Hypophosphatasia in 2026: Clinical reality, research progress, and future directions of a rare disease

Questions

1. Where does hypophosphatasia stand today in terms of recognition, clinical burden, and key challenges in diagnosis and management? (0:20)
2. How would you characterize the current treatment landscape, and what unmet needs still persist? (1:18)
3. What recent data or research developments are shaping our understanding of hypophosphatasia? (2:12)
4. What emerging therapeutic approaches or strategies show the most promise? (3:05)
5. What do you see as the key priorities for advancing care in hypophosphatasia? (3:45)

Transcript

Where does hypophosphatasia stand today in terms of recognition, clinical burden, and key challenges in diagnosis and management?

Hypophosphatasia or HPP is a rare, inherited metabolic disease that remains underdiagnosed, particularly in adults. While awareness has improved over the past decade, many patients still experience significant diagnostic delays due to its heterogeneous presentation and overlap with more common conditions, such as osteoporosis or osteomalacia.

The clinical burden is substantial, including chronic musculoskeletal pain, fractures, impaired mobility, and reduced quality of life. One of the key challenges is recognizing persistently low alkaline phosphate as a diagnostic clue, as well as differentiating HPP from other causes of low bone density. Early diagnosis remains critical to avoid inappropriate treatment and optimize patient outcomes.

How would you characterize the current treatment landscape, and what unmet needs still persist?

The treatment landscape has evolved significantly with the availability of enzyme replacement therapy with asfotase alfa, which has transformed outcomes in paediatric onset and more severe forms of the disease. However, management in adults remains more complex and less well defined.

There are still important unmet needs, especially clear guidance for milder and adult-onset cases, better ways to monitor disease activity and improved access to treatment. This is particularly relevant in Latin America, where access to specialized diagnostic and targeted therapies is still limited. Supportive multidisciplinary management like pain control, fracture prevention, physiotherapy, counselling and psychological support also remains essential.

What recent data or research developments are shaping our understanding of hypophosphatasia?

Recent research has focussed on improving our understanding of the clinical spectrum of HPP, particularly in adults, where the disease may present with subtle or non-specific features.

There is growing recognition of the burden of the disease, even in so-called milder phenotypes. Advances in genotype-phenotype correlations and real-world registry data are also helping to better define prognosis and guide management decisions.

Additionally, there is increasing awareness of the risks associated with misdiagnosis, particularly the use of anti-resorptive therapies, such as bisphosphonates, in patients with unrecognized HPP. American research is also exploring new therapeutic approaches that may further expand future treatment options.

What emerging therapeutic approaches or strategies show the most promise?

The most promising emerging therapeutic approaches in hypophosphatasia include next generation and replacement therapy with efzimfotase alfa and ilofotase alfa. Also therapy with mesenchymal stem cells with high osteogenic potential, engineered B cell therapy, and gene therapy using adeno-associated virus serotype 8 vector to enable sustained production of the missing tissue, non-specific alkaline phosphatase enzyme.

While many of these strategies are still in the early stages of development, they hold promising for expanding therapeutic options.

What do you see as the key priorities for advancing care in hypophosphatasia?

The main priorities include increasing awareness among clinicians, particularly regarding the importance of low alkaline phosphate as a diagnostic clue that should guide the clinician to perform a more comprehensive biochemical panel and reducing diagnostic delays. Of course, there’s also a need for clear clinical strategies, especially for other patients, as well as better integration of multidisciplinary care.

Expanding access to diagnostic tools and effective therapies globally is essential. Ultimately, improving early recognition and delivering more personal management strategies will be key to advancing care in HPP.