What is the approach to managing low alkaline phosphatase (alk phos) levels in adults?

Management of Low Alkaline Phosphatase in Adults

The primary concern with low alkaline phosphatase (ALP) in adults is identifying hypophosphatasia (HPP), a rare genetic disorder that can cause debilitating musculoskeletal complications including pathologic fractures, and requires specific diagnostic confirmation before any treatment decisions, particularly avoiding bisphosphonates which may be harmful. 1, 2

Initial Diagnostic Approach

Confirm True Hypophosphatasemia

• Verify persistent low ALP with repeat measurement, as transient decreases may occur; obtain at least two measurements separated by 2-4 weeks to confirm chronicity 3
• Document the degree of ALP reduction below the lower limit of normal, as severity correlates with clinical manifestations and substrate accumulation 4, 5

Immediate Medication Review

• Stop bisphosphonates immediately if the patient is taking them, as these medications can cause low ALP and may be contraindicated in true HPP 3, 6
• Review for other medications that might lower ALP, particularly in patients over 60 years who are more susceptible to drug effects 7

Biochemical Workup to Diagnose Hypophosphatasia

Essential Laboratory Tests

• Measure serum pyridoxal-5-phosphate (PLP): elevated PLP (>50 μg/L) strongly supports HPP diagnosis, with 94-100% of HPP patients showing elevation 4, 5
• Measure urine phosphoethanolamine (PEA): elevated in 94% of HPP patients and correlates inversely with ALP levels 4, 5
• Obtain serum calcium and phosphate: mild hyperphosphatemia occurs in 21% and mild hypercalcemia in 7% of cases 5
• Check bone-specific alkaline phosphatase if available to confirm the deficiency is not isolated to liver isoenzyme 3

The combination of low ALP with elevated PLP and/or PEA is diagnostic of HPP, with approximately 50% of adults with unexplained low ALP carrying pathogenic ALPL mutations 5, 3

Clinical Assessment for HPP Manifestations

Key Historical Features to Elicit

• Musculoskeletal pain (present in 41% at diagnosis), particularly chronic, non-specific bone or joint pain 4
• Fracture history, especially atypical locations: subtrochanteric femur (more common in women), metatarsal stress fractures, hip/femoral neck, or wrist 4, 6
• History of childhood rickets or delayed walking 4
• Dental abnormalities: premature tooth loss in adults (48% with mutations versus 12% without), particularly loss of teeth with intact roots 4, 5
• Chondrocalcinosis or pseudogout episodes (27% have radiographic chondrocalcinosis, 14% have documented pyrophosphate arthropathy) 4

Physical Examination Findings

• Assess for short stature 6
• Examine for joint swelling suggesting chondrocalcinosis 4
• Document any skeletal deformities 1
• Evaluate dental status for premature tooth loss 5

Genetic Testing

• Obtain ALPL gene sequencing in patients with confirmed low ALP and elevated substrates (PLP or PEA) or suggestive clinical features 5, 3
• Approximately 50-67% of adults with persistent hypophosphatasemia carry pathogenic or likely pathogenic ALPL mutations 5, 3
• Most mutations are heterozygous missense mutations with damaging effects on protein activity 5
• Genetic confirmation is critical as it establishes definitive diagnosis, informs prognosis, and guides family counseling 3

Imaging Considerations

When to Obtain Bone Imaging

• Obtain skeletal radiographs if patient reports bone pain, has history of fractures, or has significantly low ALP (<50% of lower limit of normal) 4
• Consider bone density testing (DXA), though it may be normal in HPP despite fracture risk 6
• Iliac crest bone biopsy may show osteomalacia in symptomatic cases but is not routinely necessary if biochemical diagnosis is clear 4

Differential Diagnosis Considerations

• Hypophosphatasia must be distinguished from osteomalacia: osteomalacia shows elevated (not low) ALP, low phosphate, and low vitamin D 1
• Rule out malnutrition, zinc deficiency, and hypothyroidism as alternative causes of low ALP 2
• Consider Wilson disease in younger patients with low ALP and liver abnormalities 2

Management Approach

For Confirmed or Suspected HPP

Avoid bisphosphonates and denosumab, as these antiresorptive agents may worsen bone quality and increase atypical fracture risk in HPP 3, 6

Symptomatic Patients

• Refer to endocrinology or metabolic bone disease specialist for consideration of enzyme replacement therapy (asfotase alfa) in patients with significant symptoms, recurrent fractures, or disabling musculoskeletal pain 2
• Provide supportive care including physical therapy for musculoskeletal pain and mobility impairment 1
• Manage fractures with standard orthopedic approaches; intramedullary nailing has been successful for femoral fractures 6
• Address dental issues with appropriate dental care 5

Asymptomatic Patients or Mild Disease

• Monitor clinically with periodic assessment for development of symptoms, fractures, or dental problems 5
• Repeat biochemical testing (ALP, PLP, PEA) annually to track disease activity 3
• Counsel regarding fracture risk and importance of reporting new bone pain 4
• Avoid prescribing bisphosphonates even if osteoporosis is diagnosed by DXA, as these may be harmful 3, 6

For Low ALP Without HPP Features

If PLP and PEA are normal, genetic testing is negative, and no clinical features of HPP are present:

• Consider alternative causes: malnutrition, zinc deficiency, hypothyroidism, celiac disease, or Wilson disease 2
• Monitor ALP periodically (every 6-12 months) to ensure stability 7
• Document the finding clearly in the medical record to prevent inappropriate bisphosphonate prescription 3

Critical Pitfalls to Avoid

• Never prescribe bisphosphonates to patients with unexplained low ALP without first ruling out HPP, as these drugs may cause atypical fractures in HPP patients 3, 6
• Do not dismiss low ALP as clinically insignificant; approximately 50% harbor pathogenic mutations and may develop serious complications 5, 3
• Do not assume normal bone density on DXA excludes significant bone disease, as HPP patients may have normal or even elevated BMD despite fracture risk 6
• Recognize that many HPP patients have only mild, non-specific symptoms (musculoskeletal pain) that may be dismissed, but substrate accumulation and fracture risk persist 4, 5
• Women appear more susceptible to certain manifestations including metatarsal fractures and chondrocalcinosis, requiring gender-specific vigilance 4