About this study
Background
Bone strength is crucial for mobility and overall health. It can be influenced by numerous factors including genetics, aging, environmental and lifestyle factors as well as by underlying health conditions. Osteoporosis, a condition characterised by low bone mass and deterioration of the architecture of bone tissue, is a common disease associated with increased fracture risk. As people age, the prevalence and impact of osteoporosis increase, posing significant health risks. Conditions such as diabetes, kidney disease, thyroid disorders, and certain medications among others, negatively impact bone strength and increase the risk of fractures.
While dual-energy X-ray absorptiometry (DXA) remains the gold standard for diagnosing osteoporosis by measuring bone mineral density, some individuals experience fractures despite having bone mineral density values that do not indicate osteoporosis. Hence, exploring alternative measurements is crucial to identify individuals at risk of fractures. In the past decades, technologic innovation has allowed us to research the heritability and genetic influences for many traits and diseases, including bone mineral density and fracture risk. Via genome wide association studies (GWAS), we have identified many markers in the genetic code that impact bone mineral density. These markers can then be used by researchers to identify methods to better detect, treat and prevent a disease. It also sets the ground for personalized medicine. Another way to use the genetic findings for further research is via polygenic risk scores (PRS) in the setting of Recall by Genotype (RbG) study. In every person, there is a number of genetic markers that affect a given trait, either positively or negatively. For example, if we were to sum up the effects of bone mineral density genetic markers, we would create a PRSBMD and this PRSBMD would quantify the effect of our genetic background on bone mineral density. Note that PRS is not deterministic; it only gives a glance of genetic predisposition. In a group of people, most of the individuals will have a PRSBMD value close to the average of the group, however, there will be a few individuals who will have a higher or a lower PRSBMD compared to the average of the group. Please note that this PRSBMD does not change during the life course. It is different from the measured BMD we would measure at any given point in time via DXA, which would be different at any time point due to lifestyle, environmental influences and ageing. For example, there can be individuals who have a high PRSBMD in a given group, but their measured BMD could fall in the average or low measured BMD of that group. This could be for example due to other chronic disease or/and lifestyle. Based on genetic laws PRS have a valuable characteristic: randomization. In practice this would mean for example, that the chance for a 70-year-old person to be in the lower PRS group is the same as to be in the hight PRS group. On the other hand, a person with a high measured BMD has a higher chance to be in the high PRSBMD than in the low PRS BMD. This is very important for research because when researchers want to compare two groups and identify causes of the difference between the two groups, they need to know with as much certainty as possible that the difference between two groups for a given trait, is not impacted by other factors. This characteristic is used to design RbG studies.
In the eraSmus medIcal ceNTer skEletal fRagility (SINTER) Study we aim to read the genetic information of 5250 patients visiting either the outpatient of Bone Center, Diabetes, Geriatric, Healthy Weight, Nephrology, Thyroid or Vascular medicine in the Internal Medicine department of Erasmus MC. We will then invite for further research, two groups of patients (750 each), those with genetically predicted low BMD and those with genetically predicted high BMD compared to the average genetically predicted BMD of the whole 5250 patients. The research we will conduct in these two groups of patients aims to understand and describe bone properties and characteristics in individuals with chronic diseases. For this purpose, we will measure bone mineral density, bone structural properties, material strength, muscle-bone function and low-radiation imaging of the whole skeleton in standing position; which, together can provide a holistic assessment of bone fragility. To measure BMD, dual x-ray absorptiometry (DXA) will be performed. BMD is the gold standard to diagnose osteoporosis- the disease of brittle bones. In a DXA test, you’ll first prepare by wearing comfortable clothing without any metal. Then, you’ll lie down on a table while a machine passes over your body, emitting low-dose X-ray beams. These beams, absorbed differently by bone and soft tissue, help measure bone density accurately. The process usually lasts between 10 to 30 minutes, depending on which parts of your body are scanned. Next, the PQCT technique allows precise measurements of bone density and structure skeletal sites. It enables localised assessments of bone strength and density, providing valuable insights into skeletal health at specific regions of interest. In preparation you will be expected to roll up your clothing to above your elbow. Your arm will then be measured from your elbow to your wrist. You will be then asked to sit on a chair and your arm will be placed sideways through a small cylinder (you will be able to rest your hand and wrist on the rest). X-ray beams will pass through your wrist to ensure the positioning is correct. Once the technician confirms the correct position, x-ray beams will once again be directed towards your wrist and the pQCT scan will be taken. This process will take around 10 minutes.
To measure muscle function, particularly strength, the Mechanograph jumping plate will be used. It is a reliable tool for assessing lower body strength and explosiveness, offering valuable data for analysing athletic performance and rehabilitation progress. There are two options of how to undertake this test. You could be asked to jump and land with your feet in the same position; you will be asked to do this 3 times. Should you not be able to undertake this, then a small bench will be placed behind you and you will be asked to stand and take a seat three times in quick succession. This process will take 5-10 minutes. Similarly, the dynamometer grip force instrument measures the force exerted during handgrip strength assessment, offering insights into muscle function and overall physical health. During this assessment you will be asking to grip the machine as hard as possible and a measurement will be made, after that you will be asking to grip the machine for as long and hard as possible until the technician informs you that you may release. This assessment will take around 5-10 minutes.
To assess the musculoskeletal system comprehensively, we employ EOSEdge imaging system. This system facilitates production of high-quality images of the musculoskeletal system, allowing patients to stand during the scan and providing insights into the natural standing position. The EOSEdge can capture both 2D and 3D images within seconds. These images serve to diagnose various musculoskeletal disorders, including asymptomatic vertebral fractures and osteoarthritis, and to evaluate overall alignment of the skeleton. During the procedure, you will be required remove your shoes, belt, and jewellery. You will then stand on a plate that adjusts for height for the scanner, and you will hold a bar at chin level for correct alignment. Technicians may adjust your position if needed. Then, the scan will scan your body while you remain still. The entire process takes about 10 minutes. For the assessment of bone material quality, we utilise the Osteoprobe. This tool measures the depth of indention made by the Osteoprobe tip into the tibia, providing insights into bone quality beyond traditional bone density measurements. By quantifying bone stiffness and microstructure, the Osteoprobe aids in the early detection of osteoporosis and monitoring of bone changes over time. It offers a safe and effective means for assessing bone health, with a local anaesthetic applied for patient comfort during the procedure. To visualise bone structure and density, we utilise the 3D Shaper imaging software. This software transforms standard 2D bone images captured with DXA and allows us to assess the cortical surface density and volumetric trabecular density, enhancing the effectiveness of DXA scans. You do not require any specific preparation for the application of the 3D shaper software, as it is applied directly to their DXA scan results.
This comprehensive assessment process, ensuring a thorough evaluation of bone health and muscle function.
Understanding and Perception of Genetic Research
We aim to understand participants’ perception of genetic research, their experiences with participation, and the implications of genetically informed research on bone fragility. To achieve this, we will explore the participants perspective through questionnaires and interviews. Participants will be asked to share their views on various aspects of genetic research, including their perceptions of genetic information such as polygenic risk scores. We will explore their experiences with the informed consent process, genotype testing and the overall study design. Additionally, participants will be asked to discuss their perspective of the potential benefits and risks associated with participating in genetically informed research on bone fragility. Furthermore, a knowledge test will also be conducted to evaluate their understanding of these concepts.