Circulating miRNAs and Bone Microstructure in Adults With Hypophosphatasia

The aim of the study is to accomplish a complete bone status of patients with HPP using new approaches to assess bone quality.

Study Overview

• Status: Active, not recruiting
• Conditions: Bone Diseases, Metabolic; Bone; Hypophosphatasia
• Intervention / Treatment: Other: HR-pQCT scans, BMD measurements, bone specific circulating microRNAs (miRNAs)

Detailed Description

Hypophosphatasia (HPP) is a hereditary disease of bone metabolism that is not yet curable. Clinical phenotype is variable and reaches from demineralization of bone, deformation of the skeleton, microsomia and gait abnormality to breathing difficulties. Symptoms of the adult form are low-traumatic fractures, hip or thigh pain and arthropathy. Cause of the disease is a mutation in the ALPL-gene (1p36.1-p34) coding for the tissue-nonspecific isoenzyme of alkaline phosphatase (TNAP) in liver, bone and kidney. This leads to a low activity of alkaline phosphatase (AP) and elevated levels of phosphoethanolamine (PEA) in urine.

HPP is a very rare disease with a prevalence of ~1/100 000. The Medical Department II of the St. Vincent Hospital Vienna, Department of the Medical University of Vienna and the Sigmund Freud University Vienna is a department that is specialized on bone diseases and, as a member of "Orphanet", also on In particular, (i) bone microstructure as a main component of bone strength and (ii) circulating microRNAs (miRNAs) as promising biomarkers for bone diseases will be analyzed in patients with HPP and age-, and gender-matched healthy controls.

Microstructural deteriorations of cortical and trabecular bone as well as volumetric bone density (vBMD) in radius and tibia in patients with HPP will be compared to healthy individuals using HR-pQCT (High resolution peripheral quantitative computer tomography, Scanco Medical, Brütisellen). HR-pQCT is a high-resolution, non-invasive technique to measure cortical and trabecular bone mircostructures as well as vBMD at a high resolution level (82µm).

Micro-RNAs (miRNAs) are short, non-coding RNA molecules of which some have been identified as bone specific (e.g. miR-31, miR-335, miR-155, miR-29b, miR-188, miR-550a). They play a significant role in bone metabolism controlling synthesis and function of osteoblasts as well as osteoclasts.

In recent studies we could show that these microRNAs can be detected in serum and that their serum concentration correlates with the risk for osteoporotic fractures. Data for patients with HPP do not exist yet. miRNAs will be measured by qPCR (quantitative polymerase chain reaction) in serum of patients with HPP and respective controls.

In addition, measurements of areal BMD (aBMD) by DXA (Dual Energy X-ray Absorptiometry) and DXL (Dual X-ray and Laser) will be performed. Vitamin D and established bone turnover markers including PINP (N-terminal propeptide of type I collagen), CTX (collagen type 1 cross-linked C-telopeptid) and sclerostin will be analyzed. Moreover, body composition will be determined.

• Study Type: Observational
• Enrollment (Anticipated): 60

Contacts and Locations

Study Locations

• Austria
  • Vienna, Austria, 1060
    • Medical University Vienna; St. Vincent Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Probability Sample

Study Population

30 adult patients with genetical verified childhood-onset hypophophatasia. All data will be compared to a healthy, age- and gender-matched control Group (CTRL, n=30), recruited from the general population.

Healthy controls will be matched by age and gender. All subjects will be recruited from the general population to avoid bias. The number of female and male subjects will be equal in both groups. Postmenopausal status will be taken into account.

Description

Inclusion Criteria for Hypophosphatasia (HPP)

• genetically verified hypophosphatasia
• age >18 years
• written informed consent
• complete serological and radiological examinations

Inclusion Criteria für Controls:

• healthy men and women without any history of musculoskeletal diseases
• written informed consent
• Alkaline phosphatase (AP) in reference range
• complete serological and radiological examinations

Exclusion Criteria for both Groups:

• inflammatory diseases
• other genetic disorders affecting bone such as osteogenesis imperfecta, Ehlers-Danlos-syndrome and fibrous dysplasia
• diabetes mellitus type 1 and 2
• COPD
• chronic kidney and liver dysfunction
• systemic glucocorticoid use and glucocorticoid induced osteoporosis
• eating disorders
• HIV-infections and any malignancy including plasmacytosis and lymphoma.

