What is the management approach for a 33-year-old female with hypophosphatasia (low alkaline phosphatase (ALP) levels)?

Management of Low Alkaline Phosphatase in a 33-Year-Old Female

First, determine if this represents true hypophosphatasia by measuring bone-specific ALP (if total ALP is borderline), pyridoxal-5-phosphate (vitamin B6), and urine phosphoethanolamine, followed by ALPL genetic testing if these substrates are elevated. 1, 2

Initial Diagnostic Workup

Confirm the Diagnosis

• Measure ALP substrates to establish enzyme deficiency: pyridoxal-5-phosphate (PLP/vitamin B6), urine phosphoethanolamine (PEA), and inorganic pyrophosphate 1, 3
• Order bone-specific ALP if total ALP is in the low-normal range, as total ALP can miss hypophosphatasia 2
• Obtain ALPL gene sequencing if substrates are elevated; approximately 50% of adults with persistently low ALP carry pathogenic ALPL variants 3
• Elevated PLP (above reference range) is found in all mutation carriers and strongly supports the diagnosis 3

Rule Out Secondary Causes

Before attributing low ALP to hypophosphatasia, exclude 1:

• Nutritional deficiencies: zinc, magnesium, vitamin C, protein-calorie malnutrition
• Medications: bisphosphonates, denosumab, glucocorticoids
• Endocrine disorders: hypothyroidism, vitamin D excess
• Other conditions: celiac disease, pernicious anemia, Wilson disease

Clinical Assessment Specific to Hypophosphatasia

Document the following manifestations commonly seen in adult-onset hypophosphatasia 1, 3:

• Dental history: premature tooth loss (particularly before age 5), "gray gums" in childhood, current dental problems (present in 48% of mutation carriers vs 12% without mutations) 4, 3
• Musculoskeletal symptoms: chronic bone/joint pain, stress fractures, pseudofractures, non-union fractures, chondrocalcinosis, calcific periarthritis 1, 3
• Childhood history: rickets, delayed walking, bone deformities 4, 5
• Current functional status: fatigue, weakness, exercise intolerance 2

Management Based on Findings

If Hypophosphatasia is Confirmed (Genetic Testing Positive or High Clinical Suspicion with Elevated Substrates)

Initiate asfotase alfa (enzyme replacement therapy) for symptomatic patients with documented functional impairment, recurrent fractures, or significant musculoskeletal pain 2

Critical management considerations:

• Absolutely avoid bisphosphonates and denosumab - these antiresorptive agents can cause atypical fractures and impaired fracture healing in hypophosphatasia patients 5
• Stop any current antiresorptive therapy immediately if the patient is receiving one 5
• Monitor thiamine levels (red blood cell thiamine pyrophosphate), particularly if intestinal ALP isoenzyme is absent, as this can impair thiamine absorption 4

Monitoring Parameters

• Serum calcium and phosphate: mild hyperphosphatemia (9% of cases) and hypercalcemia (3% of cases) can occur 3
• Renal function: serum creatinine, as phosphate handling may be affected 3
• Bone-specific ALP and PLP levels: to track disease activity 2, 3
• Dental surveillance: twice-yearly dental examinations to prevent tooth loss 3

If No Mutation Found but Substrates Elevated

• Approximately 50% of adults with persistently low ALP and elevated substrates have no identifiable ALPL mutation on standard exon sequencing 1, 3
• These patients may have mutations in regulatory regions, epigenetic changes, or abnormalities in other genes 1
• Manage symptomatically and avoid antiresorptive therapy regardless of genetic results if clinical and biochemical features suggest hypophosphatasia 5

Common Pitfalls to Avoid

Recognition failure: Low ALP is documented in only 3% of discharge summaries despite being present in 0.13% of hospitalized patients 5. This is a severely underrecognized condition.

Normal total ALP does not exclude hypophosphatasia: Always check bone-specific ALP in symptomatic patients, as cases exist with normal total ALP but low bone-specific ALP 2

Inappropriate bisphosphonate use: Three patients in one study were receiving bisphosphonates despite low ALP, and two developed fractures while on treatment 5. This represents potentially harmful therapy.

Assuming benign course: While many adults have mild symptoms, 50% of mutation carriers have enzyme activity low enough to cause substrate accumulation and predispose to defects in calcified tissues 3