Exome Sequencing for Atypical Femoral Fractures

December 27, 2018 updated by: Steven Mumm, PhD, Washington University School of Medicine

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.

Study Overview

Status

Completed

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

Observational

Enrollment (Actual)

38

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Child
  • Adult
  • Older Adult

Accepts Healthy Volunteers

No

Genders Eligible for Study

Female

Sampling Method

Non-Probability Sample

Study Population

Women who are or have been taking bisphosphonates for osteoporosis.

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

This section provides details of the study plan, including how the study is designed and what the study is measuring.

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:
  • Aledronate (Fosamax)
  • Zoledronate (Zometa and Reclast)
  • Risendronate (Actonel and Atelvia)
  • Etidronate (Didronel)
  • Ibandronate (Boniva)
Fracture Group
Women who are/have been on bisphosphonate therapy for osteoporosis who have suffered an atypical femoral fracture
Other Names:
  • Aledronate (Fosamax)
  • Zoledronate (Zometa and Reclast)
  • Risendronate (Actonel and Atelvia)
  • Etidronate (Didronel)
  • Ibandronate (Boniva)

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

This is where you will find people and organizations involved with this study.

Investigators

  • Principal Investigator: Steven Mumm, PhD, Washington University School of Medicine

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

April 1, 2016

Primary Completion (Actual)

March 29, 2018

Study Completion (Actual)

March 29, 2018

Study Registration Dates

First Submitted

March 28, 2016

First Submitted That Met QC Criteria

April 1, 2016

First Posted (Estimate)

April 7, 2016

Study Record Updates

Last Update Posted (Actual)

December 31, 2018

Last Update Submitted That Met QC Criteria

December 27, 2018

Last Verified

December 1, 2018

More Information

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.

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