Osteomalacia and rickets

Osteomalacia and rickets are disorders of bone mineralization. In osteomalacia, remodeling of preexisting bone is defective; in rickets, new bone formation is defective. Osteomalacia can affect individuals of any age, whereas rickets can only occur in children with open growth plates. Osteomalacia and rickets are caused by insufficient calcium, phosphate depletion, and/or direct inhibition of bone mineralization. The most common cause of both disorders is vitamin D deficiency. Patients with osteomalacia usually present with bone pain and tenderness, while patients with rickets exhibit bone deformities and impaired growth. Over time, both conditions may lead to bowing of the long bones and/or pathological fractures. The diagnosis involves a combination of clinical history, abnormal laboratory studies, and, in many cases, imaging. Treatment, which is directed at the underlying cause, most commonly involves treatment of vitamin D deficiency and ensuring sufficient calcium intake.

Vitamin D deficiency is the most common cause of both osteomalacia and rickets. Vitamin D-independent causes (i.e., hypophosphatemia, hypocalcemia, medication-induced) and hereditary causes are less common. ^[2]

The causes of osteomalacia and rickets involve at least one of the following mechanisms: ^[1][5]

• Calcipenic rickets
  • ↓ Calcium → ↑ PTH levels → ↓ phosphate → impaired bone mineralization ^[1][5]
  • See “Calcium homeostasis.”
• Phosphopenic rickets: ↓ phosphate → impaired bone mineralization
• Direct inhibition of mineralization → impaired bone mineralization

Impaired bone mineralization can affect both existing bone matrix (osteomalacia) and, if growth plates are still open, new bone formation (rickets). ^[1]

Low phosphate is present in both calcipenic and phosphopenic forms of osteomalacia and rickets. ^[1][5]

Osteomalacia ^[5]

• Occurs in adults and children
• Bone pain and tenderness
• Pathologic fractures
• Myopathy (predominantly proximal)
  • Muscle weakness causing waddling gait and difficulty walking
  • Spasms
  • Cramps
• Symptoms of hypocalcemia
• Severe osteomalacia: bone deformities, e.g., bowing of the lower limbs

Osteomalacia and rickets may be asymptomatic. ^[6][7]

Rickets ^[1]

• Only occurs in children (growth plates have not fused)
• Bone deformities
  • Bowing, primarily of the long bones
  • Distention of the bone-cartilage junctions
    • Rachitic rosary: bead-like distention of the bone-cartilage junctions in the ribs
    • Marfan sign
      • Distention of the epiphyseal plate of the distal tibia with widening and cupping of the metaphysis
      • Gives appearance of a double medial malleolus on inspection and palpation of the ankle
    • Widened wrists
  • Craniotabes: softening of the skull
  • Deformities of the knee, especially genu varum ^[1]
• Increased risk of fracture
• Harrison groove
  • A depression of the thoracic outlet
  • Caused by muscles pulling along the costal insertion of the diaphragm
• Impaired growth
• Symptoms of hypocalcemia including seizures in infants
• Late closing of fontanelles
• Delayed walking (> 18 months)
• Cardiomyopathy

Osteomalacia is defective mineralization of existing bone and can occur in individuals with open or closed growth plates. Rickets is defective mineralization of new bone formation and, therefore, only occurs in children with open growth plates (i.e., before the end of puberty). ^[8]

Vitamin D-dependent rickets type 1 ^[1][3][9]

• Pathophysiology
  • Autosomal recessive mutation in the 25-hydroxyvitamin-D-1α-hydroxylase gene ^[1]
  • Leads to impaired conversion of inactive vitamin D to the active form, 1,25‑dihydroxyvitamin D3 (calcitriol)
• Clinical features
  • Early onset of rickets (in infancy)
  • Muscle weakness
  • Growth faltering
  • Hypotonia
  • Pathological fractures
• Diagnostics ^[1][9][10]
  • Normal or elevated plasma 25-OH
  • Low or undetectable 1,25(OH)₂D
  • Hypocalcemia, hypophosphatemia, and elevated ALP
  • Elevated parathyroid hormones
• Treatment: calcitriol supplementation

Vitamin D-dependent rickets type 2 ^[1][4][9]

• Pathophysiology: : An autosomal recessive mutation in the vitamin D receptor gene causes end-organ resistance to vitamin D.
• Clinical features
  • Early onset of rickets (in infancy)
  • Growth faltering
  • Alopecia
• Diagnostics ^[1][9][10]
  • Normal or elevated plasma 25-OH
  • Extremely elevated plasma 1,25(OH)₂D
  • Hypocalcemia, hypophosphatemia, elevated ALP
  • Elevated parathyroid hormones
• Treatment ^[1][9]
  • Very high-dose vitamin D therapy ^[9]
  • Refractory disease: elemental calcium

General principles ^[1][5][11]

• Diagnosis is based on characteristic laboratory and imaging findings.
• The choice of imaging depends on whether osteomalacia or rickets is suspected.
• If there is diagnostic uncertainty, refer patients to endocrinology for advanced studies.

