Characteristics of Hypophosphatasia in Adult Patients in Rheumatology

Recruiting

• Conditions: Hypophosphatasia
• Interventions: Diagnostic Test: Second alkaline phosphatase measurement; Diagnostic Test: Extended laboratory diagnostics; Diagnostic Test: Symptom and clinical findings checklist for hypophosphatasia; Diagnostic Test: SF-36; Diagnostic Test: Short physical performance battery (SPPB) score; Diagnostic Test: Physical examination; Diagnostic Test: Bioelectrical Impedance Analysis; Diagnostic Test: Recording of vital signs; Diagnostic Test: Genetic testing of the alkaline phosphatase gene

• Registration Number: NCT06161142
• Lead Sponsor: University of Bonn

Brief Summary

With hypophosphatasia still being frequently overlooked and misdiagnosed, the primary aim of this prospective observational study is to determine the prevalence of hypophosphatasia in adult patients in rheumatology, and beyond that to establish an algorithm that promotes early hypophosphatasia detection in clinical practice.

Detailed Description

Hypophosphatasia (HPP) is a rare genetic disorder (1-3/300,000 severe cases in Europe) caused by one or more mutations in the alkaline phosphatase (ALP) gene. Hypomineralization results in symptoms such as arthralgias, insufficiency fractures, and poor dental status beginning in childhood. A fatal outcome is conceivable in circumstances of early infancy first presentation. In consistency with the musculoskeletal complaint pattern, HPP is far more common in the rheumatology patient population than in the general population.

However, HPP is still frequently misdiagnosed as some other form of bone disease (e.g., rickets, osteomalacia, or osteoporosis). Therefore, implementation of a clinically applicable algorithm for early hypophosphatasia detection is needed.

The primary aim of this prospective observational study is to determine the prevalence of hypophosphatasia in adult patients in rheumatology. Moreover, a further goal is to establish an algorithm that reliably separates adult HPP patients from other, rheumatologic and bone diseases.

Study Timeline

• Study Start: 2023-02-28
• Study First Submitted: 2023-07-03
• Status Verified: 2023-12
• Study First Submitted QC: 2023-12-05
• Last Update Submitted: 2023-12-05
• Study First Posted: 2023-12-07
• Last Update Posted: 2023-12-07
• Primary Completion: 2024-12-01
• Study Completion: 2024-12-01

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 60

Inclusion Criteria

• Written Informed consent
• Age > 18 years
• Clinical suspicion of hypophosphatasia
• Evidence of a pathological ALP value within the clinical routine screening

