What is the management approach for a patient with hypophosphatasia (low alkaline phosphatase) and unexplained fracture?

Management of Low Alkaline Phosphatase with Unexplained Fracture

A patient presenting with low alkaline phosphatase and unexplained fracture should be evaluated for hypophosphatasia through measurement of serum pyridoxal 5'-phosphate (vitamin B6), urinary phosphoethanolamine, and genetic testing for ALPL gene mutations, as this diagnosis fundamentally changes management by contraindicating standard osteoporosis treatments like bisphosphonates. 1, 2

Initial Diagnostic Workup

Essential Laboratory Tests

• Serum alkaline phosphatase confirmation: Values persistently <30-40 IU/L are highly suggestive of hypophosphatasia 3, 4
• Serum pyridoxal 5'-phosphate (vitamin B6): Elevated levels (>34.1 mcg/L) substantiate the diagnosis of hypophosphatasia 5, 2, 6
• Urinary phosphoethanolamine: Elevated levels correlate inversely with ALP activity and support the diagnosis 6
• Serum calcium and phosphate: Hypophosphatasia may present with mild hypercalcemia or hyperphosphatemia 2, 6
• Serum PTH and 25(OH) vitamin D: To exclude other metabolic bone disorders 1, 7

Genetic Testing

• ALPL gene sequencing: Should be performed when clinical and biochemical findings suggest hypophosphatasia 1, 5, 2
• Approximately 50% of adults with unexplained low ALP carry ALPL mutations, most commonly heterozygous missense mutations 6
• One case report identified a homozygous missense mutation (c.443 C>T: p.Thr148Ile) in an adult with severe manifestations 5

Radiographic Evaluation

• Skeletal survey: Look for pseudofractures, rachitic changes, premature loss of teeth, and calcification abnormalities 1
• High-resolution peripheral quantitative CT (HR-pQCT): Can assess bone microarchitecture parameters in detail 5
• Bone mineral density by DEXA: May show osteopenia but does not distinguish hypophosphatasia from osteoporosis 5, 2

Critical Differential Diagnosis Considerations

Distinguish from Other Causes of Fractures

The differential diagnosis table from genetics guidelines shows hypophosphatasia (childhood type) presents with premature tooth loss, rachitic bone changes, fractures, and undermineralization, requiring urinary phosphoethanolamine, plasma ALP, and TNSALP gene testing 1

Rule Out Non-Accidental Injury in Infants

In infants with unexplained fractures and low ALP, hypophosphatasia types I, IV, V, and VI may have few clinical features, making biochemical or DNA diagnostic testing essential to avoid misdiagnosis as non-accidental injury 1

Exclude Other Metabolic Bone Disorders

• X-linked hypophosphatemia: Presents with hypophosphatemia, elevated (not low) ALP, and elevated FGF23 1
• Osteogenesis imperfecta: May have normal ALP levels; distinguished by collagen gene mutations 1
• CKD-mineral bone disorder: Context of reduced kidney function with variable ALP levels 1

Management Approach

Immediate Actions

• Discontinue antiresorptive therapy immediately: Bisphosphonates, denosumab, and other antiresorptive drugs are contraindicated in hypophosphatasia and may worsen symptoms 3, 5, 2
• Stop calcium and vitamin D supplementation: These commonly used treatments for fractures can worsen hypophosphatasia symptoms and prognosis, potentially causing nephrocalcinosis 5

Specific Treatment for Hypophosphatasia

Asfotase alfa (enzyme replacement therapy) is the definitive treatment for hypophosphatasia with significant bone deterioration 5:

• Dosing: 2 mg/kg subcutaneously, 3 times weekly 5
• One case report demonstrated improvement in bone mineral density, HR-pQCT microstructural parameters, and functional mobility after 12 months of treatment in an adult patient 5
• Treatment prevented further kidney function deterioration in a patient with existing renal impairment 5

Monitoring During Treatment

• Bone mineral density: Reassess after 12 months of asfotase alfa therapy 5
• HR-pQCT parameters: Monitor bone microarchitecture improvements 5
• Renal function: Monitor creatinine clearance, as nephrocalcinosis and nephrolithiasis can occur 5
• Functional assessment: Evaluate ambulatory status and need for assistive devices 5

Important Clinical Pitfalls

Low ALP in Context of Antiresorptive Use

Among patients with atypical femoral fractures, 25% had at least one ALP value ≤40 IU/L, but most were associated with concurrent antiresorptive treatment rather than true hypophosphatasia 4. However, patients with genuinely low ALP had higher rates of bilateral atypical femoral fractures (50% vs 22%) and metatarsal fractures (33% vs 7%) 4.

Transient vs Persistent Low ALP

In an osteoporosis clinic cohort, 9% had at least one low ALP measurement, but only 0.4% had persistently low levels, and hypophosphatasia was confirmed in 3% of those with low ALP 3. Persistently low ALP (on majority of measurements) is the key finding that warrants full hypophosphatasia workup 3.

Associated Clinical Features to Assess

Look specifically for 1, 5, 2, 6:

• Dental manifestations: Premature loss of deciduous teeth, dental abscesses
• Skeletal features: Short stature, craniosynostosis, rachitic deformities
• Musculoskeletal complaints: Bone pain, muscle weakness, multiple fractures requiring surgical correction
• Renal complications: Nephrocalcinosis, nephrolithiasis, reduced creatinine clearance

When to Refer to Specialist

Referral to an endocrinologist or metabolic bone disease specialist is indicated for 1:

• Unexpectedly low ALP levels with fractures
• Young age at presentation with fragility fractures
• Recurrent fractures despite treatment
• Confirmed or suspected hypophosphatasia requiring enzyme replacement therapy