Diagnostic scoring systems for osteomalacia that include clinical history, biochemical results, and radiological imaging findings have been proposed, but they have not yet been validated. ^[5]

Laboratory studies ^[1][5][12]

• Obtain the studies listed in the table below.
• Common laboratory findings in vitamin D deficiency include ↓ Ca, ↓ phosphorus, ↑ PTH, and ↑ ALP).
• If findings are not consistent with osteomalacia/rickets, see “Laboratory evaluation of bone disease.”

PTH is elevated in calcipenic rickets but is typically normal in phosphopenic rickets. ^[1]

Imaging

Modalities ^[1][12][13]

• X-rays
  • Children with open growth plates: x-rays of wrists and knees to evaluate for rickets
  • Adults and children with closed growth plates: Consider x-rays of ribs, scapulae, or pelvis. ^[5][14]
• Additionally, in osteomalacia, consider:
  • DEXA
  • Bone scintigraphy

Imaging findings in osteomalacia and/or rickets ^[1][12][13]

• General
  • Evidence of bone loss ^[15]
    • ↓ Bone mineral density (i.e., osteopenia or osteoporosis)
    • Thinned cortical bone
  • Pathological fractures
  • Looser zones; (pseudofractures); , which are transverse radiolucent bands that represent insufficiency stress fractures seen in osteomalacia and severe rickets; typical features include: ^[13][15][16]
    • Multiple and symmetrical
    • Perpendicular to the periosteal surface
    • Most often occur in the ribs, scapulae, pubic rami, and medial cortex of long bones
• Additional findings in rickets may include:
  • Epiphyseal plate widening
  • Metaphyseal cupping, stippling, and fraying
  • Bone bowing (e.g., genu varum )
  • Chest x-ray: prominent costochondral junctions of the ribs (i.e., rachitic rosary)
  • X-ray skull: persistently widened suture lines (i.e., open fontanelles), occipital flattening, and a more squared appearance
  • X-ray spine: spinal curvature
• Additional findings in osteomalacia may include increased uptake on bone scintigraphy. ^[15]
  • Occurs as a result of increased bone turnover
  • May mimic metastatic cancer

Advanced studies ^[1][5][15]

• Indications
  • Diagnostic uncertainty
  • Rare etiologies suspected e.g.:
    • Tumor-induced osteomalacia
    • Vitamin D-dependent rickets type I or type II
• Potential studies
  • Serum 1,25(OH)₂D levels
  • FGF23 levels
  • Iliac bone biopsy with tetracycline labeling

Differential diagnoses of osteomalacia ^[17][18]

• Bone metastases
• Osteoporosis
• Paget disease of bone
• Hyperparathyroidism
• Renal osteodystrophy

Differential diagnoses of rickets ^[19]

• Osteoglophonic dysplasia with dwarfism
• Osteogenesis imperfecta
• Neurofibromatosis
• McCune-Albright syndrome
• Child abuse/neglect
• Congenital pseudarthrosis of the tibia

Congenital pseudarthrosis of the tibia ^[20]

• Definition: unilateral anterolateral bowing of the lower third of the tibia and possibly fibula associated with neurofibromatosis type I
• Clinical features
  • Bowing of the tibia
  • Pseudoarthrosis of the lower leg
  • Fractures of the tibia and fibula are possible.
  • Clinical features of neurofibromatosis type I
• Treatment
  • Orthoses
  • Osteotomy to excise pseudoarthrosis
  • Bone graft
  • Internal or external fixation

The differential diagnoses listed here are not exhaustive.

General principles ^[1][5][12]

• Treat any acute electrolyte abnormalities, e.g.:
  • Calcium repletion for severe and/or symptomatic hypocalcemia
  • Phosphate repletion
• Review diet and medication list to look for reversible etiologies of osteomalacia and rickets.
• Determine underlying etiology and refer to a specialist for further management, e.g.:
  • Endocrinology for treatment of vitamin D deficiency or other metabolic bone disease
  • Nephrology for treatment of underlying renal disease
• Fully complete treatment for underlying osteomalacia before treating other metabolic bone diseases (e.g., osteoporosis). ^[6][15]
• For bone deformities that persist despite medical management, refer to orthopedics for surgical correction. ^[21]

Treatment of vitamin D-associated osteomalacia and rickets ^[1][12][15]

• Pharmacological therapy
  • Treatment doses of vitamin D ^[5][11][22]
  • Adequate daily intake of calcium ^[5][11][12]
  • Calcitriol may be required for selected indications. ^[1][5]
• Ongoing management
  • Monitoring for clinical features of vitamin D toxicity (uncommon at typical treatment doses) ^[11]
  • Follow-up x-rays and laboratory studies to ensure resolution of abnormalities ^[1][15]
    • Target serum 25(OH)D: > 30 ng/mL ^[5]
    • Target PTH level: normal ^[5]
  • Maintenance dosing of vitamin D for prevention of vitamin D deficiency

In patients with malabsorption, vitamin D and calcium doses may need to be increased or given via alternative routes (i.e., IM/IV). ^[5][11]

• Prevention of vitamin D deficiency ^[1]
• Adequate dietary calcium ^[1]

Sun exposure is not recommended to prevent vitamin D deficiency because of the risk of skin cancer. ^[23]