Rickets

Vitamin D Metabolism and Calcium Homeostasis

Normal vitamin D pathway:

1. Cutaneous synthesis - UV-B radiation converts 7-dehydrocholesterol to cholecalciferol (vitamin D3) in skin
2. Hepatic hydroxylation - 25-hydroxylase converts D3 to 25-OH vitamin D (calcidiol) - main storage form
3. Renal activation - 1-alpha hydroxylase converts 25-OH D to 1,25-OH vitamin D (calcitriol) - active hormone
4. Target organ effects - calcitriol increases intestinal calcium and phosphate absorption, promotes skeletal mineralization

Regulatory mechanisms:

• PTH stimulates 1-alpha hydroxylase (increases active vitamin D production)
• Hypocalcemia triggers PTH release → secondary hyperparathyroidism
• FGF23 inhibits 1-alpha hydroxylase and increases renal phosphate excretion

Molecular Cascade at the Physis

Normal endochondral ossification requires adequate calcium, phosphate, and vitamin D. In rickets, deficiency of vitamin D (or phosphate) disrupts the mineralization of cartilage matrix at the growth plate:

Pathologic sequence:

1. Reduced calcium and phosphate availability at the growth plate
2. Chondrocyte proliferation and hypertrophy proceed normally - cartilage matrix production continues
3. Mineralization fails - calcium-phosphate crystals (hydroxyapatite) cannot be deposited
4. Accumulation of unmineralized hypertrophic cartilage - widened, irregular growth plate (10-20x normal thickness)
5. Loss of columnar organization - disorganized chondrocyte arrangement
6. Irregular zone of provisional calcification - patchy, incomplete mineralization
7. Disorganized vascular invasion and osteoblast/osteoclast activity at metaphysis
8. Metaphyseal widening, cupping, and fraying (radiographic hallmark)
9. Mechanical deformation of soft unmineralized bone under weight-bearing stress → bowing deformities
10. Growth retardation from disrupted longitudinal bone growth

Type-Specific Mechanisms

Nutritional (Calcipenic) Rickets:

• Vitamin D deficiency → reduced intestinal calcium/phosphate absorption
• Hypocalcemia → secondary hyperparathyroidism
• PTH → increased renal phosphate loss, bone resorption
• Net effect: low calcium AND phosphate, inadequate mineralization

X-Linked Hypophosphatemia (Phosphopenic Rickets):

• PHEX gene mutation → elevated FGF23 (fibroblast growth factor 23)
• FGF23 → renal phosphate wasting (reduced proximal tubule phosphate reabsorption)
• FGF23 → inhibits 1-alpha hydroxylase (reduced active vitamin D despite normal 25-OH D)
• Net effect: severe isolated hypophosphatemia, normal calcium

Vitamin D-Dependent Rickets:

• Type I: CYP27B1 mutation → 1-alpha hydroxylase deficiency → cannot produce active vitamin D
• Type II: VDR mutation → vitamin D receptor defect → resistance to calcitriol (very high 1,25-OH D levels)

Classification by Etiology

Calcipenic Rickets (Calcium Deficiency)

• Nutritional vitamin D deficiency (most common)
• Dietary calcium deficiency
• Malabsorption syndromes (celiac, cystic fibrosis)
• Drug-induced (anticonvulsants)

Phosphopenic Rickets (Phosphate Deficiency)

• X-linked hypophosphatemia (PHEX mutation)
• Autosomal dominant hypophosphatemic rickets
• Tumor-induced osteomalacia (FGF23-secreting tumors)
• Fanconi syndrome (renal tubular phosphate wasting)

Vitamin D-Dependent Rickets

• Type I: 1-alpha hydroxylase deficiency (CYP27B1 mutation)
• Type II: Vitamin D receptor defect (VDR mutation)

Advanced Classification

By Metabolic Defect

Hereditary Forms

• X-linked hypophosphatemia (PHEX): X-linked dominant, most common hereditary form
• Autosomal dominant hypophosphatemic rickets (FGF23): Elevated FGF23
• Autosomal recessive hypophosphatemia (DMP1, ENPP1)
• Hereditary hypophosphatemic rickets with hypercalciuria (SLC34A3)

Infant Rickets

Skeletal:

• Craniotabes - soft skull bones (ping-pong ball sensation)
• Frontal bossing - prominent forehead
• Delayed fontanelle closure
• Rachitic rosary - costochondral junction swelling
• Harrison's groove - indentation along diaphragm attachment

Neuromuscular:

• Hypotonia - floppy baby
• Delayed motor milestones - sitting, crawling
• Hypocalcemic seizures (if severe deficiency)
• Laryngospasm and stridor (tetany)

Growth:

• Failure to thrive
• Growth retardation

Early diagnosis critical to prevent permanent skeletal deformities.

