Prevalence of hypophosphatasia in general and selected patient populations: a systematic review

Hypophosphatasia (HPP) has diverse manifestations overlapping other skeletal and rheumatic disorders. This systematic review assessed frequency of HPP in select and general clinical populations with persistently low alkaline phosphatase (ALP) activity. Undiagnosed HPP was frequently identified. Clinicians should consider HPP for patients with persistently low ALP and hallmark manifestations.

Diagnosis of hypophosphatasia (HPP) can be missed owing to its rare disease status and heterogeneous manifestations that can overlap with other skeletal or rheumatic disorders. The objective of this systematic review was to assess the frequency of HPP among patients with persistently low alkaline phosphatase (ALP) activity and determine overall HPP prevalence in the general population.

English language articles published from January 1, 2015, to September 29, 2025, were identified in PubMed and Embase and through manual searching. Observational studies conducted in patients of any age from general and select clinical populations (e.g., rheumatology, endocrinology) were included if the frequency of HPP or potential HPP was reported or could be enumerated from results. Risk of bias was assessed based on 4 predefined criteria. HPP prevalence was determined from general clinical population studies with the lowest risk of bias.

A total of 710 articles were retrieved; 27 met the inclusion criteria. The frequency of genetically confirmed HPP among patients with persistently low ALP activity in studies with low risk of bias (≥3 predefined criteria) was 10.4-26.2% in general clinical populations, 46.4-56.5% in rheumatology populations, and 57.1-87.5% in osteoporosis populations. The total prevalence of HPP in the general population may be 17.6-36.0 per 100,000 population based on 3 studies meeting all 4 criteria.

Undiagnosed patients with HPP were frequently identified in studies of ALP screening, highlighting the importance of screening. Clinicians should consider a diagnosis of HPP for patients with persistently low ALP and hallmark manifestations.