MON-785 - Beyond Guidelines: Osteoporosis Management in Adult-Onset Hypophosphatasia

Introduction:
Hypophosphatasia (HPP) is a rare inherited metabolic bone disorder caused by loss-of-function mutations in the ALPL gene, resulting in deficient activity of tissue-nonspecific alkaline phosphatase (TNSALP) and impaired skeletal and dental mineralization. HPP and osteoporosis can coexist, posing diagnostic and therapeutic challenges, as dual-energy X-ray absorptiometry (DEXA) may not accurately reflect bone quality in HPP and bone mineral density can be normal despite increased fracture risk. Evidence guiding osteoporosis management in adults with HPP remains limited.

Case:
A 47-year-old woman was referred for evaluation of osteoporosis. DEXA demonstrated T-scores of −2.7 at the left hip and −2.6 at the lumbar spine (normal > −2.5). Her history was notable for a tibial plateau fracture at age 35 following a low-impact fall and chronic bilateral foot pain from recurrent metatarsal stress fractures. Family history was significant for osteoporosis in her mother; her three children had no history of fractures or premature tooth loss.

She had previously been treated with alendronate for three years, completed eight years prior to her current presentation and later received two doses of denosumab. Review of records revealed persistently low alkaline phosphatase levels ranging from 17–39 U/L (reference 38–126 U/L), including a value of 28 U/L documented two months prior to the first dose of denosumab. Vitamin B6 levels were markedly elevated, ranging from 150–190 μg/L (reference 3.4–65.2 μg/L). She was not receiving other osteoporosis therapies and reported only vitamin D supplementation (5,000 IU weekly). Genetic testing identified an autosomal recessive ALPL mutation, confirming adult-onset HPP. Denosumab was discontinued due to concern for worsening bone mineralization in HPP. Given limited therapeutic options, further management is yet to be determined.

Discussion:
HPP encompasses a broad clinical spectrum ranging from severe perinatal disease to milder adult-onset forms and may follow autosomal recessive or dominant inheritance patterns. Persistently low serum alkaline phosphatase and accumulation of TNSALP substrates are key biochemical hallmarks. Asfotase alfa, a recombinant TNSALP enzyme, is approved for pediatric HPP and has demonstrated improvements in fracture healing, pain, and functional outcomes in adults; however, clinical trials have not shown substantial improvements in bone mineral density. Osteoporosis management in HPP is particularly challenging, as bisphosphonates and denosumab may further impair bone mineralization. Limited case reports suggest potential benefits of teriparatide, though prospective trials are lacking. This case underscores the limitations of DEXA in assessing bone quality in HPP and highlights the need for individualized, mechanism-based osteoporosis management.

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