eraSmus medIcal ceNTer skEletal fRagility study

Skeletal fragility (i.e., predisposition to fracture) results from reduced bone
mass mainly due to an imbalance between bone resorption and formation; and/or
from defects in bone matrix composition or mineralization. Skeletal fragility
arises in response to different degrees of genetic and environmental
influences. Bone fragility can be classified as derived from osteoporosis or
secondary to predisposing diseases or conditions. Osteoporosis is defined as a
silent systemic disease manifesting with low bone mass and microarchitectural
deterioration of bone tissue, resulting in increased risk of fracture. The
prevalence and impact of osteoporosis increases with age and the burden
associated with the disease is high in both developed and developing countries.
On the other hand, bone fragility can also be secondary to diverse diseases and
metabolic conditions. There is evidence of increased risk of fractures in
individuals with alteration of calcium and mineral metabolism; both type 1 and
type 2 diabetes; increased falling risk due to sarcopenia and/or cognitive
function decline; rapid weight loss. chronic kidney disease; hyperlipidaemia
and both hypothyroidism and hyperthyroidism, among others. Altogether, up to
30% of post-menopausal women and 50 to 80% of men are found to have factors
contributing to the risk of skeletal fragility when undergoing an evaluation
for their underlying causes of the disease. Bone mineral density (BMD) measured
by dual-energy X-ray absorptiometry (DXA) is used in clinical practice to
diagnose and treat osteoporosis. For this, BMD is used in the form of a T-score
(i.e., measured BMD compared to that of a sex-matched young-adult). Diagnosis
and treatment of osteoporosis is made for a BMD T-score equal or below -2.5 SD.
This diagnostic threshold is suboptimal since more than 50% of fractures occur
above the osteoporosis threshold. Consequently, additional fracture risk
assessment tools incorporating clinical risk factor besides BMD have been
developed (i.e., FRAX) . Yet, a large number of fractures still remain to be
prevented. Moreover, current osteoporosis treatments reduce fracture risk by
only 25-50% and the field is undergoing a treatment crisis due to concerns
regarding side effects and long-term use safety. This means there is an
expanding gap between individuals who are at risk of fracture and those who are
receiving treatment, which requires novel research approximations to close it.

The aim of this study is to evaluate the added benefit of integrating genetic
information and state-of-the-art phenotypic information (clinical measurements)
of the musculoskeletal system in groups of patients with conditions presenting
with or at risk of skeletal fragility. To do this, we will set up a "Recall by
Genotype study" (RbG). The RbG study will allow assessing (unconfounded)
relationships between exposures (risk factors) and outcomes. Employing
polygenic scores a genetically-determined BMD will be calculated to be used to
facilitate the etiological study of bone fragility in patients. This approach
stands as "proof-of-concept" of study designs optimised by using polygenic risk
scores.*

The study will be observational cross-sectional, and enrollment set in two
recruitment stages using a Recall by Genotype design.*

During Stage 1, 5650 patients visiting outpatient clinics in Erasmus MC will
be invited to participate in eight outpatient clinics of the department of
Internal Medicine, including: Botcentrum, Diabetologie, Geriatrie, Centrum
Gezond Gewicht, Nephrologie, Schildkliercentrum, Vasculaire Geneesekunde and
Mastocytosis; to be genotyped genome-wide. Patients will be asked by their
treating physician whether they consent to be contacted to participate in the
study and register their answer in the electronic patient file HIX. Next, the
treating physician will give the PIF to those patients consenting to be
contacted. After a minimum of two weeks, these individuals will receive a phone
call with a formal invitation to participate and be provided the opportunity to
receive further explanation about the study. If willing to participate they
will be asked to electronically sign the informed consent. Participants
requesting to sign in person will do so by appointment with research staff on
the day of blood collection. Patients will be instructed that during their next
visit for blood drawing planned for their standard care, an extra tube of 20 ml
of blood (EDTA) will be collected and bio-banked for further genomic profiling.


During Stage 2, 1500 patients will be selected from the extremes (2x750) of the
PRSBMD distribution of genotyped participants. The PRS distribution wil be
constructed from 5250 genotyped patients. These 1500 patients, together will
all patients from the Mastocytosis clinic, will be invited to undergo detailed
musculoskeletal phenotyping at a dedicated research facility of Erasmus MC.

In Stage 1 of the study, participants will provide blood samples once, which
will be obtained during planned blood examinations part of their standard
medical care. There is no expected risks or immediate direct benefit of this
research for the patients participating in Stage 1.

In Stage 2 the participants will benefit from an assessment of bone health
status and/or evaluation of their risk for osteoporosis.

During this stage they will fill-in 3 questionnaires at home (maximum 60
minutes) and undergo musculoskeletal measurements at one time point/visit to
dedicated research facility of Erasmus MC (lasting maximum 60 minutes) as
follows:

At home:
-Food-frequency questionnaire (~30 minutes)
-Physical activity / iPAQ (~15 minutes)
-Stool microbiome (~10-15 minutes)

At research center:
-Mechanography and hand grip strength (~10 minutes)
-OsteoProbe bone microindentation (~10 minutes)

The bone microindentation performed once on the lower leg to measure material
properties of the bone holds a very low risk of swelling and infection at the
site of application.

In addition, the following radiological assessments:

- dual energy X-ray absorptiometry (DXA) bone mineral density measurement (~10
minutes)
- peripheral quantitative computed tomography (pQCT) (~10 minutes)
- x-ray whole body with EOS Edge of approximately (~10 minutes)

A potential risk of this study involves the X-ray radiation of the pQCT, EOS
Edge and DXA. The estimated total dose per participant will be 0.104
milliSievert(mSv), of which the estimate from pQCT will be 0.001 mSv, X-ray EOS
Edge 0.10 mSv and the expected dose of the DXA scan will be 0.003 mSv,
respectively. Theoretically, X-ray exposures may have harmful health effects,
but this risk is low considering these low radiation doses. There is no
expected immediate direct benefit for participating subjects, other than the
assessment of their musculoskeletal health.