- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT02731040
Exome Sequencing for Atypical Femoral Fractures
Whole Exome Sequencing to Identify Genetic Predisposition to Atypical Femoral Fractures in Women Using Bisphosphonates for Osteoporosis
Study Overview
Status
Intervention / Treatment
Detailed Description
In 2010, a Task Force convened by the American Society for Bone and Mineral Research (ASBMR) investigated an apparent association of atypical subtrochanteric and diaphyseal femoral fractures (AFFs) with long-term bisphosphonate (BP) treatment given for the important and common disorder osteoporosis (OP).(1,2) Because the investigators had reported(2) in 2009 that the prodromal lesion for AFFs in OP resembles the femoral pseudofractures encountered in the rare adult form of hypophosphatasia (HPP),(3-5) they recommended sequencing the tissue non-specific alkaline phosphatase (TNSALP) gene of OP AFF patients to determine if mutations or polymorphisms in TNSALP genetically predispose to OP AFFs.(2)
In 2012, the investigators reported a 55-year-old woman treated for four years with BPs for presumed OP who then suffered simultaneous atraumatic bilateral AFFs.(4) Upon sequencing her TNSALP, a heterozygous mutation changing an arginine (Arg) to a histidine (His) (c.212 G>A, p.Arg71His) was discovered that the investigators had documented in the investigators' large cohort of HPP patients. She had been undiagnosed with HPP although her pre-BP serum ALP was persistently low (26 U/L, Nl 32 - 116 U/L). The investigators then recruited and sequenced TNSALP for 24 new OP AFF patients given BPs, and identified a second OP AFF patient carrying a TNSALP defect.(3) These two OP AFF patients with TNSALP defects support the investigators' hypothesis (below) that high-impact rare genetic variants in TNSALP, and perhaps other genes, can predispose to OP AFFs.(4) Furthermore, the investigators reported in 2009(2) that the prodromal lesions of OP AFFs can resemble the femoral pseudofractures seen in another, but more prevalent, heritable metabolic bone disease, X-linked hypophosphatemia (XLH). This is the most common genetic cause of osteomalacia,(6) and is inherited as an X-linked dominant trait caused by deactivating mutations in the PHEX gene.
Osteoporosis (OP) is a complex disorder likely involving the effects of multiple low-impact, common changes in the human genome that alter bone remodeling and/or mineralization.(7-9) The investigators propose that high-impact, rare, genetic variants predispose some OP patients to AFFs. Treatment with BPs could engender OP AFFs. The investigators' hypothesis: High-impact rare variants (i.e., mutations) that occur in genes/proteins that regulate pyrophosphate/phosphate homeostasis or BP metabolism predispose to OP AFFs and are unmasked in OP patients given BPs. Identification of these variants will guide OP therapies, perhaps on an individual basis (i.e., "personalized medicine"),(9) and reduce the incidence of OP AFFs.
The investigators will identify high-impact rare genetic variants using whole exome sequencing in two patient groups: 1) women using BPs for OP and have had one or more AFF, 2) women using BPs for OP but have not had an AFF. The investigators will focus on genes/proteins that: i) regulate pyrophosphate/phosphate effects, ii) others that regulate BP metabolism, and iii) have been associated with OP. The investigators will use gene burden analysis to determine whether there is an excess of novel or rare genetic variants for the group with AFFs.
Study Type
Enrollment (Actual)
Participation Criteria
Eligibility Criteria
Ages Eligible for Study
- Child
- Adult
- Older Adult
Accepts Healthy Volunteers
Genders Eligible for Study
Sampling Method
Study Population
Description
Inclusion Criteria:
- Female
- Previous and/or current use of bisphosphonate therapy for the management of osteoporosis
For inclusion in the fracture group must have:
-sustained one or more atypical subtrochanteric or diaphyseal femoral shaft fracture(s) as defined by the the 2010 ASBMR task force.
Exclusion Criteria:
- None
Study Plan
How is the study designed?
