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Circulating miRNAs and Bone Microstructure in Adults With Hypophosphatasia
| Condition or disease | Intervention/treatment |
|---|---|
| Hypophosphatasia Bone Diseases, Metabolic Bone | Other: HR-pQCT scans, BMD measurements, bone specific circulating microRNAs (miRNAs) |
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 |
| Estimated Enrollment : | 60 participants |
| Observational Model: | Case-Control |
| Time Perspective: | Prospective |
| Official Title: | Circulating miRNAs and Bone Microstructure in Adults With Hypophosphatasia |
| Actual Study Start Date : | August 1, 2017 |
| Estimated Primary Completion Date : | June 1, 2021 |
| Estimated Study Completion Date : | September 1, 2021 |
| Group/Cohort | Intervention/treatment |
|---|---|
HPP-Group
|
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
|
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. |
- HR-pQCT [ Time Frame: Assessment once after Inclusion is completed. ]non-invasively measurement of trabecular and cortical bone microstructure
- microRNA pattern [ Time Frame: Assessment once after Inclusion is completed ]bone specific circulating microRNAs (miRNAs) in the serum of adult patients
- DXA Scanning [ Time Frame: Assessment once after Inclusion is completed. ]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
- Bone Turnover Markers (BTMs) [ Time Frame: Assessment once after Inclusion is completed. ]serological analysis of established BTMs including PINP, CTX and sclerostin
- Patient Characteristics [ Time Frame: Assessment once after Inclusion is completed. ]Demographic and clinical Data
Biospecimen Retention: Samples With DNA
| Ages Eligible for Study: | 18 Years and older (Adult, Older Adult) |
| Sexes Eligible for Study: | All |
| Accepts Healthy Volunteers: | Yes |
| Sampling Method: | Probability Sample |
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.
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.
| Contact: Roland Kocijan, M.D. | +431599880 | Roland.kocijan@wgkk.at | |
| Contact: Judith Haschka, M.D. | +431599880 | judith.haschka@bhs.at |
| Austria | |
| Medical University Vienna; St. Vincent Hospital | Recruiting |
| Vienna, Austria, 1060 | |
| Contact: Heinrich Resch, M.D. +43159988 ext 0 heinrich.resch@bhs.at | |
| Contact: Roland Kocijan, M.D. +43159988 ext 0 roland.kocijan@wgkk.at | |
| Principal Investigator: Roland Kocijan, M.D. | |
| Sub-Investigator: Zora Messner, M.D. | |
| Sub-Investigator: Christian Muschitz, M.D. | |
| Sub-Investigator: Heinrich Resch, M.D. | |
| Sub-Investigator: Judith Haschka, M.D. | |
| Sub-Investigator: Ursula Renner, M.D. | |
| Sub-Investigator: Christoph Puempel | |
| Principal Investigator: | Roland Kocijan | Vinforce Study Group |
| Tracking Information | |||||||||
|---|---|---|---|---|---|---|---|---|---|
| First Submitted Date | June 13, 2019 | ||||||||
| First Posted Date | July 12, 2019 | ||||||||
| Last Update Posted Date | April 20, 2021 | ||||||||
| Actual Study Start Date | August 1, 2017 | ||||||||
| Estimated Primary Completion Date | June 1, 2021 (Final data collection date for primary outcome measure) | ||||||||
| Current Primary Outcome Measures |
|
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| Original Primary Outcome Measures | Same as current | ||||||||
| Change History | |||||||||
| Current Secondary Outcome Measures |
|
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| Original Secondary Outcome Measures | Same as current | ||||||||
| Current Other Pre-specified Outcome Measures |
Patient Characteristics [ Time Frame: Assessment once after Inclusion is completed. ] Demographic and clinical Data
|
||||||||
| Original Other Pre-specified Outcome Measures | Same as current | ||||||||
| Descriptive Information | |||||||||
| Brief Title | Circulating miRNAs and Bone Microstructure in Adults With Hypophosphatasia | ||||||||
| Official Title | Circulating miRNAs and Bone Microstructure in Adults With Hypophosphatasia | ||||||||
| Brief Summary | The aim of the study is to accomplish a complete bone status of patients with HPP using new approaches to assess bone quality. | ||||||||
| 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. |
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| Study Type | Observational | ||||||||
| Study Design | Observational Model: Case-Control Time Perspective: Prospective |
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| Target Follow-Up Duration | Not Provided | ||||||||
| Biospecimen | Retention: Samples With DNA Description:
Plasma/Serum Samples
|
||||||||
| 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. |
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| Condition |
|
||||||||
| Intervention | 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. |
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| Study Groups/Cohorts |
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| Publications * | Not Provided | ||||||||
|
* Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline. |
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| Recruitment Information | |||||||||
| Recruitment Status | Recruiting | ||||||||
| Estimated Enrollment |
60 | ||||||||
| Original Estimated Enrollment | Same as current | ||||||||
| Estimated Study Completion Date | September 1, 2021 | ||||||||
| Estimated Primary Completion Date | June 1, 2021 (Final data collection date for primary outcome measure) | ||||||||
| Eligibility Criteria |
Inclusion Criteria for Hypophosphatasia (HPP)
Inclusion Criteria für Controls:
Exclusion Criteria for both Groups:
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| Sex/Gender |
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| Ages | 18 Years and older (Adult, Older Adult) | ||||||||
| Accepts Healthy Volunteers | Yes | ||||||||
| Contacts |
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| Listed Location Countries | Austria | ||||||||
| Removed Location Countries | |||||||||
| Administrative Information | |||||||||
| NCT Number | NCT04018287 | ||||||||
| Other Study ID Numbers | HPP-study | ||||||||
| Has Data Monitoring Committee | No | ||||||||
| U.S. FDA-regulated Product |
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| IPD Sharing Statement |
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| Responsible Party | Dr. Christian Muschitz, Medical University of Vienna | ||||||||
| Study Sponsor | Medical University of Vienna | ||||||||
| Collaborators | Not Provided | ||||||||
| Investigators |
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| PRS Account | Medical University of Vienna | ||||||||
| Verification Date | April 2021 | ||||||||
