Persistently Low Alkaline Phosphatase in Fibromyalgia: Hypophosphatasia or Confounding Clinical Context?

Dear Editor,

I read with great interest the article by Rodríguez-Araya et al. [1] entitled “The Challenge of Hypophosphatasia Diagnosis in Patients with Fibromyalgia,” recently published in Medical Principles and Practice. The authors should be commended for systematically evaluating persistently low alkaline phosphatase (ALP) levels in a large cohort of patients with fibromyalgia (FM) and for highlighting the diagnostic challenges of mild adult hypophosphatasia (HPP) in this complex clinical setting. Drawing attention to rare metabolic bone diseases in patients presenting with chronic widespread pain is both timely and clinically relevant.

The finding that 3.2% of patients with fibromyalgia exhibited persistently low ALP levels, while none carried pathogenic or likely pathogenic variants in the ALPL gene, which encodes the tissue-nonspecific ALP, strongly supports the notion that low ALP values alone are insufficient for diagnosing HPP. This is particularly important in patient populations such as FM, where comorbid conditions, long-term medication use, and lifestyle-related factors are highly prevalent. Reliance on isolated laboratory abnormalities in such settings risks diagnostic oversimplification and potential misclassification.

As demonstrated in the study, several secondary conditions, including thyroid disorders, autoimmune diseases, glucocorticoid exposure, nutritional status, and dietary supplement use, may substantially influence ALP measurements and ALP substrate levels. These factors are common among patients with FM and may confound biochemical interpretation if not systematically addressed. The authors’ careful exclusion of secondary causes represents a major strength of the study and underscores the importance of comprehensive clinical assessment.

Another noteworthy observation is that approximately one-third of patients with persistently low ALP showed elevated pyridoxal-5′-phosphate (PLP) levels in the absence of genetic confirmation of HPP. While PLP elevation is traditionally considered supportive of HPP, its interpretation requires particular caution in FM populations. The widespread use of multivitamins and dietary supplements among patients with chronic pain syndromes may lead to spurious PLP elevations, thereby increasing the risk of false-positive biochemical profiles suggestive of HPP. Systematic documentation of supplement intake and, when feasible, temporary discontinuation prior to biochemical testing appear essential to improve diagnostic specificity.

The study also highlights the delicate balance between avoiding missed diagnoses of rare conditions and preventing overdiagnosis in patients with chronic pain syndromes. Although routine ALP screening in FM may be reasonable in selected clinical contexts, the present findings argue against reflexive escalation to genetic testing based solely on persistently low ALP or isolated substrate abnormalities. Instead, a stepwise diagnostic strategy integrating clinical features, exclusion of secondary causes, cautious interpretation of ALP substrates, and judicious use of genetic testing seems most appropriate.

In conclusion, this well-conducted study provides compelling evidence that persistently low ALP levels in patients with FM more often reflect a complex clinical and biochemical context rather than true HPP. The authors’ emphasis on a measured, multidisciplinary approach offers valuable guidance for improving diagnostic accuracy and avoiding unnecessary investigations in this challenging patient population.

Statement of Ethics

This letter is based on a previously published article and does not involve new studies with human participants or animals performed by the author.

Conflict of Interest Statement

The author declares no conflict of interest.

Funding Sources

This work did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Author Contributions

Halil Harman conceived the letter, critically reviewed the published article, drafted and revised the manuscript, and approved the final version.

Funding Statement

This work did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Data Availability Statement

No new data were generated or analyzed in this letter.