Design Details
- Observational Models: Case-Control
- Time Perspectives: Other
Cohorts and Interventions
Group / Cohort |
Intervention / Treatment |
---|---|
Controls
Women who are/have been on bisphosphonate therapy for osteoporosis who have not suffered an atypical femoral fracture
|
Other Names:
|
Fracture Group
Women who are/have been on bisphosphonate therapy for osteoporosis who have suffered an atypical femoral fracture
|
Other Names:
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Whole Exome Sequencing to identify mutations in genes that regulate pyrophosphate metabolism.
Time Frame: Within the first year of study
|
Whole Exome Sequencing will be used to identify changes in DNA sequences of genes which regulate pyrophosphate metabolism.
These changes could alter the amino acid sequence, and may include termination of translation, or affect mRNA splicing.
|
Within the first year of study
|
Whole Exome Sequencing to identify mutations in genes that regulate phosphate metabolism.
Time Frame: Within the first year of study
|
Whole Exome Sequencing will be used to identify changes in DNA sequences of genes which regulate phosphate metabolism.
These changes could alter the amino acid sequence, and may include termination of translation, or affect mRNA splicing.
|
Within the first year of study
|
Whole Exome Sequencing to identify mutations in genes that regulate bisphosphonate metabolism.
Time Frame: Within the first year of study
|
Whole Exome Sequencing will be used to identify changes in DNA sequences of genes which regulate bisphosphonate metabolism.
These changes could alter the amino acid sequence, and may include termination of translation, or affect mRNA splicing.
|
Within the first year of study
|
Collaborators and Investigators
Investigators
- Principal Investigator: Steven Mumm, PhD, Washington University School of Medicine
Publications and helpful links
General Publications
- Shane E, Burr D, Ebeling PR, Abrahamsen B, Adler RA, Brown TD, Cheung AM, Cosman F, Curtis JR, Dell R, Dempster D, Einhorn TA, Genant HK, Geusens P, Klaushofer K, Koval K, Lane JM, McKiernan F, McKinney R, Ng A, Nieves J, O'Keefe R, Papapoulos S, Sen HT, van der Meulen MC, Weinstein RS, Whyte M; American Society for Bone and Mineral Research. Atypical subtrochanteric and diaphyseal femoral fractures: report of a task force of the American Society for Bone and Mineral Research. J Bone Miner Res. 2010 Nov;25(11):2267-94. doi: 10.1002/jbmr.253. Erratum In: J Bone Miner Res. 2011 Aug;26(8):1987.
- Shane E, Burr D, Abrahamsen B, Adler RA, Brown TD, Cheung AM, Cosman F, Curtis JR, Dell R, Dempster DW, Ebeling PR, Einhorn TA, Genant HK, Geusens P, Klaushofer K, Lane JM, McKiernan F, McKinney R, Ng A, Nieves J, O'Keefe R, Papapoulos S, Howe TS, van der Meulen MC, Weinstein RS, Whyte MP. Atypical subtrochanteric and diaphyseal femoral fractures: second report of a task force of the American Society for Bone and Mineral Research. J Bone Miner Res. 2014 Jan;29(1):1-23. doi: 10.1002/jbmr.1998. Epub 2013 Oct 1.
- 2013 Annual Meeting of the American Society for Bone and Mineral Research, October 4-7, 2013, Baltimore, MD. J Bone Miner Res. 2013 Feb;28 Suppl 1:S1. doi: 10.1002/jbmr.2201. No abstract available.
- Sutton RA, Mumm S, Coburn SP, Ericson KL, Whyte MP. "Atypical femoral fractures" during bisphosphonate exposure in adult hypophosphatasia. J Bone Miner Res. 2012 May;27(5):987-94. doi: 10.1002/jbmr.1565.
- Whyte MP. Hypophosphatasia. In Pediatric Bone: Biology & Diseases, 3rd ed. Glorieux FH, Jueppner H, Pettifor J, eds. San Diego, CA: Elsevier, 2012;771-794.
