What does a low alkaline phosphatase (ALP) level indicate?

Low Alkaline Phosphatase: Clinical Significance

A low alkaline phosphatase (ALP) level most commonly signals hypophosphatasia—a genetic disorder of bone mineralization—or reflects secondary causes including malnutrition, zinc/magnesium deficiency, hypothyroidism, pernicious anemia, or use of antiresorptive medications (bisphosphonates, denosumab). 1, 2, 3

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Primary Cause: Hypophosphatasia

Hypophosphatasia (HPP) is the most common genetic cause of persistently low serum ALP, resulting from pathogenic variants in the ALPL gene that encodes tissue-nonspecific alkaline phosphatase. 3

Prevalence and Detection

• Approximately 50% of adults with unexplained low ALP carry an ALPL mutation, most commonly heterozygous missense variants with damaging effects on enzyme activity. 4
• In osteoporosis clinic populations, 9% have at least one low ALP measurement (<30 IU/L), 2.7% have persistently low levels, and 0.3–3% are ultimately diagnosed with HPP. 5
• HPP occurs in approximately 2 of 22 patients (9%) with atypical femoral fractures, making low ALP a critical screening marker in this high-risk group. 5

Clinical Manifestations in Adults

Adult-onset HPP typically presents with milder manifestations than pediatric forms: 3

• Skeletal pain and stress fractures (particularly metatarsal fractures)
• Premature tooth loss (48% of mutation carriers versus 12% of non-carriers) 4
• Chondrocalcinosis and calcific periarthritis
• Dental problems including "gray gums" in childhood 6
• Progressive fatigue, weakness, and joint pain 6

Biochemical Markers

The diagnosis is supported by measuring ALP substrates that accumulate when enzyme activity is deficient: 3

• Elevated pyridoxal phosphate (vitamin B6): Present in approximately 24% of individuals with low ALP, and all patients with elevated PLP carry an ALPL mutation. 4 Serum PLP inversely correlates with ALP levels (r = -0.51, p = 0.001). 4
• Elevated urine phosphoethanolamine (PEA): Inversely correlates with ALP (r = -0.49, p = 0.001). 4
• Mild hyperphosphatemia: Present in approximately 21% of cases, more common in mutation carriers (p = 0.03). 4
• Mild hypercalcemia: Occurs in approximately 7% of cases. 4 Serum calcium inversely correlates with ALP (r = -0.38, p = 0.012). 4

Diagnostic Pitfall: Normal Total ALP

Critically, some patients with HPP have normal total ALP but low bone-specific ALP, as demonstrated by a case of confirmed HPP (genetic variant c.542C>T) with total ALP within normal limits but bone-specific ALP of 4.4 μg/L (reference 5.3–19.5 μg/L). 6 This highlights that bone-specific ALP should be measured when clinical suspicion exists despite normal total ALP. 6

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Secondary Causes of Low ALP

Nutritional and Metabolic Disorders 3

• Malnutrition (protein-calorie deficiency)
• Zinc deficiency (zinc is a cofactor for ALP)
• Magnesium deficiency
• Vitamin C deficiency (scurvy)
• Vitamin B12 deficiency (pernicious anemia)

Endocrine Disorders 3

• Hypothyroidism
• Hypopituitarism

Medication-Induced 2, 7, 3

• Bisphosphonates (alendronate, risedronate, zoledronic acid)
• Denosumab
• These antiresorptive agents lower ALP by suppressing bone turnover, which may cause pyridoxal phosphate (PLP) to appear relatively elevated due to reduced enzymatic degradation. 7

Acute Critical Illness 3

• Severe acute injuries and critical illnesses can cause transiently low ALP as an epiphenomenon of systemic stress.

