Characteristics of Hypophosphatasia in Adult Patients in Rheumatology (COHIR)

The COHIR Study - a Non-interventional, Prospective, Single-center Investigation With Exploratory Data Analysis to Assess the Proportion of Patients With Hypophosphatasia Presenting at the Department of Rheumatology and Establishment of an Algorithm to HPP Diagnosis.

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.

Study Overview

• Status: Recruiting
• Conditions: Hypophosphatasia
• Intervention / Treatment: 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: Recording of vital signs; Diagnostic test: Bioelectrical Impedance Analysis; Diagnostic test: Genetic testing of the alkaline phosphatase gene

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 Type: Observational
• Enrollment (Estimated): 60

Contacts and Locations

• Study Contact: Name: Valentin S. Schäfer, Dr. med.; Phone Number: +49 228 287-17000; Email: rheumatologie@ukbonn.de

Study Locations

• Germany
  • North Rhine-Westphalia
    • Bonn, North Rhine-Westphalia, Germany, 53127
      • Recruiting
      • Clinic of Internal Medicine III, Department of Oncology, Haematology, Rheumatology and Clinical Immunology, University Hospital Bonn
      • Contact: Valentin S. Schäfer, Dr. med.; Phone Number: +49 228 287-17000; Email: rheumatologie@ukbonn.de

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

• Sampling Method: Probability Sample

Study Population

Any adult patient presenting at the University Hospital Bonn's rheumatology department with musculoskeletal complaints within the timeframe of the study conduct.

Description

Inclusion Criteria:

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

Exclusion Criteria:

• Failure to meet the inclusion criteria listed above

Study Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Persistant hypophosphatasemia; 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.	Diagnostic test: Second alkaline phosphatase measurement; (2-4 weeks after the 1st measurement); Diagnostic test: Extended laboratory diagnostics; Laboratory testing investigating features that support the diagnosis of hypophosphatasia or exclude it by indicating secondary hypophosphatasemia for other reasons (including parameters such as serum calcium, inorganic serum phosphate, vitamin B6, vitamin B12, folic acid, bone-specific alkaline phosphatase, vitamin D3, and more).; Diagnostic test: Symptom and clinical findings checklist for hypophosphatasia; Checklist including numerous symptoms and clinical findings regarding the musculoskeletal system and non-musculoskeletal body parts; Diagnostic test: SF-36; Quality of life questionnaire; Diagnostic test: Short physical performance battery (SPPB) score; The short physical performance battery is a group of measures that combines the results of the gait speed, chair stand and balance tests. It has been used as a predictive tool for possible disability and can aid in the monitoring of function in older or disease-affected people. The scores range from 0 (worst performance) to 12 (best performance). The SPPB has been shown to have predictive validity showing a gradient of risk for mortality, nursing home admission, and disability.; Diagnostic test: Physical examination; A full rheumatological examination will be performed.; Diagnostic test: Recording of vital signs; (including body temperature, blood pressure, heart rate); Diagnostic test: Bioelectrical Impedance Analysis; A body composition measurement by BIA (Bioelectrical Impedance Analysis [proportional mass of muscle, water and fat in kg]) will be performed.; Diagnostic test: Genetic testing of the alkaline phosphatase gene; Investigation of mutations regarding the alkaline phosphatase gene
Transient hypophosphatasemia (Control group without 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.	Diagnostic test: Second alkaline phosphatase measurement; (2-4 weeks after the 1st measurement); Diagnostic test: Symptom and clinical findings checklist for hypophosphatasia; Checklist including numerous symptoms and clinical findings regarding the musculoskeletal system and non-musculoskeletal body parts; Diagnostic test: SF-36; Quality of life questionnaire; Diagnostic test: Short physical performance battery (SPPB) score; The short physical performance battery is a group of measures that combines the results of the gait speed, chair stand and balance tests. It has been used as a predictive tool for possible disability and can aid in the monitoring of function in older or disease-affected people. The scores range from 0 (worst performance) to 12 (best performance). The SPPB has been shown to have predictive validity showing a gradient of risk for mortality, nursing home admission, and disability.; Diagnostic test: Physical examination; A full rheumatological examination will be performed.; Diagnostic test: Recording of vital signs; (including body temperature, blood pressure, heart rate); Diagnostic test: Bioelectrical Impedance Analysis; A body composition measurement by BIA (Bioelectrical Impedance Analysis [proportional mass of muscle, water and fat in kg]) will be performed.

What is the study measuring?

Primary Outcome Measures

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

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Frequency of musculoskeletal pathology in hypophosphatasia patients in comparison with normal controls.	Frequency of musculoskeletal pathology in people with biochemistry suggestive of hypophosphatasia and positive ALP gene test as compared with normal controls.	24 months
Health-related quality of life: Short Form-36	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.	24 months
Frequency of specific symptoms and clinical findings in patients with hypophosphatasia	This will be derived from the symptom and clinical findings checklist.	24 months
Frequency of specific patient history findings and the occurence of hypophosphatasia	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)	24 months
Correlation between physical performance abnormalities and hypophosphatasia	Physical performance is determined by standardized "short physical performance battery"	24 months
Correlation between body composition abnormalities and hypophosphatasia	Body composition is determined by bioelectrical impedance analysis.	24 months

Collaborators and Investigators

• Sponsor: University of Bonn
• Investigators: Principal Investigator: Valentin S. Schäfer, Dr. med., University Hospital of Bonn

Study record dates

Study Major Dates

• Study Start (Actual): February 28, 2023
• Primary Completion (Estimated): December 1, 2024
• Study Completion (Estimated): December 1, 2024

Study Registration Dates

• First Submitted: July 3, 2023
• First Submitted That Met QC Criteria: December 5, 2023
• First Posted (Estimated): December 7, 2023

Study Record Updates

• Last Update Posted (Estimated): December 7, 2023
• Last Update Submitted That Met QC Criteria: December 5, 2023
• Last Verified: December 1, 2023

More Information

Terms related to this study

• Keywords: Prevalence; Hypophosphatasia; Rare disease; Genetic disorder; Rheumatic disease; Diagnostic Algorithm; ALP; Hypophosphatasemia; Musculoskeletal complaints; Alkaline phosphatase gene; ALP gene; COHIR study; Metabolic bone diseases
• Additional Relevant MeSH Terms: Metabolic Diseases; Genetic Diseases, Inborn; Metabolism, Inborn Errors; Metal Metabolism, Inborn Errors; Hypophosphatasia
• Other Study ID Numbers: 407/21

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Data will be available upon reasonable request

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No