Study Plan

How is the study designed?

Design Details

• Observational Models: Case-Control
• Time Perspectives: Prospective

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
HPP-Group; genetical verified hypophosphatasia; age >18 years; written informed consent; complete serological and radiological examinations	Other: HR-pQCT scans, BMD measurements, bone specific circulating microRNAs (miRNAs); HR-pQCT scans (XtremeCT, SCANCO Medical, Brütisellen, Switzerland) will be performed in all patients with HPP and all CTRL at the ultradistal radius and the distal tibia, using the manufacturer's standard protocol. Volumetric bone Mineral density (vBMD) will be carried out. The peripheral trabecular density adjacent to the cortex and the central medullary trabecular density will be automatically evaluated. Bone microstructure including trabecular bone volume fraction, trabecular number, trabecular thickness inhomogeneity of the network, cortical thickness and cortical porosity will be analyzed. Measurements will be carried out by two well-trained physicians and performed with the latest available software (software version 6.0). Daily crosscalibrations with standardized control phantoms (Moehrendorf, Germany) will be conducted for validation.
Control-Group; healthy men and women without any history of musculoskeletal diseases; Alkaline phosphatase (AP) in reference range; written informed consent; complete serological and radiological examinations	Other: HR-pQCT scans, BMD measurements, bone specific circulating microRNAs (miRNAs); HR-pQCT scans (XtremeCT, SCANCO Medical, Brütisellen, Switzerland) will be performed in all patients with HPP and all CTRL at the ultradistal radius and the distal tibia, using the manufacturer's standard protocol. Volumetric bone Mineral density (vBMD) will be carried out. The peripheral trabecular density adjacent to the cortex and the central medullary trabecular density will be automatically evaluated. Bone microstructure including trabecular bone volume fraction, trabecular number, trabecular thickness inhomogeneity of the network, cortical thickness and cortical porosity will be analyzed. Measurements will be carried out by two well-trained physicians and performed with the latest available software (software version 6.0). Daily crosscalibrations with standardized control phantoms (Moehrendorf, Germany) will be conducted for validation.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
HR-pQCT	non-invasively measurement of trabecular and cortical bone microstructure	Assessment once after Inclusion is completed.
microRNA pattern	bone specific circulating microRNAs (miRNAs) in the serum of adult patients	Assessment once after Inclusion is completed

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
DXA Scanning	measurement of areal bone mineral density (aBMD) at the lumbar spine, radius, total body and hip by DXA • measurement of aBMD at the calcaneus by DXL	Assessment once after Inclusion is completed.
Bone Turnover Markers (BTMs)	serological analysis of established BTMs including PINP, CTX and sclerostin	Assessment once after Inclusion is completed.

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Patient Characteristics	Demographic and clinical Data	Assessment once after Inclusion is completed.

Collaborators and Investigators

• Sponsor: Medical University of Vienna
• Investigators: Principal Investigator: Roland Kocijan, Vinforce Study Group

Study record dates

Study Major Dates

• Study Start (Actual): August 1, 2017
• Primary Completion (Anticipated): March 1, 2023
• Study Completion (Anticipated): June 1, 2023

Study Registration Dates

• First Submitted: June 13, 2019
• First Submitted That Met QC Criteria: July 10, 2019
• First Posted (Actual): July 12, 2019

Study Record Updates

• Last Update Posted (Estimate): January 26, 2023
• Last Update Submitted That Met QC Criteria: January 25, 2023
• Last Verified: January 1, 2023

More Information

Terms related to this study

• Keywords: microRNAs, bone microstructure
• Additional Relevant MeSH Terms: Genetic Diseases, Inborn; Musculoskeletal Diseases; Metabolism, Inborn Errors; Metal Metabolism, Inborn Errors; Bone Diseases; Bone Diseases, Metabolic; Metabolic Diseases; Hypophosphatasia
• Other Study ID Numbers: HPP-Study

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Undecided

Drug and device information, study documents

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