Adult hypophosphatasia

Adult hypophosphatasia (adult HPP) is a rare inherited metabolic bone disease caused by loss-of-function mutations in the ALPL gene, which encodes tissue-nonspecific alkaline phosphatase (TNSALP). This enzyme plays a critical role in bone and tooth mineralization. In adult hypophosphatasia, reduced TNSALP activity leads to accumulation of its natural substrates, including inorganic pyrophosphate (PPi) and pyridoxal 5'-phosphate (PLP), resulting in impaired mineralization of bones and teeth. The condition typically manifests in middle adulthood, though patients may report a history of early loss of deciduous teeth or rickets-like symptoms in childhood. Key clinical features include recurrent metatarsal stress fractures, poorly healing fractures, osteomalacia, musculoskeletal pain, and premature loss of adult teeth (often with intact roots). Patients may also experience chondrocalcinosis, pseudogout-like arthropathy, and significant muscle weakness or fatigue. Laboratory findings characteristically show low serum alkaline phosphatase activity, elevated serum PLP (vitamin B6), and elevated urinary phosphoethanolamine. Bone mineral density testing may show osteopenia or osteoporosis, and the condition is sometimes misdiagnosed as osteoporosis, leading to inappropriate treatment with bisphosphonates, which can worsen the disease. The treatment landscape has been transformed by the availability of asfotase alfa (Strensiq), an enzyme replacement therapy approved for the treatment of hypophosphatasia. This bone-targeted recombinant TNSALP helps restore mineralization and has shown clinical benefit in improving skeletal outcomes and reducing pain. Supportive management includes appropriate pain control, dental care, physical therapy, and avoidance of bisphosphonates. Teriparatide (parathyroid hormone analog) has also been used off-label in some adult patients with fracture healing difficulties, with variable results.

Data sourced from FDA regulatory filings and ClinicalTrials.gov. Updated periodically.

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