SUN-729 Delayed Diagnosis of Hypophosphatasia in a 91-year-old: An Opportunity to Improve Screening

Abstract Disclosure: J.A. Aurora: None. G. Alvarez: None. L. Ceglia: None. Background: Hypophosphatasia (HPP) is a rare, inherited bone mineralization disease caused by loss-of-function mutations in the ALPL gene encoding tissue nonspecific alkaline phosphatase enzyme, which results in an accumulation of alkaline phosphate (ALP) substrate - inorganic pyrophosphate, pyridoxal-5’-phosphate, and phosphoethanalomine. Due to the heterogeneity in ALPL gene mutations, clinical manifestations of HPP in children and adults can be variable, often leading to missed or delayed diagnosis and significant disease burden. We present a case of the oldest known patient with a delayed diagnosis of HPP. Clinical Case: A 91-year-old Asian male with degenerative joint disease, spinal stenosis, dental carries, sensorineural hearing loss, and depression presented with longstanding low bone mineral density (BMD) by dual-energy x-ray absorptiometry (DXA) but no fracture history. In 2024, his lowest BMD T-score was -2.6 at the left femoral neck. His low BMD had been treated with six 5-mg doses of zoledronate (ZOL) from 2010 to 2023 and alendronate prior to 2010. Of note, he reported no exacerbation of his musculoskeletal disease following repeated ZOL infusions. Biochemical testing revealed chronically low serum ALP ranging from 17-32 U/L (reference range [RR] 30-130 U/L), low bone specific-ALP level of 3 mcg/L (RR 7.6-14.9 mcg/L), low osteocalcin level of 6 ng/mL (RR 9-38 ng/mL), low P1NP level of 26 mcg/L (RR 30-110 mcg/L), intact PTH level of 43.6 pg/mL (RR 15-65 pg/mL), serum calcium level of 9.2 mg/dL (RR 8.5-10.5 mg/dL), serum phosphate level of 3.7 md/dL (RR 2.4-4.9 mg/dL), serum 25-OH vitamin D level of 39 ng/mL (RR 20-100 ng/mL), serum TSH level of 1.09 uIU/mL (RR 0.27-4.94 uIU/mL), serum morning cortisol level of 10.4 mcg/dL (RR 3.7-22.4 mcg/dL), and high serum vitamin B6 level of 176 mcg/L (RR 3.4-65.2 mcg/L). Subsequent genetic testing confirmed a pathogenic ALPL variant (exons 3-6). Additional ZOL was held and he was evaluated for asfotase alfa. Conclusion: HPP may be overlooked particularly in older adults with low BMD and low ALP on long-term bisphosphonate therapy as illustrated in this case. Our patient’s low ALP level was presumed secondary to longstanding suppression of bone turnover from many years of bisphosphonate exposure. Although bisphosphonates can increase risk of atypical femur fractures in HPP, our patient had no such complications. However, his dental, musculoskeletal, and neurological problems prompted workup for HPP. The importance in identifying HPP can prevent adverse sequelae from contraindicated bone therapies and allow for improved management of HPP bone disease and its non-skeletal manifestations. Opportunities to improve HPP screening may include provider education, electronic medical record alerts, and accessible genetic testing. Presentation: Sunday, July 13, 2025