The Challenge of Hypophosphatasia Diagnosis in Patients with Fibromyalgia

Recent reports suggest that mild forms of hypophosphatasia (HPP) may be misdiagnosed as fibromyalgia (FM), thus exposing patients to potential complications (e.g., fractures). It seems reasonable to determine alkaline phosphatase (ALP) levels in all patients diagnosed with FM. We aimed to study this clinical recommendation by assessing the prevalence of HPP in a cohort of patients diagnosed with FM in a specialized unit.

This retrospective study (2014-2021) included 713 patients with FM and previous determinations of ALP levels from a Multidisciplinary Fibromyalgia Unit of a Rheumatology Department. Medical records (ALP levels, history of fractures, radiologic studies, pharmacological treatment, and comorbidities) were reviewed. Patients with at least two ALP determinations under normal values were further evaluated with a study of bone metabolic parameters, ALP substrate [PLP: pyridoxal-5'-phosphate] and genetic testing for alkaline phosphatase, liver/bone/kidney (ALPL) pathogenic variants.

16 (3.2%) FM patients (all women with a median age of 50 years) showed low ALP levels. Notably, 5 patients (31.3%) also showed elevated PLP levels, suggesting HPP. However, none presented pathogenic ALPL variants in the genetic study. Other associated conditions, such as subclinical hypothyroidism and the use of dietary supplements/multivitamins, were observed in some of these patients.

In the present cohort, 3.2% presented persistently decreased ALP levels. The increased ALPL substrate, PLP, observed in one third of these subjects, together with the negative genetic study in all these subjects, indicate the need to better identify the subjects with FM that may have mild forms of HPP.