What is the treatment approach for adults with hypophosphatasia?

Treatment Approach for Adults with Hypophosphatasia

For symptomatic adults with hypophosphatasia (HPP), treatment with active vitamin D together with oral phosphorus supplements is recommended to reduce osteomalacia and its consequences and improve oral health. 1

Clinical Presentation in Adults

Adult HPP presents with various manifestations that significantly impact quality of life:

• Musculoskeletal manifestations:

  • Osteomalacia
  • Pseudofractures
  • Musculoskeletal pain
  • Enthesopathies (prevalent by third decade of life)
  • Early osteoarthritis
  • Muscle weakness
  • Stiffness due to joint involvement 1, 2

• Dental issues:

  • Periodontitis
  • Frequent dental abscesses 1

• Neurological symptoms:

  • Fatigue (66%)
  • Headache (61%)
  • Sleep disturbance (51%)
  • Gait abnormalities (44%)
  • Vertigo (43%)
  • Depression (39%)
  • Anxiety (35%)
  • Neuropathy (35%)
  • Hearing loss (33%) 3

Diagnostic Approach

HPP diagnosis is based on:

1. Clinical features: Rickets/osteomalacia, musculoskeletal pain, dental issues
2. Laboratory findings:
   • Low serum alkaline phosphatase (ALP) - key diagnostic marker
   • Elevated urinary phosphoethanolamine (PEA)
3. Genetic testing: Mutations in the ALPL gene (definitive diagnosis) 4, 5

Treatment Algorithm for Adults with HPP

Step 1: Determine if treatment is indicated

• Treat if symptomatic: Musculoskeletal pain, pseudofractures, dental issues, planned orthopedic/dental surgery, or biochemical evidence of osteomalacia with elevated bone-specific ALP 1
• No treatment recommended for asymptomatic adults 1

Step 2: Conventional Treatment (First-line)

For symptomatic adults:

• Active vitamin D:

  • Calcitriol: 0.50-0.75 μg daily OR
  • Alfacalcidol: 0.75-1.5 μg daily 1

• Oral phosphate supplements:

  • Dose: 750-1,600 mg daily (based on elemental phosphorus)
  • Administration: Divide into 2-4 doses
  • Formulation: Available as sodium-based or potassium-based salts (oral solutions, capsules, tablets) 1

Step 3: Monitoring and Dose Adjustments

• Monitor for secondary hyperparathyroidism
• If PTH levels are markedly increased:
  • Stop phosphate supplements
  • Consider active vitamin D without phosphate supplements 1
• Reduce active vitamin D doses if long-term immobilization is anticipated 1
• Supplement with native vitamin D (cholecalciferol/ergocalciferol) if vitamin D deficient 1

Step 4: Non-Pharmacological Management

• Physical therapy for pain relief and improving function
• Analgesics (short-term NSAIDs)
• Intra-articular joint infiltrations for degenerative changes 1

Step 5: Consider Advanced Therapies

For severe cases:

• Enzyme replacement therapy: Asfotase alfa (recombinant enzyme) is approved for treatment of patients with perinatal/infantile and juvenile-onset HPP, including adults 6

Important Cautions and Contraindications

• Contraindicated medications in adults with HPP:

  • Bisphosphonates
  • Denosumab
  • Potent antiresorptive agents
  • Vitamin D (without proper monitoring) 4

• Special considerations:

  • Pregnancy and lactation: Consider active vitamin D with phosphate supplements if needed 1
  • Immobilization: Reduce or stop active vitamin D supplementation during periods of immobilization 1

Treatment Efficacy and Expectations

Conventional treatment with active vitamin D and phosphate:

• Improves pain
• Reduces osteomalacia
• Improves oral health (periodontitis and dental abscesses)
• Does not prevent or improve hearing loss or enthesopathies 1

The burden of HPP in adults is significant, with chronic pain, recurrent fractures, and orthopedic problems leading to severe disability and negative impacts on quality of life 2. Early diagnosis and appropriate treatment are essential to improve outcomes and prevent complications.