Persistently low serum alkaline phosphatase in adults: prevalence and clinical characteristics in a large tertiary care hospital.

backgroundAlkaline phosphatase (ALP) plays an essential role in skeletal mineralization and bone metabolism. While elevated ALP levels are commonly investigated in clinical practice, persistently low ALP values are often overlooked despite their potential association with hypophosphatasia (HPP), a rare metabolic bone disorder caused by pathogenic variants in the ALPL gene. This study aimed to determine the prevalence and clinical characteristics of adults with persistently low ALP in a large tertiary care hospital.

methodsWe conducted a retrospective review of adult patients who underwent serum ALP testing at King Abdulaziz Medical City, Riyadh, between January 2017 and December 2024. Patients with ≥ 2 ALP measurements < 40 IU/L separated by at least 30 days were identified. Secondary causes of low ALP were excluded through review of clinical history, laboratory data, and medication records. Demographic, clinical, biochemical, and imaging data were analyzed.

resultsAmong 243,362 adults with 928,403 ALP measurements, 7,307 patients (3.0%) had at least one ALP value < 40 IU/L. A total of 179 patients had ≥ 2 ALP measurements < 40 IU/L. After excluding 154 patients with secondary causes or incomplete data, 25 patients were identified with unexplained persistently low ALP (0.01% of the total tested population). The mean age was 52.2 years (range 18-92), and 68% were female. The mean nadir ALP was 30.2 IU/L. Musculoskeletal (MSK) symptoms (92%) and fatigue (79%) were the most common clinical manifestations, followed by dental abnormalities (50%), anxiety (33%), and depression (29%). Fractures were reported in 46% of patients, most commonly affecting the vertebrae, hips, and metatarsals. In subgroup analysis, patients with MSK symptoms had significantly lower nadir ALP levels (p = 0.021). Familial clustering of persistently low ALP was observed in 25% of patients. Notably, none of the reviewed electronic medical records documented recognition of persistently low ALP or consideration of hypophosphatasia.

conclusionPersistently low ALP is uncommon but clinically relevant. Many affected patients demonstrated clinical features compatible with possible adult hypophosphatasia, and familial clustering suggests a possible genetic contribution. Greater awareness of this biochemical finding may improve recognition of potential HPP, prevent inappropriate antiresorptive therapy, and facilitate earlier diagnostic evaluation, including biochemical and genetic testing.