Toddler Rickets

Skeletal (most visible at this age):

• Genu varum (bow legs) - most common deformity
• Widened wrists and ankles - visible and palpable
• Delayed walking - due to leg bowing and muscle weakness
• Waddling gait
• Rachitic rosary - prominent beading

Growth:

• Short stature
• Delayed tooth eruption and dental enamel defects

Fractures:

• Greenstick fractures with minimal trauma
• Metaphyseal fractures (may mimic non-accidental injury)

Peak age for orthopedic presentation.

Late-Onset Rickets

Skeletal:

• Genu valgum (knock knees) - more common than varum in older children
• Windswept deformity - varus one side, valgus other
• Coxa vara
• Spinal deformities - scoliosis, kyphosis

Growth:

• Short stature relative to genetic potential
• Delayed puberty (if severe)

Musculoskeletal:

• Proximal muscle weakness
• Bone pain - especially lower limbs
• Easy fatigability

Often due to hereditary forms (X-linked hypophosphatemia) or chronic kidney disease.

Nutritional (Calcipenic) Rickets

Loading dose (for active disease):

• Vitamin D3 (cholecalciferol) 2000-6000 IU daily for 8-12 weeks
• Dose based on severity and age
• Alternative: single dose 50,000-150,000 IU (Stoss therapy)

Calcium supplementation:

• Elemental calcium 500-1000 mg daily (divided doses)
• Essential in first 4-6 weeks to prevent hungry bone syndrome

Monitoring:

• Calcium, phosphate, ALP at 1, 3, 6 months
• 25-OH vitamin D at 3 months - target greater than 75 nmol/L
• X-rays at 3-6 months - assess healing (return of zone of provisional calcification)

Maintenance (after healing):

• Vitamin D 400-600 IU daily lifelong
• Dietary calcium 800-1000 mg daily

Expected response:

• Biochemistry normalizes by 3-6 months
• Radiographic healing by 6-12 months
• Spontaneous deformity correction by 12-18 months (if mild-moderate)

Medical optimization is the primary treatment for nutritional rickets.

X-Linked Hypophosphatemia (XLH)

Chronic treatment (lifelong):

• Oral phosphate 20-60 mg/kg/day (divided 4-5 times daily)
• Calcitriol 20-60 ng/kg/day (enhances intestinal phosphate absorption)

Monitoring:

• Serum phosphate - target low-normal range
• Calcium, PTH - avoid secondary hyperparathyroidism
• Renal ultrasound annually - screen for nephrocalcinosis
• Growth velocity and bone age

Burosumab (anti-FGF23 antibody):

• Emerging therapy approved for XLH
• Subcutaneous injection every 2 weeks
• Normalizes phosphate without need for oral phosphate
• Improved growth and reduces skeletal deformities
• Preferred first-line in many centers

Surgical correction:

• Often required for residual deformities after skeletal maturity
• Guided growth (hemiepiphysiodesis) during growth
• Osteotomies after growth plate closure

XLH requires multidisciplinary care (endocrinology, nephrology, orthopedics, genetics).

Vitamin D-Dependent Rickets

Type I (1-alpha hydroxylase deficiency):

• Calcitriol 0.25-2 micrograms daily
• Calcium supplementation initially
• Lifelong treatment required
• Monitor for hypercalcemia and hypercalciuria

Type II (Vitamin D receptor defect):

• Very high-dose calcitriol (up to 20 micrograms daily)
• IV calcium infusions if oral therapy fails
• Some cases resistant to all vitamin D therapy
• May require calcium and phosphate infusions indefinitely

Genetic counseling for autosomal recessive inheritance.

