Review identifies hypophosphatasia among patients with persistently low alkaline phosphatase

Hypophosphatasia (HPP) can be overlooked because its manifestations overlap with osteoporosis and rheumatic disorders. A systematic review in Osteoporosis International assessed HPP frequency among patients with persistently low alkaline phosphatase (ALP) and estimated population prevalence. Searches covering January 2015 through September 2025 identified 710 articles, of which 27 observational studies met inclusion criteria.

Among patients with persistently low ALP in studies meeting at least three of four predefined quality criteria, genetically confirmed HPP occurred in 10.4–26.2% of general clinical populations, 46.4–56.5% of rheumatology populations, and 57.1–87.5% of osteoporosis populations. Based on three general clinical population studies meeting all four criteria, the authors estimated overall HPP prevalence at 17.6–36.0 per 100,000 people. The higher percentages in selected populations should not be interpreted as general-population prevalence.

The findings support considering HPP in patients with persistently low ALP and characteristic features, including fractures, early tooth loss, or musculoskeletal symptoms, while excluding secondary causes of low ALP. Recognition matters because antiresorptive treatment for presumed osteoporosis may be inappropriate in HPP. Interpretation is limited by differences in clinical settings, ALP thresholds, and diagnostic assessments; the population estimate rests on only three studies. The review included English-language publications only, and its protocol was not registered.