What is Hypophosphatasia?

From the Guidelines

Hypophosphatasia should be managed with a comprehensive approach that includes enzyme replacement therapy, supportive care, and regular monitoring by a multidisciplinary team to improve outcomes and quality of life. This condition is characterized by defective mineralization of bones and teeth due to low activity of the enzyme alkaline phosphatase, resulting in skeletal abnormalities, fractures, and dental problems 1. The primary issue is a mutation in the ALPL gene, which leads to insufficient mineralization of bones. Symptoms vary widely but can include premature loss of teeth, bone pain, fractures, short stature, and in severe cases, respiratory complications in infants.

Diagnosis and Treatment

Diagnosis typically involves measuring alkaline phosphatase levels in the blood, which are abnormally low, along with elevated levels of phosphoethanolamine in urine and genetic testing. Treatment options have evolved with the approval of asfotase alfa (Strensiq), an enzyme replacement therapy that can significantly improve outcomes, especially when started early 1. Supportive care is also important, including pain management, physical therapy, dental care, and nutritional support.

Management Considerations

Genetic counseling is recommended for affected families due to the hereditary nature of the condition. Regular monitoring by a multidisciplinary team is essential to manage complications and adjust treatment as needed. In patients with X-linked hypophosphataemia, burosumab treatment may be considered in children with radiographic evidence of overt bone disease and disease that is refractory to conventional therapy, with a starting dose of 0.4mg/kg body weight given subcutaneously every 2 weeks 1.

Key Recommendations

• Enzyme replacement therapy with asfotase alfa should be considered to improve outcomes in patients with hypophosphatasia.
• Supportive care, including pain management, physical therapy, dental care, and nutritional support, is essential to manage symptoms and improve quality of life.
• Regular monitoring by a multidisciplinary team is crucial to manage complications and adjust treatment as needed.
• Genetic counseling is recommended for affected families due to the hereditary nature of the condition.

From the FDA Drug Label

The FDA drug label does not answer the question.

From the Research

Definition and Classification of Hypophosphatasia

• Hypophosphatasia (HPP) is a rare and under-recognised genetic defect in bone mineralisation 2
• HPP is classified into six forms according to the age of onset and severity: perinatal (lethal), perinatal benign, infantile, childhood, adult, and odontohypophosphatasia 3
• The causative gene of the disease is the ALPL gene that encodes tissue-nonspecific alkaline phosphatase (TNAP) 3

Symptoms and Diagnosis of Hypophosphatasia

• Patients with HPP may present with fragility fractures, rickets, or osteomalacia 2, 3
• Low serum alkaline phosphatase (ALP) and increased serum vitamin B6 level can signal the diagnosis of HPP 2
• Identification of a mutation in the ALPL gene is confirmatory for HPP 2, 3
• Symptoms of HPP can include non-traumatic and non-healing fractures, musculoskeletal pain, chondrocalcinosis, seizures, premature loss of fully rooted teeth, respiratory insufficiency, and calcinosis in muscles, kidneys, and joints 4

Treatment and Management of Hypophosphatasia

• Supportive treatment is important for HPP patients, including mechanical ventilation, accurate fracture treatment, physical therapy, dental monitoring, and follow-up care 4
• Enzyme replacement therapy with asfotase alfa has been approved for the treatment of HPP and can improve respiratory insufficiency, bone mineralization, and long-term survival 5, 4
• Physical therapy can play an important role in the management of HPP, particularly in infants and children, to improve functional independence and mobility 6
• Treatment with anabolic bone agents such as teriparatide has been reported, but further study is needed to determine its effectiveness in forming normally mineralized bone 2

Effectiveness and Safety of Asfotase Alfa

• Asfotase alfa has been shown to be effective and safe in treating people with HPP of different ages and levels of symptom severity 5
• Asfotase alfa can improve bone health, mobility, growth, and breathing ability, and relieve pain in patients with HPP 5
• The treatment is generally well-tolerated, with some patients experiencing mild reactions at injection sites 5