Atypical Femoral FracturesNCT02731040
Exome Sequencing for Atypical Femoral Fractures
An observational study of Atypical Femoral Fractures and Osteoporosis, run by Washington University School of Medicine.
Trial summary
The purpose of this study is to determine whether women who have atypical subtrochanteric and diaphyseal femoral fractures after treatment with bisphosphonates for osteoporosis, have a genetic predisposition to these unusual fractures. Read more about this study
- Who is it for?
- Any age, women only
- Conditions the study is for
- Atypical Femoral Fractures, Osteoporosis, Bisphosphonate Therapy
- What is being tested?
- Bisphosphonate
- How many people
- 38 participants
- Where
- No sites listed yet
- Study dates
- Apr 2016to 29 Mar 2018
- Phase
- Observational
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages Any age
- Women only
- No healthy volunteers
- Child, Adult, Older adult
Study population: Women who are or have been taking bisphosphonates for osteoporosis.
Who may be able to join
- 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.
Who cannot join
- None
About this study
Official title: Whole Exome Sequencing to Identify Genetic Predisposition to Atypical Femoral Fractures in Women Using Bisphosphonates for Osteoporosis
The purpose of this study is to determine whether women who have atypical subtrochanteric and diaphyseal femoral fractures after treatment with bisphosphonates for osteoporosis, have a genetic predisposition to these unusual fractures.
Read the 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.
- Being tested
- Bisphosphonate
- Medical subject headings
- Osteoporosis
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
BisphosphonateDrug
Also called Aledronate (Fosamax), Zoledronate (Zometa and Reclast), Risendronate (Actonel and Atelvia), Etidronate (Didronel)
| Study group | Role | What they receive |
|---|---|---|
| Controls | Women who are/have been on bisphosphonate therapy for osteoporosis who have not suffered an atypical femoral fracture Receives: Drug: Bisphosphonate | |
| Fracture Group | Women who are/have been on bisphosphonate therapy for osteoporosis who have suffered an atypical femoral fracture Receives: Drug: Bisphosphonate |
What is being measured
The primary outcome is the main question the study is designed to answer.
Whole Exome Sequencing to identify mutations in genes that regulate pyrophosphate metabolism.
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.
Measured: Within the first year of study
Whole Exome Sequencing to identify mutations in genes that regulate phosphate metabolism.
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.
Measured: Within the first year of study
Whole Exome Sequencing to identify mutations in genes that regulate bisphosphonate metabolism.
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.
Measured: Within the first year of study
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted7 Apr 2016 (estimated)
- Study startApr 2016
- Primary completion29 Mar 2018
- Study completion29 Mar 2018
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (9)Papers the sponsor has linked to this study.
- Other trials for Atypical Femoral FracturesStudies of the same condition, open and under way.
- More trials run by Washington University School of MedicineThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Observational
- Observational model
- Case-control
- Time perspective
- Other
- Enrolment
- 38 participants (actual)
Sponsor and investigators
- Lead sponsor
- Washington University School of Medicine
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Steven Mumm, PhD, Washington University School of Medicine
- Investigators
- Steven Mumm, PhD, Principal investigator, Washington University School of Medicine
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02731040
- Sponsor's protocol ID
- 53302
- Status last verified
- Dec 2018
- First submitted
- 28 Mar 2016
- Last updated
- 31 Dec 2018
- Results posted
- No
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.
PubMed 20842676Shane 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.
PubMed 237124422013 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.
PubMed 24585702Sutton 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.
PubMed 22322541Whyte 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.
