Hypophosphatasia (HPP) is a rare genetic disease, which leads to poor mineralization of bones and also affects other body systems. HPP may first emerge at any age, presenting in infancy, childhood or adulthood. HPP is associated with a range of complications including infantile rickets (e.g., growth failure, bowed legs), fractures, dental caries (e.g., cavities), bone pain, muscle weakness, and seizures that respond to vitamin B6. HPP is caused by a form of the ALPL gene, which disrupts a chemical called alkaline phosphatase present in the bones, liver and kidneys. Although HPP has been studied in the UK previously, relatively few studies have looked at the population level to understand the overall extent of HPP across the UK, or the characteristics of the patient population living with HPP.
This study aims to provide an updated estimate of the extent (prevalence) of HPP in the UK, overall and by adult versus childhood forms. This will enable a more detailed understanding of HPP and its impact in the UK. This is expected to confer a public health benefit by establishing an up-to-date overview of the disease burden of HPP overall and by age in the UK; this may help to increase rates of HPP detection and treatment.
Hypophosphatasia (HPP) is a rare heritable metabolic disease affecting the musculoskeletal system and tooth mineralisation. HPP is caused by low activity of tissue-nonspecific alkaline phosphatase, arising from pathogenic mutations of the ALPL gene. Clinical presentation typically includes rickets (in infants and children), dental caries and premature tooth loss, osteomalacia with fractures and pseudofractures, pain, myopathy and ambulatory challenges. There is a lack of current, large-scale studies of the epidemiology of HPP in the UK. The aim of this study is to provide an updated estimate of the prevalence of HPP in the UK, overall and by adult/paediatric forms. The study population will be primary care patients within the UK, with a HPP diagnosis recorded during the period January 1st 2000 to December 31st 2022. This is an observational, cross-sectional study using data collected from primary care, via patient encounters with their GP. Data sources for the study will be CPRD Gold and CPRD Aurum – linked with ONS mortality records. Descriptive analyses will be applied to understand the comorbidities, procedures, treatments and mortality associated with the study population; no inferential testing or statistical modelling will be performed. Descriptive analyses will include: estimation of prevalence proportions; mortality rates; and summaries of the frequencies (i.e., Ns, %) of comorbidities, procedures and treatments within the period of prevalence estimation (2018-2022). The intended public health benefit of the study will be to help better understand the HPP burden in the UK. This may be of benefit in the development of better patient identification and diagnosis strategies, together with improving HPP clinical management and disease outcomes.
Prevalence:
Prevalence proportions will be calculated with respect to the CPRD reference population, expressed per 100,000 of population. Prevalence will be calculated and reported as annual period prevalence per year of the prevalence period (2018-2022), and as 5-year period prevalence (i.e., across the entire period, 2018-2022). Prevalence will be reported for the full HPP patient population, and stratified by age (paediatric/adult) and sex.
Comorbidities:
Comorbidities will be summarized as conditions present in the prevalence period (2018-2022) in those patients captured in the prevalence period cohort (2018-2022); in addition, for prevalent patients in the year 2022, comorbidities will be reported as conditions occurring within that year. Comorbidities will be reported separately for the prevalence period and the year 2022 as: i) the top 10 most frequent comorbidities across patients (based on unique patient counts), stratified by age (paediatric/adult); ii) the frequencies of HPP-specific signs and symptoms, stratified by age (paediatric/adult); iii) the frequencies of mood and sleep disorders, stratified by age (paediatric/adult).
Mortality:
Mortality rates associated with HPP will be calculated with respect to the HPP patient population, expressed per 100,000 of population. Mortality rates will be calculated and reported as annual period mortality per year of the prevalence period, and as 5-year mortality across the period 2018-2022. Mortality rates will be reported for the full HPP patient population, and stratified by age (paediatric/adult) and sex.
Procedures and referrals:
Procedures and referrals will be summarised as any occurring in the prevalence period (2018-2022), in those patients captured in the prevalence period cohort (2018-2022); in addition, for prevalent patients in the year 2022, procedures and referrals will be reported as conditions occurring within that year. Procedures will be reported as the top 10 across each period (ranked by unique patient counts), stratified by age (paediatric/adult); referrals will be reported separately in the same manner.
Treatments:
Treatments will be summarised as follows: i) any occurring within the prevalence period (2018-2022)/the year 2022, for those patients captured in the prevalence cohort (2018-2022)/prevalent in 2022; ii) any instance of key HPP-specific treatments (asfotase alfa), for those patients captured in the prevalence cohort (2018-2022)/the year 2022. Treatments will be reported separately for the prevalence period/the year 2022 as: i) the top 10 (ranked by unique patient counts), stratified by age (paediatric/adult); and ii) frequencies of asfotase alfa, stratified by age (paediatric/adult).
Shona Fang - Chief Investigator - Alexion Pharmaceuticals, Inc ( USA )
Luke McGuinness - Corresponding Applicant - Alexion Pharma International Operations Limited (Ireland)
Feifei Yang - Collaborator - Alexion Pharmaceuticals, Inc ( USA )
Luke McGuinness - Collaborator - Alexion Pharma International Operations Limited (Ireland)
ONS Death Registration Data