Guided Growth (Hemiepiphysiodesis)

Indications

• Growing child with open physes
• Residual deformity greater than 10-15 degrees after medical optimization
• Genu varum or valgum

Eight-Plate Technique

1. Position: Supine on radiolucent table
2. Fluoroscopy to confirm physis level
3. Small incision over target physis (medial for varus, lateral for valgus)
4. Position plate straddling physis with 2 screws (one epiphyseal, one metaphyseal)
5. Confirm position fluoroscopically

Corrective Osteotomy

• For severe deformity (greater than 30 degrees) or closed physes
• Location: Proximal tibia or distal femur
• Fixation: Plate and screws or external fixator
• Opening or closing wedge based on deformity

Advanced Surgical Considerations

Guided Growth Considerations

• Expected correction rate: 1-2 degrees per month
• Follow-up every 3-6 months with standing alignment radiographs
• Remove plates promptly when corrected to prevent overcorrection
• May need bilateral and multi-level (femur and tibia)

Osteotomy Technique

• Determine CORA (center of rotation of angulation)
• Plan correction angle and level
• Opening wedge: Add bone graft, more technically demanding
• Closing wedge: Simpler but shortens limb
• Dome osteotomy: Gradual correction with external fixator

Special Considerations in Rickets

• Bone quality may be compromised (osteopenic)
• Use larger implants for better fixation
• Delayed healing: Longer non-weight-bearing period
• Ensure biochemical optimization before and after surgery
• Higher malunion/nonunion risk in active disease

Medical Complications

Acute (Untreated Rickets):

Skeletal Complications:

• Pathologic fractures - metaphyseal fractures with minimal trauma (greenstick, Salter-Harris II)
• Progressive deformities - genu varum/valgum, coxa vara, spinal deformities (scoliosis, kyphosis)
• Slipped capital femoral epiphysis (SCFE) - increased risk in untreated/undertreated rickets
• Craniosynostosis - premature fusion of skull sutures (rare complication)
• Respiratory compromise - severe rachitic rosary causing chest wall deformity

Systemic Complications:

• Cardiomyopathy - dilated cardiomyopathy in severe chronic hypocalcemia (rare)
• Immune dysfunction - vitamin D plays role in immune regulation; increased infection risk
• Muscle weakness - proximal myopathy, waddling gait
• Bone pain - diffuse skeletal pain, difficulty walking

Treatment-Related Complications

Hungry Bone Syndrome:

• Severe hypocalcemia and hypophosphatemia after initiating vitamin D replacement
• Skeleton avidly takes up minerals once vitamin D replenished
• Risk factors: severe rickets, very high ALP, prolonged deficiency
• Presentation: tetany, seizures within first 2 weeks of treatment
• Prevention: concurrent calcium supplementation, close monitoring (calcium q48h for first 2 weeks)
• Treatment: IV calcium gluconate, increase oral calcium dose

Vitamin D Toxicity (Overcorrection):

• Hypercalcemia - nausea, vomiting, polyuria, constipation, altered mental status
• Hypercalciuria - nephrocalcinosis, renal stones
• Risk factors: excessive supplementation (greater than 10,000 IU daily for prolonged periods), vitamin D-dependent rickets type I on calcitriol
• Monitoring: serum calcium, urinary calcium/creatinine ratio
• Management: reduce or stop vitamin D, hydration, loop diuretics if severe

Nephrocalcinosis (X-Linked Hypophosphatemia):

• Complication of conventional therapy (oral phosphate + calcitriol)
• Mechanism: hypercalciuria from high-dose calcitriol + phosphate load
• Screening: renal ultrasound annually in children on conventional therapy
• Reduced risk with burosumab (anti-FGF23 therapy)

Surgical Complications

Recurrent Deformity:

• Most common complication if surgery performed on active rickets
• Incidence: 60% recurrence if operated before medical optimization vs less than 10% after 12-18 months treatment
• Prevention: confirm biochemical normalization, radiographic healing, adequate treatment duration before surgery
• Management: repeat medical optimization, consider revision surgery only after full healing

Delayed Union/Nonunion:

• Risk factors: active rickets, inadequate medical optimization, poor compliance with vitamin D
• Management: optimize vitamin D and calcium, bone stimulation, revision surgery if persistent nonunion

Overcorrection/Undercorrection (Guided Growth):

• Mechanism: unpredictable correction rate with hemiepiphysiodesis, especially in metabolic bone disease
• Prevention: close follow-up (every 3-6 months), standing alignment radiographs, remove implants promptly when corrected
• Management: observation if mild, contralateral surgery if asymmetric, osteotomy if severe

Hardware Complications:

• Implant fracture - plates/screws in osteopenic bone
• Migration - eight-plate migration in soft bone
• Infection - surgical site infection (standard orthopedic risk)

Long-Term Sequelae

If Untreated or Undertreated:

• Permanent short stature - growth potential lost if treated after puberty
• Residual skeletal deformities - bow legs, knock knees, coxa vara requiring adult reconstruction
• Early osteoarthritis - knee (tibial-femoral), hip from malalignment and abnormal loading
• Chronic pain - skeletal deformities causing mechanical pain
• Gait abnormalities - waddling gait, limping