- Reid IR, Hardy DC, Murphy WA, Teitelbaum SL, Bergfeld MA, Whyte MP. X-linked hypophosphatemia: a clinical, biochemical, and histopathologic assessment of morbidity in adults. Medicine (Baltimore). 1989 Nov;68(6):336-52.
- Duncan, E.L., Brown, M.A. Genome-wide association studies (2013) Genetics of Bone Biology and Skeletal Disease, pp. 93-100
- Nguyen, T.V., Eisman, J.A. Pharmacogenetics and pharmacogenomics of osteoporosis: personalized medicine outlook (2013) Genetics of Bone Biology and Skeletal Disease, pp. 151-167
- Rivadeneira, F., Uitterlinden, A.G. Osteoporosis Genes Identified by Genome-wide Association Studies (2013) Genetics of Bone Biology and Skeletal Disease, pp. 243-256.
Study record dates
Study Major Dates
Study Start
Primary Completion (Actual)
Study Completion (Actual)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Estimate)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Additional Relevant MeSH Terms
Other Study ID Numbers
- 53302
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
Clinical Trials on Osteoporosis
-
Radius Health, Inc.CompletedOsteoporosis | Osteoporosis Risk | Osteoporosis, Postmenopausal | Osteoporosis Fracture | Osteoporosis, Age-Related | Osteoporosis Localized to Spine | Osteoporosis Senile | Osteoporosis of Vertebrae | Osteoporosis VertebralUnited States
-
Radius Health, Inc.CompletedOsteoporosis | Age Related Osteoporosis | Osteoporosis, Age-Related | Osteoporosis Localized to Spine | Osteoporosis Senile | Osteoporosis of VertebraeUnited States, Poland, Italy
-
Hoffmann-La RocheCompletedPostmenopausal OsteoporosisUnited States
-
Hoffmann-La RocheCompletedPost Menopausal OsteoporosisUnited States, Puerto Rico
-
Centre Hospitalier Universitaire de Saint EtienneMinistry of Health, FranceRecruitingPost Menopausal OsteoporosisFrance
-
AmgenCompletedPost Menopausal OsteoporosisFrance
-
Hoffmann-La RocheCompletedPost Menopausal OsteoporosisUnited States
-
Hoffmann-La RocheCompletedPost Menopausal OsteoporosisSpain, South Africa, Germany, Mexico, United States, Canada, France, United Kingdom, Italy, Belgium, Australia, Poland, Denmark, Hungary, Czech Republic, Norway
-
Hoffmann-La RocheGlaxoSmithKlineCompletedPost Menopausal OsteoporosisFrance
-
Novartis PharmaceuticalsCompletedPost-menopausal OsteoporosisColombia, Belgium, Sweden, Hong Kong, United States, Hungary, Switzerland, Australia, Germany, Italy, Canada, Poland, Argentina, Thailand, Norway, New Zealand, France, Finland
Clinical Trials on Bisphosphonate
-
Queen's UniversityCompletedChronic Kidney DiseaseCanada
-
Eulji University HospitalCompleted
-
AmgenNot yet recruiting
-
Université Catholique de LouvainFonds National de la Recherche ScientifiqueCompletedPaget's Disease of BoneBelgium
-
Ultragenyx Pharmaceutical IncRecruitingOsteogenesis ImperfectaUnited States, Canada, Germany, France, Poland, Netherlands, Italy, Brazil
-
Northwestern UniversityUnited States Department of DefenseCompletedOsteoporosis | Bone Loss | Spinal Cord Injury | Acute Spinal Cord InjuryUnited States
-
AmgenAarhus University Hospital; Optum, Inc.; University of Alabama at Birmingham...Active, not recruiting
-
Peking Union Medical College HospitalRecruitingBreast Cancer FemaleChina
-
Wake Forest University Health SciencesNational Institute on Aging (NIA)Recruiting
-
Parc de Salut MarInstituto de Salud Carlos IIIRecruitingOsteoporosis | Osteoporosis Fracture | Arthralgia GeneralizedSpain