Hypophosphatasia (HPP) is a rare genetic disorder that impacts the development of bones and teeth. This condition disrupts mineralization, a process where minerals like calcium and phosphorus are deposited to form strong bones and teeth. HPP stems from a defect in the ALPL gene, which provides instructions for making an enzyme called tissue-nonspecific alkaline phosphatase (TNSALP). A shortage of functional TNSALP leads to the buildup of substances like inorganic pyrophosphate (PPi), hindering bone and tooth hardening. The severity of HPP varies widely, ranging from life-threatening forms at birth to milder manifestations appearing in adulthood.
Enzyme Replacement Therapy
Asfotase alfa, marketed as Strensiq, is an enzyme replacement therapy (ERT) that replaces the deficient TNSALP enzyme. It reduces levels of substances like inorganic pyrophosphate (PPi) and pyridoxal 5′-phosphate (PLP) that accumulate due to low TNSALP activity, promoting bone mineralization. Asfotase alfa is administered through subcutaneous injection, three times per week at a dosage of 2 mg/kg, or six times per week at 1 mg/kg. It is approved for patients with perinatal, infantile, and juvenile-onset HPP.
Clinical studies show that asfotase alfa improves outcomes for individuals with severe HPP. Patients with perinatal and infantile-onset HPP treated with asfotase alfa have demonstrated improved overall survival and ventilator-free survival, with 97% of treated patients alive at one year of age compared to 42% of historical controls. The therapy also leads to improvements in bone mineralization, reduced rickets, better respiratory function, and enhanced motor development. While well-tolerated, side effects include injection site reactions (redness, pain, swelling), serious allergic reactions (anaphylaxis), calcium buildup in the eyes or kidneys, and fat redistribution or skin changes at the injection site.
Symptomatic and Supportive Care
Beyond enzyme replacement therapy, symptomatic and supportive care manages HPP’s diverse manifestations. Pain management involves nonsteroidal anti-inflammatory drugs (NSAIDs) to alleviate bone and joint discomfort. Physical therapy also helps restore strength, improve flexibility, and enhance mobility. Therapists develop individualized plans to correct bone misalignments, manage fractures, and improve functioning. Occupational therapists can also assist with mobility skills and recommend adaptive devices.
Orthopedic interventions are necessary to address skeletal abnormalities and fractures. This includes bracing for deformities or surgery to repair broken bones or correct structural issues. Dental care is also important due to common premature tooth loss. Regular dental assessments and oral hygiene are important, and dentures may be recommended if permanent teeth cannot be preserved.
For severe infantile HPP, respiratory support like ventilation may be required due to compromised lung function. Nutritional considerations include vitamin B6 for infant seizures and careful management of calcium and phosphate intake to avoid high blood levels.
Treatment Strategies by HPP Type
Treatment approaches for HPP are tailored to the specific type and severity of the condition. Perinatal and infantile HPP, the most severe forms, present with significant skeletal hypomineralization and respiratory complications. These cases necessitate aggressive enzyme replacement therapy with asfotase alfa to improve survival and respiratory function, alongside respiratory support. Neonatal intensive care settings are necessary for these patients.
Childhood HPP manifests between 6 months and 18 years of age, with symptoms like skeletal deformities, short stature, and gait disturbances. Enzyme replacement therapy is indicated for these children to improve bone health and growth.
In addition to ERT, care focuses on orthopedic interventions for bone issues and dental care for premature tooth loss. For adult HPP and odontohypophosphatasia, with milder or primarily dental symptoms, supportive care is the main focus. This includes managing chronic musculoskeletal pain, recurrent fractures, and specialized dental care for premature tooth loss and dental caries. Enzyme replacement therapy may be considered for adults with a history of childhood involvement and severe manifestations like disabling pain, recurrent fractures, or impaired healing.
Monitoring Treatment and Long-Term Outlook
Monitoring the effectiveness of HPP treatment involves a comprehensive approach, including clinical evaluations, biochemical markers, and radiological imaging. Regular clinical assessments track growth, motor development, pain levels, and quality of life. A coordinated, multidisciplinary team, including specialists in orthopedics, endocrinology, pain management, and dentistry, is recommended for patient care.
Biochemical markers are regularly assessed, including alkaline phosphatase (ALP) levels, which are low in HPP, and other substances like inorganic pyrophosphate (PPi) and pyridoxal 5′-phosphate (PLP), which are elevated. Reductions in plasma PPi and PLP levels are observed with asfotase alfa treatment, indicating improved enzyme activity. Radiological imaging, like X-rays, assesses bone mineralization and monitors rickets healing, providing evidence of treatment response. The long-term outlook for individuals with HPP has improved significantly with treatments, especially enzyme replacement therapy. Many individuals achieve an improved quality of life with appropriate management, though ongoing and individualized care remains necessary to address the condition’s systemic nature.