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Exclusion Criteria

• Failure to meet the inclusion criteria listed above

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Study & Design

• Study Type: OBSERVATIONAL
• Study Design: Not specified

Arm && Interventions

Group	Intervention	Description
Persistant hypophosphatasemia	SF-36	Patients with persistant hypophosphatasemia are highly suspicious for hypophosphatasia, and as such are the main focus of this study. In case of persistently low alkaline phosphatase (2nd measurement, 2-4 weeks after the 1st measurement) with normal serum calcium and phosphate values (exclusion of secondary hypophosphatemia due to e.g. rickets or malnutrition) and exclusion of other causes of secondary hypophosphatemia, genetic testing for a pathological ALP gene is performed as part of routine diagnostics. This study involves the structured recording of specific symptoms, the entire course of the disease since childhood, laboratory parameters and genetic testing.
Persistant hypophosphatasemia	Physical examination	Patients with persistant hypophosphatasemia are highly suspicious for hypophosphatasia, and as such are the main focus of this study. In case of persistently low alkaline phosphatase (2nd measurement, 2-4 weeks after the 1st measurement) with normal serum calcium and phosphate values (exclusion of secondary hypophosphatemia due to e.g. rickets or malnutrition) and exclusion of other causes of secondary hypophosphatemia, genetic testing for a pathological ALP gene is performed as part of routine diagnostics. This study involves the structured recording of specific symptoms, the entire course of the disease since childhood, laboratory parameters and genetic testing.
Persistant hypophosphatasemia	Extended laboratory diagnostics	Patients with persistant hypophosphatasemia are highly suspicious for hypophosphatasia, and as such are the main focus of this study. In case of persistently low alkaline phosphatase (2nd measurement, 2-4 weeks after the 1st measurement) with normal serum calcium and phosphate values (exclusion of secondary hypophosphatemia due to e.g. rickets or malnutrition) and exclusion of other causes of secondary hypophosphatemia, genetic testing for a pathological ALP gene is performed as part of routine diagnostics. This study involves the structured recording of specific symptoms, the entire course of the disease since childhood, laboratory parameters and genetic testing.
Persistant hypophosphatasemia	Second alkaline phosphatase measurement	Patients with persistant hypophosphatasemia are highly suspicious for hypophosphatasia, and as such are the main focus of this study. In case of persistently low alkaline phosphatase (2nd measurement, 2-4 weeks after the 1st measurement) with normal serum calcium and phosphate values (exclusion of secondary hypophosphatemia due to e.g. rickets or malnutrition) and exclusion of other causes of secondary hypophosphatemia, genetic testing for a pathological ALP gene is performed as part of routine diagnostics. This study involves the structured recording of specific symptoms, the entire course of the disease since childhood, laboratory parameters and genetic testing.
Transient hypophosphatasemia (Control group without hypophosphatasia)	Symptom and clinical findings checklist for hypophosphatasia	In patients, in which the initial hypophosphatasemia does not confirm with the second ALP testing, the former suspicion of hypophosphatasia must be discarded. With the exclusion of a hypophosphatasia (characterized by a persistant hypophosphatasemia among other criteria) this group of patients qualifies as a control group of patients without hypophosphatasia. Data from this control group will be analyzed in order to investigate patient historical, clinical and laboratory features that may help in the discrimination of hypophosphatasia patients against healthy individuals.
Transient hypophosphatasemia (Control group without hypophosphatasia)	Short physical performance battery (SPPB) score	In patients, in which the initial hypophosphatasemia does not confirm with the second ALP testing, the former suspicion of hypophosphatasia must be discarded. With the exclusion of a hypophosphatasia (characterized by a persistant hypophosphatasemia among other criteria) this group of patients qualifies as a control group of patients without hypophosphatasia. Data from this control group will be analyzed in order to investigate patient historical, clinical and laboratory features that may help in the discrimination of hypophosphatasia patients against healthy individuals.
Transient hypophosphatasemia (Control group without hypophosphatasia)	Physical examination	In patients, in which the initial hypophosphatasemia does not confirm with the second ALP testing, the former suspicion of hypophosphatasia must be discarded. With the exclusion of a hypophosphatasia (characterized by a persistant hypophosphatasemia among other criteria) this group of patients qualifies as a control group of patients without hypophosphatasia. Data from this control group will be analyzed in order to investigate patient historical, clinical and laboratory features that may help in the discrimination of hypophosphatasia patients against healthy individuals.
Transient hypophosphatasemia (Control group without hypophosphatasia)	Bioelectrical Impedance Analysis	In patients, in which the initial hypophosphatasemia does not confirm with the second ALP testing, the former suspicion of hypophosphatasia must be discarded. With the exclusion of a hypophosphatasia (characterized by a persistant hypophosphatasemia among other criteria) this group of patients qualifies as a control group of patients without hypophosphatasia. Data from this control group will be analyzed in order to investigate patient historical, clinical and laboratory features that may help in the discrimination of hypophosphatasia patients against healthy individuals.
Persistant hypophosphatasemia	Symptom and clinical findings checklist for hypophosphatasia	Patients with persistant hypophosphatasemia are highly suspicious for hypophosphatasia, and as such are the main focus of this study. In case of persistently low alkaline phosphatase (2nd measurement, 2-4 weeks after the 1st measurement) with normal serum calcium and phosphate values (exclusion of secondary hypophosphatemia due to e.g. rickets or malnutrition) and exclusion of other causes of secondary hypophosphatemia, genetic testing for a pathological ALP gene is performed as part of routine diagnostics. This study involves the structured recording of specific symptoms, the entire course of the disease since childhood, laboratory parameters and genetic testing.
Persistant hypophosphatasemia	Genetic testing of the alkaline phosphatase gene	Patients with persistant hypophosphatasemia are highly suspicious for hypophosphatasia, and as such are the main focus of this study. In case of persistently low alkaline phosphatase (2nd measurement, 2-4 weeks after the 1st measurement) with normal serum calcium and phosphate values (exclusion of secondary hypophosphatemia due to e.g. rickets or malnutrition) and exclusion of other causes of secondary hypophosphatemia, genetic testing for a pathological ALP gene is performed as part of routine diagnostics. This study involves the structured recording of specific symptoms, the entire course of the disease since childhood, laboratory parameters and genetic testing.
Persistant hypophosphatasemia	Short physical performance battery (SPPB) score	Patients with persistant hypophosphatasemia are highly suspicious for hypophosphatasia, and as such are the main focus of this study. In case of persistently low alkaline phosphatase (2nd measurement, 2-4 weeks after the 1st measurement) with normal serum calcium and phosphate values (exclusion of secondary hypophosphatemia due to e.g. rickets or malnutrition) and exclusion of other causes of secondary hypophosphatemia, genetic testing for a pathological ALP gene is performed as part of routine diagnostics. This study involves the structured recording of specific symptoms, the entire course of the disease since childhood, laboratory parameters and genetic testing.
Transient hypophosphatasemia (Control group without hypophosphatasia)	Second alkaline phosphatase measurement	In patients, in which the initial hypophosphatasemia does not confirm with the second ALP testing, the former suspicion of hypophosphatasia must be discarded. With the exclusion of a hypophosphatasia (characterized by a persistant hypophosphatasemia among other criteria) this group of patients qualifies as a control group of patients without hypophosphatasia. Data from this control group will be analyzed in order to investigate patient historical, clinical and laboratory features that may help in the discrimination of hypophosphatasia patients against healthy individuals.
Transient hypophosphatasemia (Control group without hypophosphatasia)	SF-36	In patients, in which the initial hypophosphatasemia does not confirm with the second ALP testing, the former suspicion of hypophosphatasia must be discarded. With the exclusion of a hypophosphatasia (characterized by a persistant hypophosphatasemia among other criteria) this group of patients qualifies as a control group of patients without hypophosphatasia. Data from this control group will be analyzed in order to investigate patient historical, clinical and laboratory features that may help in the discrimination of hypophosphatasia patients against healthy individuals.
Persistant hypophosphatasemia	Recording of vital signs	Patients with persistant hypophosphatasemia are highly suspicious for hypophosphatasia, and as such are the main focus of this study. In case of persistently low alkaline phosphatase (2nd measurement, 2-4 weeks after the 1st measurement) with normal serum calcium and phosphate values (exclusion of secondary hypophosphatemia due to e.g. rickets or malnutrition) and exclusion of other causes of secondary hypophosphatemia, genetic testing for a pathological ALP gene is performed as part of routine diagnostics. This study involves the structured recording of specific symptoms, the entire course of the disease since childhood, laboratory parameters and genetic testing.
Persistant hypophosphatasemia	Bioelectrical Impedance Analysis	Patients with persistant hypophosphatasemia are highly suspicious for hypophosphatasia, and as such are the main focus of this study. In case of persistently low alkaline phosphatase (2nd measurement, 2-4 weeks after the 1st measurement) with normal serum calcium and phosphate values (exclusion of secondary hypophosphatemia due to e.g. rickets or malnutrition) and exclusion of other causes of secondary hypophosphatemia, genetic testing for a pathological ALP gene is performed as part of routine diagnostics. This study involves the structured recording of specific symptoms, the entire course of the disease since childhood, laboratory parameters and genetic testing.
Transient hypophosphatasemia (Control group without hypophosphatasia)	Recording of vital signs	In patients, in which the initial hypophosphatasemia does not confirm with the second ALP testing, the former suspicion of hypophosphatasia must be discarded. With the exclusion of a hypophosphatasia (characterized by a persistant hypophosphatasemia among other criteria) this group of patients qualifies as a control group of patients without hypophosphatasia. Data from this control group will be analyzed in order to investigate patient historical, clinical and laboratory features that may help in the discrimination of hypophosphatasia patients against healthy individuals.

