Bone, Bone Diseases, Metabolic, Hypophosphatasia
Conditions
Keywords
microRNAs, bone microstructure
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.
Interventions
OTHERHR-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.
Sponsors
Medical University of Vienna
Study design
Observational model
CASE_CONTROL
Time perspective
PROSPECTIVE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
Yes
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| HR-pQCT | Assessment once after Inclusion is completed. | non-invasively measurement of trabecular and cortical bone microstructure |
| microRNA pattern | Assessment once after Inclusion is completed | bone specific circulating microRNAs (miRNAs) in the serum of adult patients |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| DXA Scanning | 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) | Assessment once after Inclusion is completed. | serological analysis of established BTMs including PINP, CTX and sclerostin |
Other
| Measure | Time frame | Description |
|---|---|---|
| Patient Characteristics | Assessment once after Inclusion is completed. | Demographic and clinical Data |
Countries
Austria
Outcome results
None listed