PubMed 2811660Duncan, 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 at a glance
From the registry record, last updated by the sponsor on 31 Dec 2018. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Whole Exome Sequencing to Identify Genetic Predisposition to Atypical Femoral Fractures in Women Using Bisphosphonates for Osteoporosis
- ClinicalTrials.gov ID
- NCT02731040
- Acronym / sponsor ID
- 53302
- Study type
- Observational
- Recruitment status
- Completed
- Enrolment
- 38 participants (actual)
- Lead sponsor
- Washington University School of MedicineUniversity, hospital or other
- Study start
- Apr 2016
- Primary completion
- 29 Mar 2018 (actual)
- Study completion
- 29 Mar 2018 (actual)
- First posted
- 7 Apr 2016 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
The purpose of this study is to determine whether women who have atypical subtrochanteric and diaphyseal femoral fractures after treatment with bisphosphonates for osteoporosis, have a genetic predisposition to these unusual fractures.
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 design
- Observational model
- Case-control
- Time perspective
- Other
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Controls | – | Drug: BisphosphonateWomen who are/have been on bisphosphonate therapy for osteoporosis who have not suffered an atypical femoral fracture |
| Fracture Group | – | Drug: BisphosphonateWomen who are/have been on bisphosphonate therapy for osteoporosis who have suffered an atypical femoral fracture |
Who may qualify
- Sex
- Female only
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult, Older adult
- Study population
- Women who are or have been taking bisphosphonates for osteoporosis.
Key inclusion criteria (4 listed)
- Female
- Previous and/or current use of bisphosphonate therapy for the management of osteoporosis
- -sustained one or more atypical subtrochanteric or diaphyseal femoral shaft fracture(s) as defined by the the 2010 ASBMR task force.
Key exclusion criteria (1 listed)
- None
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| BisphosphonateAlso: Aledronate (Fosamax), Zoledronate (Zometa and Reclast), Risendronate (Actonel and Atelvia), Etidronate (Didronel) | Drug | Controls, Fracture Group |
Primary outcome
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.
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.
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.
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 31 Dec 2018.
- Background: PubMed 20842676Shane 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.
- Background: PubMed 23712442Shane 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.
- Background: PubMed 245857022013 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.
- Background: PubMed 22322541Sutton 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.
- BackgroundWhyte MP. Hypophosphatasia. In Pediatric Bone: Biology & Diseases, 3rd ed. Glorieux FH, Jueppner H, Pettifor J, eds. San Diego, CA: Elsevier, 2012;771-794.
- Background: PubMed 2811660Reid 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.
- BackgroundDuncan, E.L., Brown, M.A. Genome-wide association studies (2013) Genetics of Bone Biology and Skeletal Disease, pp. 93-100
- BackgroundNguyen, T.V., Eisman, J.A. Pharmacogenetics and pharmacogenomics of osteoporosis: personalized medicine outlook (2013) Genetics of Bone Biology and Skeletal Disease, pp. 151-167
- BackgroundRivadeneira, F., Uitterlinden, A.G. Osteoporosis Genes Identified by Genome-wide Association Studies (2013) Genetics of Bone Biology and Skeletal Disease, pp. 243-256.
Related trials for Atypical Femoral Fractures
Active, not recruitingObservational study
Quebec Registry for Atypical Femur Fractures
Atypical Femur Fracture
RecruitingObservational study
Atypical Fracture Cohort Study
Atypical Femur Fracture, Atypical Subtrochanteric Fracture
Active, not recruitingObservational study
Personalizing Osteoporosis Care: Clinical & Genetic Risk Factors for AFFs
Atypical Femur Fracture
Active, not recruitingObservational study
Evaluation of IVA (SE Femur Scans) to Identify Incomplete AFFs
Atypical Femur Fracture
Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Steven Mumm, PhD principal investigator
Washington University School of Medicine
Questions about this trial
What is this clinical trial studying?
An observational study of Atypical Femoral Fractures and Osteoporosis, run by Washington University School of Medicine.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 4 inclusion and 1 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 31 Dec 2018. Status can change between updates, so confirm with the study contact before making plans.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Whole Exome Sequencing to identify mutations in genes that regulate pyrophosphate metabolism. (time frame: Within the first year of study). The study lists 3 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT02731040, which also lists 9 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 31 Dec 2018.