What is the best course of treatment for a patient with Hypophosphatasia (HPP)?

Treatment of Hypophosphatasia (HPP)

For patients with Hypophosphatasia, enzyme replacement therapy with asfotase alfa is the primary treatment that directly addresses the underlying pathophysiology and improves morbidity and mortality, particularly in pediatric-onset disease. 1, 2

Critical Distinction: HPP vs. XLH

It is essential to recognize that Hypophosphatasia (HPP) is fundamentally different from X-linked hypophosphatemia (XLH)—the conditions have opposite therapeutic approaches despite both affecting bone mineralization. 3, 4

• HPP is caused by loss-of-function mutations in the ALPL gene, leading to deficient tissue-nonspecific alkaline phosphatase (TNSALP) activity 3, 4
• The pathophysiology involves accumulation of TNSALP substrates (inorganic pyrophosphate and phosphorylated osteopontin), which inhibit bone mineralization 4
• Low serum alkaline phosphatase is the hallmark of HPP, distinguishing it from other metabolic bone diseases 5

Primary Treatment: Asfotase Alfa

Asfotase alfa, a bone-targeted recombinant TNSALP enzyme, is the definitive causal therapy for HPP, approved by the FDA in 2015. 1, 5

Mechanism and Efficacy

• Asfotase alfa replaces the deficient TNSALP enzyme, directly addressing the underlying enzymatic defect 1
• The therapy improves respiratory insufficiency, bone mineralization, and long-term survival with a very good safety profile 1
• In adult HPP presenting with arthralgia, enzyme replacement therapy can reduce or eliminate joint pain attacks within one year of treatment 2

Indications

• Pediatric-onset hypophosphatasia (perinatal, infantile, and childhood forms) represents the primary indication 1
• Adult HPP with significant symptoms (recurrent fractures, severe bone pain, arthralgia, respiratory complications) should be considered for treatment 2

Supportive Care Measures

While asfotase alfa addresses the root cause, comprehensive supportive management remains essential for all HPP patients. 1

Specific Interventions

• Mechanical ventilation for patients with respiratory insufficiency 1
• Accurate fracture treatment with appropriate orthopedic management of non-traumatic and non-healing fractures 1
• Physical therapy to maintain mobility and muscle strength 1
• Dental monitoring and preventive care for premature tooth loss and delayed tooth development 1
• Pain management for musculoskeletal pain and arthralgia 1, 2

Critical Contraindications

Several commonly used bone therapies are absolutely contraindicated in HPP and can worsen outcomes—this is a critical pitfall to avoid. 4

Prohibited Medications

• Bisphosphonates are contraindicated in adults with HPP 4
• Denosumab is contraindicated 4
• Potent antiresorptive agents should be avoided 4
• Vitamin D supplementation is contraindicated in HPP patients 4

Rationale

These medications further suppress bone turnover in a condition where mineralization is already impaired, potentially worsening bone quality and fracture risk. 4

Diagnostic Confirmation Before Treatment

Definitive diagnosis should be established before initiating therapy, particularly given the high cost and lifelong nature of enzyme replacement. 4, 5

Diagnostic Criteria

• Low serum alkaline phosphatase (markedly reduced total ALP) is the biochemical hallmark 5
• Elevated pyridoxal-5-phosphate (PLP) and phosphoethanolamine (PEA) in serum/urine are sensitive and specific biomarkers 5, 2
• Elevated plasma inorganic pyrophosphate supports the diagnosis 2
• Genetic testing for ALPL mutations provides definitive confirmation 4, 5, 2
• Radiographic findings showing pathognomonic changes suggestive of HPP 5

Clinical Presentation Variability

HPP severity ranges from lethal perinatal forms to mild adult presentations, requiring tailored treatment intensity. 5

Severe Forms

• Perinatal lethal and infantile HPP are autosomal recessive with early onset and require immediate enzyme replacement therapy 1
• Respiratory insufficiency, seizures, and failure to thrive characterize severe disease 1, 5

Milder Forms

• Adult HPP may present solely with arthralgia without classic bone-related symptoms, making diagnosis challenging 2
• Recurrent non-traumatic fractures, chondrocalcinosis, and musculoskeletal pain are common adult manifestations 3, 1
• Odontohypophosphatasia has only dental manifestations with premature loss of fully rooted teeth 1, 5

Common Pitfalls to Avoid

• Misdiagnosis as rickets/osteomalacia leading to inappropriate vitamin D therapy 4
• Delayed diagnosis due to limited awareness of the condition 4
• Treatment with bisphosphonates or other antiresorptive agents before recognizing HPP 4
• Failure to recognize adult HPP in patients with isolated arthralgia and low ALP 2
• Not checking alkaline phosphatase levels in patients with unexplained bone or joint symptoms 5