2026-06-16 | Experiences with the use of asfotase alfa in three patients with childhood-onset hypophosphatasia.

Hypophosphatasia (HPP) is a rare inherited metabolic disorder characterized by deficient activity of serum alkaline phosphatase due to loss-of-function mutations in the ALPL gene. Diagnosis confirmation, management, and follow-up of HPP are challenging, and clinical guidance is scant due to the difficulty in gathering high-level evidence. Asfotase alfa is the first long-term enzyme replacement therapy indicated in patients with pediatric-onset HPP to treat the bone manifestations of the disease. In the absence of large clinical studies, sharing clinical observations is an important source of information and support for clinicians. This article presents three case studies. A woman affected by HPP with manifestations of the disease at pediatric age began asfotase alfa therapy at the age of 43 years, resulting in improvements in bone density and epilepsy management. A man diagnosed with HPP in childhood had a severely compromised quality of life. He experienced improvements in bone fragility, respiratory function, sleep quality, and physical function with asfotase alfa therapy. Finally, a woman with infantile-onset HPP, presenting with severe bone deformity, musculoskeletal pain, pseudofractures, and cardiovascular and neurological involvement, showed radiological and clinical improvements in bone health, reduced pain, and increased walking autonomy during asfotase alfa treatment. Delayed diagnosis of HPP is common and can cause morbidity. Asfotase alfa significantly improves clinical outcomes in childhood-onset HPP, even when initiated in adulthood. Asfotase alfa therapy provides benefits beyond bone health. Monitoring treatment response requires a comprehensive clinical evaluation beyond DXA measurements. Real-world clinical experience is crucial for optimizing treatment strategies for HPP.

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2026-05-15 | Effects of comorbid chronic kidney disease on late-onset hypophosphatasia mice under treatment with asfotase alfa.

Hypophosphatasia (HPP) is a rare bone disorder caused by loss-of-function mutations in the ALPL gene, leading to deficient tissue-nonspecific alkaline phosphatase (TNAP) activity and impaired skeletal/dental mineralization. Asfotase alfa (AA), the only FDA-approved therapy, improves survival and skeletal/dental mineralization. Because of its mineral-binding properties, AA also binds to sites of ectopic calcification, including vasculature. Overexpression of TNAP in either the vascular media or intima has been shown to induce severe calcification. Here, we examined what might occur if a disease that features medial artery calcification, such as CKD-mineral and bone disorder (CKD-MBD), were to develop in a subject with HPP undergoing AA treatment. Two-month-old AlplPrx1/- (HPP) or Alplflox/- (non-HPP control) mice were treated with s.c. AA injections (8.2 mg/kg, 3×/week) for 4 mo. After 3 mo of treatment, CKD was induced via a 0.2% adenine and 1.8% phosphorus diet. Mice were euthanized at 6 mo of age, and skeletal, renal, cardiac, and vascular tissues were analyzed. Alkaline phosphatase levels slightly increased with AA but significantly increased after inducing CKD in control and HPP female mice. In males, ALP activity was elevated in the AA and AA+CKD cohorts. Micro-CT analysis showed improved bone parameters in HPP under AA treatment. However, the improvements were dampened when CKD was induced, compared to non-CKD Alplflox/- . Immunohistochemistry of the kidney revealed increased TNAP immunolocalization in the AA+CKD cohort, in both females and males. Ectopic renal and vascular calcification was observed in the AA+CKD group. Gene expression profiling in the kidney revealed that AA treatment modulates the immune and mineral metabolism pathways, while CKD superimposition induces a shift toward pro-inflammatory and pro-fibrotic responses, compromising renal and skeletal homeostasis. These findings underscore the importance of carefully evaluating HPP patients under treatment with mineral-targeted TNAP at risk of developing comorbid conditions associated with ectopic calcification.

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2026-04-25 | Successful treatment using asfotase alfa for delayed healing of a metatarsal stress fracture in an adolescent girl with hypophosphatasia.

Hypophosphatasia (HPP) is a rare metabolic bone disorder that can present with a wide spectrum of skeletal and extraskeletal signs and symptoms. Biochemically, HPP is characterized by a decreased activity of the tissue nonspecific alkaline phosphatase (TNSALP) and subsequent accumulation of inorganic pyrophosphate (PPi). Fractures in patients with HPP can show delayed healing or even progress to nonunion. In pediatric patients, fractures can be particularly debilitating, as children usually engage in high levels of physical activity. The 16-year-old girl, carrying a pathogenic variant in the ALPL gene, presented 17 weeks (4 months) after the initial diagnosis of a fracture at the base of the fifth metatarsal (MT-V). The patient was still symptomatic, and magnetic resonance imaging and cone beam computed tomography (CBCT) showed no radiological signs of healing despite immobilization. Given the prolonged absence of fracture consolidation, TNSALP enzyme replacement therapy with asfotase alfa (AA) was initiated and dosed according to body weight, in line with approved pediatric regimens. Thirteen weeks after initiation of AA, CBCT demonstrated full radiological consolidation. Furthermore, bone mineral density (BMD) in the fracture gap increased by 36%, returning to the average BMD level of the MT-V. Here we present, to the best of our knowledge, the first pediatric case in which treatment with AA supported healing of a delayed union stress fracture in the context of clinically diagnosed and genetically supported HPP. Our findings support considering AA initiation in pediatric patients diagnosed with HPP who present delayed fracture healing despite standard conservative management.

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