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A substantial minority of patients diagnosed with fibromyalgia at one medical center in Southern California had "consistently low" levels of alkaline phosphatase (ALP), researchers said, which could have accounted for their symptoms.

Among 611 presumed cases of fibromyalgia, 57 (9.3%) had three or more consecutive ALP measurements below the reference range's lower limit of 37 U/L, according to Christina Downey, MD, of Loma Linda University in California, and colleagues.

None of the 57 had undergone genomic analysis or other testing for hypophosphatasia (HPP), the clinical syndrome caused by ALP deficiency, suggesting that it had escaped clinicians' notice at the time, the researchers . But many of them probably did have the condition, as 25 had a history of fractures despite a relatively young age (averaging 52 years old).

What makes the finding of probable HPP important is that, besides decreased bone density, its symptoms include chronic muscle and joint pain like that seen in fibromyalgia. Moreover, ALP levels can be normalized easily with asfotase alfa (Strensiq), an enzyme replacement therapy.

"The availability of medical treatment for HPP is perhaps the most pressing reason to identify these patients correctly," Downey and colleagues wrote. "Due to the potential clinical consequences that stem from the misdiagnosis of HPP, we urge clinicians to consistently screen for HPP."

Specifically, they recommended serial ALP testing along with serum or urine measurements of vitamin B6 and phosphoethanolamine, which can confirm an HPP diagnosis. Low ALP can stem from other conditions such as malnutrition or hypothyroidism that must be ruled out.

Being aware of the possibility that HPP could mimic fibromyalgia in routine practice, Downey and colleagues checked records of patients diagnosed with fibromyalgia from 2015 to 2022 who also had ALP testing performed. Those with ALP above the normal range were excluded.

Of the 611 included in the study, 411 had ALP levels consistently within normal limits (group 1); 143 had one or more instances of below-normal ALP but without three in a row (group 2), which was the investigators' definition of consistent deficiency. Those with three consecutive below-normal readings were considered to have probable HPP (group 3).

In group 1, rates of bone disease and fractures were markedly lower than in the other groups: for example, just 11% had fracture histories, as compared with 33% in group 2 and 44% in group 3 (P<0.0001). Rates of osteoporosis followed a similar pattern. Also, half of group 3 had osteoarthritis, versus 37% of group 1 and 24% of group 2 (P=0.0017).

One thing to note about group 3, the investigators stressed, was that about one-quarter were taking bisphosphonates, which can depress ALP. "A limitation of this study is the inability to determine whether the low ALP levels in these 16 patients were present prior to the administration of bisphosphonates due to clinical documentation in the medical record and the research design. This is a significant clinical concern and should be investigated separately," Downey and colleagues wrote.

Other limitations included the small number of patients in group 3 and the retrospective study design that relied on patients' medical records.

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