Management of Hypophosphatasemia (Low Alkaline Phosphatase)
Low alkaline phosphatase (ALP) levels should be thoroughly investigated for hypophosphatasia (HPP), a rare inherited disorder that requires specific management and avoidance of antiresorptive therapies. 1, 2
Diagnostic Approach
Initial Evaluation
- Confirm persistently low ALP levels with repeat testing
- Measure bone-specific ALP (particularly important as total ALP can occasionally be normal in HPP) 3
- Test for elevated ALP substrates:
- Pyridoxal-5'-phosphate (PLP) (elevated levels have a significant negative correlation with ALP) 4
- Pyrophosphate
- Phosphoethanolamine
Clinical Assessment
- Evaluate for symptoms and signs of HPP:
- Musculoskeletal: bone pain, joint pain, fractures (particularly stress fractures)
- Dental: history of premature tooth loss, dental abscesses
- Neurological: headaches (potential craniosynostosis)
- Systemic: fatigue, weakness
Genetic Testing
- Consider ALPL gene testing to confirm diagnosis in suspected cases 2
- Family screening is recommended for first-degree relatives of patients with confirmed HPP 1
Management Recommendations
Monitoring
- Monitor blood levels of ALP, calcium, phosphate, creatinine, PTH, and 25(OH) vitamin D every 6 months 1
- Calculate urinary calcium:creatinine ratio to assess for hypercalciuria 1
- Kidney ultrasonography every 2 years (annually if nephrocalcinosis is present) 1
- Dental evaluation twice yearly to prevent and treat dental infections 1
Treatment Options
For Children with Confirmed HPP
- Consider burosumab treatment for children ≥1 year with:
- Radiographic evidence of bone disease
- Disease refractory to conventional therapy
- Complications from conventional therapy
- Inability to adhere to conventional therapy 1
- Starting dose: 0.4 mg/kg body weight subcutaneously every 2 weeks
- Maximum dose: 2.0 mg/kg (not exceeding 90 mg)
- Titrate to maintain fasting serum phosphate levels within lower end of normal range 1
For Adults with HPP
- Conventional therapy with phosphate supplements and active vitamin D
- Phosphate supplementation: 750-1,600 mg daily (elemental phosphorus) in 2-4 divided doses 1, 5
- Active vitamin D (calcitriol or alfacalcidol) to improve intestinal calcium absorption
- Maintain normal calcium intake (minimum 1g daily) 1
Special Considerations
- Avoid antiresorptive therapy (bisphosphonates) in patients with HPP as it may worsen the condition 6, 7
- Monitor for secondary hyperparathyroidism (adjust vitamin D dose upward and/or phosphate dose downward if PTH elevated) 1, 5
- Consider cinacalcet for persistent hyperparathyroidism unresponsive to conventional management 1
- For pregnant women with HPP:
- Monitor 25(OH) vitamin D levels
- May require higher phosphate supplementation (up to 2,000 mg daily)
- Continue treatment during pregnancy with close biochemical monitoring 1
Potential Complications to Monitor
- Nephrocalcinosis (especially with phosphate supplementation)
- Secondary hyperparathyroidism
- Hypercalciuria
- Bone deformities requiring orthopedic intervention
Prevalence and Clinical Significance
- HPP is found in approximately 3% of patients with low ALP attending osteoporosis clinics 6
- Misdiagnosis as osteoporosis is common and can lead to inappropriate treatment with antiresorptives 6, 7
Regular monitoring and appropriate management can significantly improve outcomes in patients with hypophosphatasemia, particularly when the underlying cause is identified and treated appropriately.