Primary Outcome Measures

Name	Time	Method
Prevalence of hypophosphatasia in adult patients in rheumatology	24 months	The primary aim of this prospective observational study is to determine the prevalence of hypophosphatasia in adult patients presenting with musculoskeletal symptoms in rheumatology.

Secondary Outcome Measures

Name	Time	Method
Health-related quality of life: Short Form-36	24 months	The possible score ranges from 0 to 100 points, where 0 points represent the greatest possible health limitation, while 100 points represent no health limitation at all.
Frequency of specific symptoms and clinical findings in patients with hypophosphatasia	24 months	This will be derived from the symptom and clinical findings checklist.
Correlation between physical performance abnormalities and hypophosphatasia	24 months	Physical performance is determined by standardized "short physical performance battery"
Correlation between body composition abnormalities and hypophosphatasia	24 months	Body composition is determined by bioelectrical impedance analysis.
Frequency of musculoskeletal pathology in hypophosphatasia patients in comparison with normal controls.	24 months	Frequency of musculoskeletal pathology in people with biochemistry suggestive of hypophosphatasia and positive ALP gene test as compared with normal controls.
Frequency of specific patient history findings and the occurence of hypophosphatasia	24 months	Data will be derived from the medical history of hypophosphatasia patients (patient clinical data will be collected regarding the diagnosis, onset, progression, treatment course and outcome for patients with hypophosphatasia)

Trial Locations

Locations (1)

Clinic of Internal Medicine III, Department of Oncology, Haematology, Rheumatology and Clinical Immunology, University Hospital Bonn; 🇩🇪 Bonn, North Rhine-Westphalia, Germany