What is the appropriate evaluation and management approach for a patient with low alkaline phosphatase (ALP) levels?

Evaluation and Management of Low Alkaline Phosphatase

A persistently low serum alkaline phosphatase (ALP) below 30-40 IU/L requires systematic evaluation to identify hypophosphatasia or secondary causes, as this finding is clinically significant and often overlooked despite occurring in approximately 0.13-0.6% of hospitalized patients. 1, 2, 3

Initial Recognition and Confirmation

• Confirm persistence by repeating ALP measurement if initially low, as transient reductions may occur with acute illness 1, 2
• Low ALP is defined as values persistently below 30-40 IU/L (laboratory-specific lower limit of normal) 1, 3
• Recognition rates are alarmingly poor—only 3% of cases are documented in discharge summaries despite clear laboratory abnormalities 2

Differential Diagnosis Framework

Primary Cause: Hypophosphatasia (HPP)

Hypophosphatasia is the most common genetic cause of persistently low ALP, resulting from pathogenic variants in the ALPL gene encoding tissue-nonspecific alkaline phosphatase 1, 4

Clinical manifestations in adults include:

• Recurrent stress fractures or atypical fractures (particularly metatarsal and femoral) 1, 5, 3
• Chronic musculoskeletal pain and bone pain 1, 4
• Premature tooth loss or severe dental disease (loss of teeth with intact roots) 1, 4
• Chondrocalcinosis and calcific periarthritis 1, 2
• Pseudofractures on imaging 5, 3

Secondary Causes to Exclude

Evaluate for acquired conditions that lower ALP: 1

• Malnutrition and severe protein-calorie deficiency
• Vitamin and mineral deficiencies (zinc, magnesium, vitamin C)
• Hypothyroidism and other endocrine disorders
• Medications: bisphosphonates, denosumab, or other antiresorptive therapy 2, 3
• Severe acute illness (transient phenomenon)
• Pernicious anemia
• Cardiac surgery with cardiopulmonary bypass

Diagnostic Algorithm

Step 1: Biochemical Confirmation of HPP

Measure ALP substrates that accumulate when the enzyme is deficient: 1, 5

• Serum pyridoxal 5'-phosphate (PLP): Markedly elevated levels (>3× upper limit of normal) strongly support HPP diagnosis
• Plasma phosphoethanolamine (PEA): Elevated in HPP
• Plasma or urine inorganic pyrophosphate (PPi): Elevated in HPP

Additional supportive laboratory findings: 1, 5

• Serum calcium: typically normal
• Serum inorganic phosphate: may be elevated
• Parathyroid hormone: normal or slightly elevated

Step 2: Genetic Testing

Sequence the ALPL gene to identify pathogenic variants if clinical suspicion and biochemical findings support HPP 1, 4

Important caveats:

• A substantial proportion of patients with clinical and biochemical HPP have normal ALPL exon sequencing, possibly due to mutations in regulatory regions, epigenetic changes, or other unidentified genetic abnormalities 1
• Both heterozygous and compound heterozygous mutations can cause adult-onset HPP 4, 5

Step 3: Imaging Assessment

Obtain skeletal imaging when HPP is suspected: 1, 5

• Plain radiographs of symptomatic areas to identify stress fractures, pseudofractures, or osteomalacia
• Bone mineral density by DXA may be normal or show osteopenia 5
• Consider bone scan if localized bone pain suggests stress fracture 6

Critical Management Considerations

Avoid Harmful Therapies

Do NOT prescribe bisphosphonates or other antiresorptive agents in confirmed or suspected HPP, as these drugs:

• Are ineffective for treating the underlying mineralization defect 5, 3
• May potentially worsen bone disease by further suppressing already-deficient ALP activity 2, 3
• Have been associated with fractures occurring during treatment in HPP patients 2

This is particularly important because:

• HPP is frequently misdiagnosed as osteoporosis due to fractures and low bone density 3
• 9% of osteoporosis clinic patients may have low ALP, with 0.3-3% having actual HPP 3
• Two of 22 patients with atypical femoral fractures had low ALP, suggesting possible undiagnosed HPP 3

Specific Treatment Approaches

For confirmed HPP with significant symptoms:

• Enzyme replacement therapy with asfotase alfa is available for severe pediatric-onset and perinatal forms; adult data are emerging 1
• Supportive care for fractures, including orthopedic management of non-union fractures 5
• Dental care for tooth abnormalities 4
• Pain management for musculoskeletal symptoms 4

For secondary causes:

• Address underlying nutritional deficiencies (zinc, magnesium, vitamin C supplementation as indicated) 1
• Treat endocrine disorders appropriately 1
• Consider discontinuing causative medications if clinically feasible 1, 2

Prevalence and Screening Context

In osteoporosis clinic populations:

• 9% have at least one low ALP measurement 3
• 2.7% have low ALP on ≥2 occasions 3
• 0.4% have persistently low ALP 3
• 3% of those with low ALP have confirmed HPP 3

Common pitfall: Low ALP is rarely recognized or documented despite being readily identifiable in routine laboratory panels, leading to missed diagnoses and inappropriate treatment 2