Even with Treatment:

• X-linked hypophosphatemia: often requires multiple surgeries despite good medical control, residual short stature common
• Vitamin D-dependent type II: some patients resistant to all therapy, permanent skeletal changes
• Dental issues: enamel defects from critical period of deficiency persist despite treatment

Postoperative Protocol

After Guided Growth

• Weight-bearing as tolerated immediately
• No cast or immobilization required
• Follow-up at 6 weeks, then every 3-6 months
• Standing alignment radiographs at each visit
• Continue vitamin D and calcium supplementation

After Osteotomy

• Protected weight-bearing 6-12 weeks (longer than typical due to metabolic bone disease)
• Cast or brace immobilization
• Serial radiographs to assess healing
• Progress weight-bearing based on callus formation

Medical Management

• Continue vitamin D supplementation lifelong
• Maintain calcium intake
• Monitor biochemistry during healing

Advanced Rehabilitation

Guided Growth Follow-up Schedule

Implant Removal Timing

• Remove eight-plates when mechanical axis normalized
• Do not delay - risk of overcorrection
• Brief anesthesia for plate removal
• Observe for rebound deformity (especially XLH)

Osteotomy Healing in Rickets

• Delayed healing expected (bone metabolism compromised)
• Monitor closely for nonunion
• Ensure ongoing vitamin D optimization
• Consider bone stimulation if delayed healing

Long-Term Surveillance

• Monitor for recurrence especially in XLH
• Annual biochemistry checks
• Growth monitoring
• Consider repeat surgery if deformity recurs

Treatment Outcomes

Medical Treatment (Nutritional Rickets)

• Biochemistry normalizes: 3-6 months
• Radiographic healing: 6-12 months
• Spontaneous deformity correction: 12-18 months
• Growth catch-up: Variable, better if treated early

Surgical Outcomes

• Guided growth success rate: greater than 90% correction
• Osteotomy union rate: 85-95% (lower than normal bone)
• Recurrence rate after proper optimization: less than 10%

Long-Term Prognosis

• Excellent if treated early and completely
• Full height potential achievable in nutritional rickets
• Hereditary forms require lifelong management

Advanced Outcome Analysis

Factors Affecting Outcomes

Type-Specific Outcomes

Nutritional Rickets

• Full recovery expected with adequate treatment
• Mild deformities correct spontaneously
• Height potential preserved if treated before age 2
• Rare need for surgery with proper medical management

X-Linked Hypophosphatemia

• Lifelong treatment required
• Often requires multiple surgeries despite medical optimization
• Short stature common (average height loss 2-3 SD)
• Burosumab showing improved outcomes vs conventional therapy

Surgical Timing Impact

• Surgery on active rickets: 60% recurrence rate
• Surgery after optimization: less than 10% recurrence
• Guided growth preferred - 90% success rate

Australian Practice Considerations

Epidemiology in Australia

• Re-emergence of nutritional rickets in recent decades
• High-risk groups: Dark-skinned migrants, refugees, veiled women
• Southern states (Melbourne, Hobart) higher risk due to lower UV-B
• Breastfed infants of vitamin D-deficient mothers

Prevention Guidelines

• Royal Australasian College of Physicians recommendations
• All breastfed infants should receive vitamin D 400 IU daily
• Higher-risk groups may need 400-800 IU daily
• Pregnant and lactating women should maintain vitamin D greater than 50 nmol/L

Healthcare Access

• Pediatric endocrinology services available in major centers
• Multidisciplinary clinics for metabolic bone disease
• PBS coverage for vitamin D supplements

Advanced Australian Context

PBS and MBS Considerations

• Vitamin D testing (25-OH D): Medicare rebate available with clinical indication
• Vitamin D supplements: Available over-the-counter and PBS-subsidized
• Burosumab (for XLH): PBS-listed with specialist prescription

Genetic Testing

• Available through pediatric genetics services
• PHEX, CYP27B1, VDR gene testing
• Funding through state health systems

Orthopedic Management

• Guided growth implants available at pediatric orthopedic centers
• MBS item numbers for osteotomy and internal fixation procedures
• Pediatric orthopedic subspecialty fellowship training includes metabolic bone disease

Multicultural Considerations

• Risk factors common in migrant populations
• Cultural sensitivity regarding sun exposure
• Interpreter services for patient education
• Community health programs for high-risk groups