Wilson Disease (Acute Liver Failure Presentation) 1, 2

In acute liver failure, markedly subnormal ALP (typically <40 IU/L) is characteristic of Wilson disease, accompanied by:

• Coombs-negative hemolytic anemia
• Coagulopathy
• Relatively modest aminotransferase elevations (typically <2000 IU/L)
• Alkaline phosphatase-to-total bilirubin ratio <2.0 strongly suggests Wilson disease 1

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Diagnostic Algorithm for Low ALP

Step 1: Confirm Persistent Low ALP

• Repeat ALP measurement to confirm persistence (at least two measurements over 2 months). 5, 8
• Define low ALP as <30 IU/L (the threshold used in osteoporosis clinic screening). 5

Step 2: Exclude Secondary Causes 8, 3

• Comprehensive medication review: Identify bisphosphonates, denosumab, or other drugs affecting bone turnover. 2, 7
• Nutritional assessment: Screen for zinc, magnesium, vitamin C, and vitamin B12 deficiency.
• Thyroid function tests: Rule out hypothyroidism.
• Liver function tests: If acute liver failure is suspected, calculate ALP-to-bilirubin ratio to assess for Wilson disease. 1

Step 3: Measure ALP Substrates 4, 3

• Serum pyridoxal phosphate (vitamin B6): Elevated levels (above reference range) strongly suggest HPP and all such patients carry an ALPL mutation. 4
• Urine phosphoethanolamine (PEA): Elevated levels support enzyme deficiency.
• Serum calcium and phosphate: Mild elevations may be present.

Step 4: Bone-Specific ALP 6

• If total ALP is normal but clinical suspicion for HPP remains high (e.g., history of stress fractures, premature tooth loss, skeletal pain), measure bone-specific ALP. 6
• Low bone-specific ALP (<5.3 μg/L) warrants genetic testing even when total ALP is normal. 6

Step 5: Genetic Testing 6, 4, 3

• Sequence the ALPL gene to identify pathogenic variants.
• Missense mutations are most common (86% of cases), typically heterozygous. 4
• Six novel mutations were identified in a cohort of 42 adults, indicating ongoing discovery of new variants. 4
• A substantial proportion of patients with low ALP and elevated substrates show normal ALPL sequencing, suggesting unidentified mutations in regulatory regions, epigenetic changes, or abnormalities in other genes. 3

Step 6: Family Screening 8

• Evaluate first-degree relatives with ALP measurement and clinical history.
• If relatives have normal ALP but the proband has persistently low ALP with no secondary cause, genetic testing is appropriate to confirm asymptomatic adult HPP. 8

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Clinical Significance and Management Implications

Risk of Misdiagnosis

HPP may be misdiagnosed as osteoporosis, leading to inappropriate treatment with antiresorptive therapy (bisphosphonates or denosumab), which is relatively contraindicated in HPP because it further suppresses bone turnover in a condition already characterized by impaired mineralization. 5 Persistently low ALP in osteoporosis clinic attendees is easy to identify and signals the possibility of HPP. 5

Treatment Considerations

• Asfotase alfa (enzyme replacement therapy) is available for HPP and improves symptoms in confirmed cases. 6
• Avoid bisphosphonates and denosumab in patients with confirmed or suspected HPP. 5

Atypical Femoral Fractures

Low ALP occurs in 9% of patients with atypical femoral fractures, a complication associated with both HPP and long-term bisphosphonate use. 5 Screen all patients with atypical fractures for low ALP and consider HPP in the differential diagnosis. 5

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Key Pitfalls to Avoid

• Do not dismiss low ALP as clinically insignificant: Even mild reductions may reflect enzyme deficiency with substrate accumulation and predispose to defects in calcified tissues. 4
• Do not rely solely on total ALP: Measure bone-specific ALP when clinical suspicion exists despite normal total ALP. 6
• Do not overlook medication history: Bisphosphonates and denosumab lower ALP and may mask or mimic HPP. 2, 7
• Do not assume normal genetics exclude HPP: Approximately 50% of patients with low ALP and elevated substrates have normal ALPL sequencing, suggesting unidentified genetic or epigenetic mechanisms. 3
• Do not prescribe antiresorptive therapy without checking ALP: Misdiagnosis of HPP as osteoporosis leads to inappropriate treatment that worsens bone mineralization. 5