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.
- Rickets: Occurs in children with deficient mineralization at the growth plate.
- 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.
- Low dietary calcium OR decreased absorption (e.g., celiac disease).
- Vitamin D–related deficits in calcium absorption.
- Ranges from vitamin D deficiency, 1α-hydroxylation defect, or receptor abnormalities.
- Chronic hypocalcemia → secondary hyperparathyroidism → partial correction of calcium but excretes phosphate → hypophosphatemia.
- Decreased intestinal absorption of calcium.
- 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:
- X-linked (most common; PHEX gene mutation).
- Autosomal dominant (activating mutations in FGF23).
- Autosomal recessive (DMP1 mutations → ↑ FGF23).
- 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.