SAT-733 - Persistently Low Alkaline Phosphatase as an Overlooked Diagnostic Clue to Adult-Onset Hypophosphatasia: A Case Report

Background
Hypophosphatasia (HPP) is a rare inherited disorder of bone and mineral metabolism caused by pathogenic variants in the ALPL gene, resulting in deficient tissue-nonspecific alkaline phosphatase activity and impaired skeletal mineralization. While severe pediatric forms are well recognized, adult-onset HPP remains underdiagnosed due to heterogeneous clinical manifestations and frequent misinterpretation of persistently low alkaline phosphatase as clinically insignificant. Because delayed recognition may lead to inappropriate antiresorptive therapy and missed opportunities for individualized metabolic bone care, heightened awareness of subtle biochemical patterns is essential in endocrine practice.

Case Presentation
A 65-year-old postmenopausal woman was referred to endocrinology for evaluation of long-standing obesity and metabolic risk factors. Review of longitudinal laboratory data revealed persistently low serum alkaline phosphatase levels (25–30 U/L) documented over more than two years, which had not previously prompted further evaluation. Given this sustained biochemical abnormality, a targeted metabolic bone workup was initiated. Plasma pyridoxal-5-phosphate (vitamin B6) levels were markedly elevated, raising suspicion for hypophosphatasia. The patient reported chronic musculoskeletal pain and had a history of severe degenerative joint disease requiring bilateral shoulder arthroplasties but denied fragility fractures, nephrolithiasis, or dental abnormalities. Bone mineral density testing demonstrated osteopenia without osteoporosis, with fracture risk below treatment thresholds. Genetic testing subsequently identified a heterozygous pathogenic variant in the ALPL gene, confirming a diagnosis of adult-onset hypophosphatasia. Management focused on patient education, avoidance of contraindicated osteoporosis therapies, optimization of calcium and vitamin D intake, fracture risk assessment, and referral for genetic counseling.

Conclusion
This case highlights the importance of recognizing persistently low alkaline phosphatase levels in adult patients, rather than dismissing them as a benign laboratory finding. In this context, elevated vitamin B6 served as a key biochemical marker supporting the diagnosis of hypophosphatasia, even in the absence of hallmark features such as fractures or dental disease, which can be seen in adult-onset HPP. Recognizing this biochemical and clinical pattern is essential for accurate diagnosis, appropriate counseling, and avoidance of potentially harmful therapies, ultimately informing individualized long-term skeletal management.

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