Case · Presentation

Twelve years ago her ALP was 23. Nobody followed it up.

Antonia R is 62, post‑menopausal, with chronic joint and bone pain, difficulty walking any distance without resting, and fatigue that has worsened over the years. She denies fractures but reports a strong family history — her father and two siblings with similar symptoms. Depressive symptoms have worsened over recent months, which she attributes to her declining quality of life.

The history runs back to childhood: struggling with gym class and team sports because of bone and joint pain; premature loss of primary dentition followed by malalignment of the permanent teeth and extensive dental work as an adult; muscle weakness from adolescence dismissed as “growing pains”.

She was diagnosed with fibromyalgia at 54 after years of diffuse pain, and treatment has been largely ineffective. At 50, a routine wellness check found an alkaline phosphatase of 23 U/L. No further evaluation was conducted.

Weight · BMI

72 kg · 28.1

Fibromyalgia diagnosis

8 years

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Case · Workup

Everything comes back normal except two labs.

ALP is 18.0 U/L against an adult reference range of 30–120, and plasma pyridoxal 5’‑phosphate — vitamin B6 — is 250 nmol/L against 23–223. Calcium, phosphorus, magnesium, electrolytes, urea, creatinine and glucose are all within range.

Nothing else is abnormal. CRP 0.5 mg/dL and ESR 10 mm/h exclude an inflammatory or autoimmune picture; ANA is negative; thyroid function, parathyroid hormone and vitamin D are normal; the complete blood count is normal. The DXA scan is normal — lumbar spine T‑score +0.5, total hip +0.2, whole body +0.4 — with no osteopenia, and X‑rays of femur, tibia and spine are unremarkable.

The dental history is the clue that was always there: several primary teeth fell out spontaneously by the age of 4, with the roots intact.

Brief Pain Inventory

6 of 10

Health Assessment Q.

1.5 moderate disability

Go to the decision

Case · Decision

What is the diagnosis?

Twelve years of low ALP, a lifetime of symptoms, and a normal scan. Choose one.

• AHypophosphatasia (HPP)
• BFibromyalgia
• COsteoporosis
• DOsteomalacia
• EOsteogenesis imperfecta
• FPaget disease of bone

Lock in my answer Select a diagnosis to continue

Case · Verdict

Low ALP is the finding that rules the others out.

• AHypophosphatasia (HPP)CorrectPersistently low ALP activity, bone pain, elevated vitamin B6 and early loss of primary teeth are hallmark characteristics (Michigami T et al., 2020; Khan AA et al., 2024; Rush ET et al., 2024).
• BFibromyalgiaRuled outUnlikely given the lack of response to standard treatment including duloxetine over several years. The low ALP, high vitamin B6 and early tooth loss point to a metabolic bone disorder rather than a central pain syndrome (Kia S and Choy E et al., 2017; Michigami T et al., 2020).
• COsteoporosisRuled outUnlikely given the normal DXA scan and normal X‑ray findings (Porter JL et al., 2025).
• DOsteomalaciaRuled outRuled out on normal vitamin D of 35 ng/mL, with no pseudofractures or other characteristic radiographic findings (Gentile C and Chiarelli F et al., 2021; Michigami T et al., 2020).
• EOsteogenesis imperfectaRuled outUnlikely on history, imaging and laboratory results: no hearing loss and no family history of OI‑specific features (Biggin A and Munns CF et al., 2014).
• FPaget disease of boneRuled outTypically involves elevated ALP, which contrasts with this patient's significantly and persistently low ALP activity (Bouchette P, Boktor SW et al., 2024).

See what confirms it

Case · Evidence

Persistently low ALP is a red flag.

The genetic test eventually returned positive: c.571G>A p.(E191K), a pathogenic variant confirming an ALPL gene mutation and supporting the diagnosis.

• 01ALP is not incidental. It plays a critical role in bone mineralization, and persistently low levels may result in impaired bone metabolism — skeletal abnormalities, fractures, muscle weakness. Low ALP warrants further investigation (Cheng X and Zhao C et al., 2023; Michigami T et al., 2020).
• 02Compare against age and sex. Low serum ALP is an important finding, but it must be read against reference values for age and sex (Michigami T et al., 2020).
• 03Measure it more than once. ALP can occasionally normalize in a patient with a metabolic bone disorder through transient physiological change. Measure over time — for example 30 days apart (Lowe D et al., 2023).
• 04No biopsy needed. A bone biopsy is unwarranted at this stage: clinical history, biochemical markers, imaging and ALPL genetic testing typically give enough to guide the diagnosis (Michigami T et al., 2020).

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