes.
    • Some kindreds also have alopecia totalis (hair loss).
  • Treatment
    • High-dose calcitriol (5–60 μg/day) to overcome receptor resistance if possible.
    • Otherwise, prolonged IV calcium infusions.
    • Monitor bone healing, lab parameters (Ca, phosphate, PTH, alkaline phosphatase).

HYPOPHOSPHATEMIC RICKETS/OSTEOMALACIA

  • Core Mechanism
    • Renal phosphate wasting (isolated or part of Fanconi syndrome).
    • Biochemical: Hypophosphatemia, normal Ca, normal/high PTH, ↑ FGF23.
    • 4 main groups:
      1. X-linked (most common; PHEX gene mutation).
      2. Autosomal dominant (activating mutations in FGF23).
      3. Autosomal recessive (DMP1 mutations → ↑ FGF23).
      4. Hypercalciuric forms (Dent disease).

X-Linked Hypophosphatemic Rickets

  • Presentation
    • Rickets signs/symptoms + growth retardation.
    • Enthesopathy (tendon/ligament calcifications), dental issues (early decay, abscess).
  • Typical Labs
    • Low phosphate, low 1,25(OH)2D, normal Ca, normal/↑ PTH, ↑ FGF23, ↑ urinary phosphate excretion, ↑ alkaline phosphatase.
  • Therapy
    • Oral phosphate + calcitriol (to limit secondary hyperparathyroidism).
    • Monitor labs, bone radiographs. Over-suppression → risk hypercalcemia, hypercalciuria, nephrocalcinosis.

Tumor-Induced Osteomalacia (Acquired)

  • Pathophysiology
    • Small, benign mesenchymal tumors hypersecrete FGF23.
    • Identical labs to X-linked form but no personal/family history.
  • Diagnosis & Treatment
    • Imaging (somatostatin receptor scintigraphy, full-body MRI) to find tumor.
    • Tumor removal cures the condition.

RICKETS IN CHILDHOOD: CLINICAL MANIFESTATIONS

  • General
    • Abnormal epiphyseal mineralization in growing bones → epiphyseal plate widening, irregular shape.
    • Common in knees, costochondral junctions, distal forearm.
    • Signs:
      • “Rachitic rosary” (costochondral thickening).
      • Wrist enlargement, bowed radius/ulna.
      • Genu varum (bowlegs) if child is ambulatory; genu valgum (knock-knee) in some.
      • Delayed fontanelle closure, frontal bossing, craniotabes.
      • Harrison groove (diaphragmatic pull on softened ribs).
  • Symptoms
    • Skeletal pain, fractures, bone deformities, short stature, muscle weakness, hypotonia, delayed motor milestones.
  • Laboratory Profile
    • High alkaline phosphatase always.
    • Hypocalcemia in calcipenic rickets; normal/low in phosphopenic rickets.
    • Hypophosphatemia in both.
    • Elevated PTH in calcipenic rickets; normal in hypophosphatemic rickets.
  • Radiographic Findings
    • Widened growth plates, irregular metaphyses.
    • Thinned cortices, poor trabeculation, subperiosteal erosions if hyperparathyroid.
    • Looser zones/pseudofractures in advanced cases.
  • Diagnosis & Management
    • Detailed dietary, medication history.
    • Labs: Ca, phosphate, PTH, 25(OH)D, + possible additional tests.
    • Specific therapy based on cause (nutritional deficiency, pseudovitamin D deficiency, hypophosphatemia).
    • Corrective therapy can allow natural remodeling <4 yrs old; older children → permanent deformities.

OSTEOMALACIA IN ADULTS: CLINICAL MANIFESTATIONS

  • Definition
    • Impaired mineralization of osteoid (adult equivalent to rickets).
    • Often from hypophosphatemia, less commonly from hypocalcemia or low alkaline phosphatase activity (hypophosphatasia).
  • Presentation
    • Range: Incidental osteopenia on X-ray → severe bone pain, proximal muscle weakness, fractures.
    • Fractures typically at vertebrae (leading to compression), ribs, or long bones.
  • Imaging
    • Diffuse osteopenia, cortical thinning.
    • “Codfish” vertebrae from end-plate concavity.
    • Looser zones (pseudofractures): radiolucent lines with sclerotic margins, perpendicular to cortex.
    • Subperiosteal erosions if secondary hyperparathyroidism.
    • Bowing deformities in severe longstanding disease (tibia, radius, ulna).
  • Laboratory
    • Dependent on underlying cause (e.g., low 25(OH)D, or abnormal phosphate, etc.).
    • Elevated PTH if secondary hyperparathyroidism from low Ca.
  • Bone Biopsy
    • Tetracycline labeling can confirm unmineralized osteoid seams, slow bone formation rate.
  • Treatment
    • Correct underlying cause: e.g., vitamin D ± calcium in nutritional deficiency.
    • Monitor with labs (Ca, phosphate, PTH, alkaline phosphatase) ± imaging.

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