Rickets - Basic Science

Summary
- Rickets is a metabolic bone disease caused by a defect in mineralization of osteoid matrix caused by inadequate calcium and phosphate that occurs prior to closure of the physes. Patients present with characteristic features such as bowing of long bones, ligamentous laxity, brittle bones and enlargement of costal cartilage.
- Diagnosis is made based on a thorough evaluation of serum labs, clinical features, and radiographic findings.
- Treatment involves medical management to resolve the underlying etiology of rickets.

Etiology
- Pathophysiology
  - Vitamin D and PTH play an important role in calcium homeostasis
  - disruption of calcium/phosphate homeostasis
  - poor calcification of cartilage matrix of growing long bones
    
    occurs at zone of provisional calcification
  - leads to increased physeal width and cortical thinning/bowing
- Mechanism
  - rickets is
    
    known as osteomalacia if it occurs after physeal closure
    
    can be congenital or acquired
    
    treatment is usually non-operative with supplementation
- Associated conditions
  - orthopaedic manifestations include
    
    brittle bones with physeal cupping/widening
    
    bowing of long bones
    
    ligamentous laxity
    
    flattening of skull
    
    enlargement of costal cartilage (rachitic rosary)
    
    kyphosis (cat back)

Classification
- Vitamin D-resistant (familial hypophosphatemic)
  - most common form of heritable rickets
  - presents at 1-2 years of age
  - caused by inability of renal tubules to absorb phosphate
    
    GFR is normal
    
    vitamin D3 response is impaired
  - genetics
    
    X-linked dominant
    
    most common form
    
    results from mutation in PHEX gene
    
    leads to increased levels of FGF23, which decreases renal phosphate absorption and suppresses renal 25-(OH)-1α-hydroxylase activity
    
    autosomal dominant
    
    results from mutation in FGF23
    
    leads to decreased FGF23 degradation
    
    autosomal recessive
    
    results from mutation in dentin matrix protein 1 (DMP1) gene
    
    leads to impaired osteocyte maturation and bone mineralization, and increased levels of FGF23
- Vitamin D-deficient (nutritional)
  - results from decreased dietary intake of Vitamin D
    
    rare now that Vitamin D is added to milk
  - presents at 6 months - 3 years of age
  - risk factors
    
    premature infants
    
    black children > 6 months who are still breastfed
    
    patients with malabsorption syndromes (celiac sprue) or chronic parenteral nutrition
    
    Asian immigrants
    
    patients with unusual dietary choices (vegetarian diet)
  - pathophysiology
    
    low Vitamin D levels lead to decreased intestinal absorption of calcium
    
    low calcium levels leads to a compensatory increase in PTH and bone resorption
    
    bone resorption leads to increased alkaline phosphatase levels
- Vitamin D-dependent (type I & type II)
  - rare disorder
  - leads to clinical features similar to Vitamin D-deficient rickets but more severe
  - clinical characteristics
    
    type I
    
    hypotonia, muscle weakness, growth failure, hypocalcemic seizures, joint pain/deformity, fractures in early infancy
    
    type II
    
    hypotonia, muscle weakness, growth failure, hypocalcemic seizures, growth retardation, bone pain, severe dental caries or dental hypoplasia
  - pathophysiology
    
    type I
    
    results from autosomal recessive mutation in renal 25-(OH)-1α-hydroxylase
    
    responsible gene 12q14
    
    prevents conversion of inactive form of vitamin D to active form
    
    leads to decreased calcitriol
    
    type II
    
    results from autosomal recessive mutation in intracellular receptor for 1,25-(OH)2-vitamin D
    
    leads to increased calcitriol

Presentation
- Symptoms
  - listlessness
  - irritability
  - generalized weakness
- Physical exam
  - tibial bowing
    
    due to widened proximal tibial physes
  - rachitic rosary
    
    enlargement of costochondral junction
  - bowing of knees
  - retarded bone growth
  - muscle hypotonia
  - waddling gait
  - dental abnormalities
    
    delayed dental eruption
    
    defective enamel
  - pathologic fractures

Imaging
- Radiographs
  - recommended views
    
    AP and lateral of affected bone
  - findings
    
    physeal widening
    
    metaphyseal cupping
    
    decreased bone density
    
    Looser's zones
    
    pseudofracture on the compression side of bone
    
    rachitic rosary
    
    prominence of rib heads at the osteochondral junction
    
    lower extremity bowing
    
    often genu varum
    
    codfish vertebrae
    
    cat back
    
    dorsal kyphosis

Studies
- Serum labs
- Histology
  - disordered and elongated zone of proliferation
  - poorly defined zone of provisional calcification
  - widened osteoid seams
  - "swiss cheese" trabeculae
  - abnormally arranged collagen fibers
    
    run perpendicular to haversian canals

Tested Differential
- Renal osteodystrophy
- Hypophosphatasia

Treatment
- Nonoperative
  - calcitriol
    
    indications
    
    Vitamin D-resistant (familial hypophosphatemic) rickets
    
    type I Vitamin D-dependent rickets
  - phosphate replacement
    
    indications
    
    Vitamin D-resistant (familial hypophosphatemic) rickets
  - Vitamin D
    
    indications
    
    Vitamin D-deficient (nutritional) rickets
    
    type II Vitamin D-dependent rickets (partial 1,25-(OH)2-vitamin D resistance)
  - Calcium
    
    indications
    
    type II Vitamin D-dependent rickets (total 1,25-(OH)2-vitamin D resistance)
  - Burosumab
    
    human monoclonal antibody to FGF-23
    
    approved for the treatment of X-linked hypophosphatemia among children 1 year and older
- Operative
  - corrective surgery (multilevel osteotomy)
    
    indications
    
    severe tibial bowing

Techniques
- Calcitriol
  - technique
    
    20-30 μg/kg/day split into 2-3 doses in children
    
    0.5-0.75 μg/day split into 2 doses in adults
- Phosphate replacement
  - technique
    
    20-40 mg/kg/day split into 3-5 doses in children
    
    750-1000 mg/day split into 3-4 doses in adults
    
    Must be given in combination with active vitamin D (i.e. calcitriol) in XLH patients, as this prevents the development of secondary hyperparathyroidism as seen in patients treated with phosphate salts alone
- Vitamin D
  - technique
    
    5000 IU/day for 6-10 weeks
- Corrective surgery (multilevel osteotomy)
  - technique
    
    variety of fixation devices including K-wires, plates, intramedullary nails, and/or external fixation

Action	Numeric Key	Letter Key	Function Key
Show Bullets		S	Enter (frontside only)
20%	1	N
40%	2	H
60%	3	F	Enter (backside only)
80%	4	E
100%	5	M
Toss	0	T