Clinical trial NCT06509776: Skeletal Maturation and Endocrine Health in Young Adults
Official title: Early Life Determinants of Skeletal Maturation and Endocrine Health in Young Adults - A Nationwide Birth Cohort Study
Study type: OBSERVATIONAL
Overall status: ENROLLING_BY_INVITATION
Conditions: Osteoporosis
Sarcopenia
Obesity
Cardiovascular Diseases
Keywords: Bone and Bones
Bone mineralization
Bone mineral density
Bone density
Endocrinology
Hormones
Thyroid Hormones
Parathyroid Hormone
Puberty
Adolescent
Glucocorticoids
Genetics
Human Genetics
Epigenomics
Neonatal Screening
Body Composition
Cohort Study
Epidemiology
Phenotype
Lead sponsor: Holbaek Sygehus
Sponsor class: OTHER
Collaborators: name: Aarhus University Hospital
name: Aalborg University Hospital
name: University of Southern Denmark
name: University Hospital Bispebjerg and Frederiksberg
name: Zealand University Hospital
name: Odense University Hospital
name: Rigshospitalet, Denmark
name: Statens Serum Institut
name: Hvidovre University Hospital
First posted: 2024-07-19
Enrollment: 2000
Sex: ALL
Minimum age (years): 18
Maximum age (years): 19
Standard ages: ADULT
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: PROBABILITY_SAMPLE
Study population: The Danish Personal Civil Registration will be used to identify all alive individuals born in Denmark in 2006 and 2007 using civil registration numbers. Invitations will be sent through secure e-mail (E-boks) in blocks until 2,000 participants have been reached. The study population will be selected with representative geographical distribution in Denmark.

Brief summary: Diseases which can be the result of poor lifestyle choices in adult life, such as osteoporosis, obesity or poor muscle mass (sarcopenia) can also be driven by heritable genetic factors. More surprisingly, perhaps, the genes we inherit from our parents can be modified as a result of influences that affected the health and pregnancy of our mothers and hence the environment experienced in the womb and at birth. The purpose of this study is to investigate which factors are needed for good bone health and hormonal health in young adulthood as well as good muscle mass and normal fat mass, and how this is influenced by factors before birth and by childhood health. Specifically, we will measure bone mass and body composition in young adults (18 years of age) and measure hormones in blood and in hair samples. The clinical visits will be available nationwide at several centers to make participation swift and easy for participants. The changes (known as epigenetic modification) to genes at birth will be studied in dried blood spot samples stored from birth 18 years ago in the Danish Serum Institute and we will use national health registers to identify factors during pregnancy and in childhood that contribute to health effects at age 18.

Detailed description: Population-based, nationwide, cross-sectional, clinical study with already available early life exposure data including bio banked neonatal biological samples. An embedded design using the full 2006+2007 birth cohorts is used to demonstrate external validity of the clinically assessed cohort. We will obtain the necessary ethics and regulatory approval and individual consent from the participants who are all aged 18.

The overall aim of the project addresses whether the following sets of potential determinants are associated with young adult hormonal status, lipids, bone turnover markers, bone mineral density (BMD), fat mass and lean body mass at age 18 years: a) maternal risk factors during preconception and pregnancy; b) risk factors at birth; c) neonatal epigenetic signature; d) childhood risk factors.

Aim 1 - Epigenetics - Is peak bone mass and body size influenced by epigenetic profile for endocrine signals at birth? From the second trimester of pregnancy and until early adulthood, bone is gradually developed and shaped, with longitudinal growth dominating the later stages of fetal life, infancy, and childhood. This is followed by a period of rapid bone mineral accrual occurring up to and during puberty, with bone mass accretion ultimately reaching a plateau in young adult life. It is strongly suggested by prior research that epigenetic variation at birth can result from differences in maternal health, lifestyle, nutrition, smoking and medication usage and result in long-term changes in gene expression and metabolism.

As existing childhood cohorts either lack BMD information, suffer from significant cohort attrition, and low recruitment success, there is an opportunity to instead use national invitations to recruit directly into an efficient endocrine and bone outcomes study and use already archived biological material from early infancy and register data and obtain individual study subject consent.

Aim 2 - Endocrine status in young adulthood - Does maternal medication use and health issues prior to pregnancy or in pregnancy affect endocrine health in young adults? This question will be addressed using data from Danish national registers. While it is straightforward to link binary events data e.g., malformations or paediatric admissions (eg epilepsy, diabetes, failure to thrive) to registry capture of their maternal exposures, we will be obtaining detailed information about continuous outcomes including endocrine serum biochemistry (thyroid axis, GH axis, PTH-vitamin D-calcium axis, lipids, HbA1c), hair cortisol levels (a cumulative serum cortisol metric) as well as body composition and bone density metrics.

Aim 3 - DXA measured muscle, fat mass and lipid status in young adults - Do suboptimal conditions prior to pregnancy, during pregnancy, birth, and childhood, such as lifestyle, poor health and low socioeconomics adversely influence establishment of healthy body composition and lipid status in young adulthood? Detailed register-based information prior to pregnancy, about pregnancy, birth and childhood health will be used to identify areas open to prevention. Detailed information will be obtained via the Danish national health registers.

Statistical consideration - With a study population of 2,000, the power (given α=0.05) available to detect a 0.2 SD effect on a continuous outcome such as PBM for a risk factor with a population prevalence of 20% is 90%. With inclusion of 1,500 subjects, the corresponding study power is 90% for detection of an effect size of 0.24 SD or 80% for detection of an effect size of 0.2 SD. The study needs this resolving power to be able to address multiple contributing factors and for the inclusion of factors in the model that may have a population prevalence below 20%. Less common factors would, even if powerful drivers of skeletal health, be somewhat less useful in population impact even if successfully modified.

Biological material - All material for use in the current project will be stored in a research biobank during the current study during its term. Any remaining material is transferred to biobank for future research with the approval of the Danish Data Protection Agency. The purpose of the biobank is to ensure validation of the analysis methods used over time. The participants must give consent to the storage of their biological material in the biobank. It is completely optional if the participants want to donate their excess biological material to the biobank and if they do not want this, it does not affect their participation in the study. For new research, new consent must be obtained, but the Scientific Ethics Committee can grant exemption from the consent requirement.

All material will be stored in compliance with Danish legislation on data protection.

24 mL of blood will be drawn. All blood samples are encoded so that all samples are anonymized, and the key is under special protection and only with access for authorized personnel. All extra material will be kept in the biobank.

To ensure uniformity between neonatal and adolescent samples, DBS will be created from the freshly drawn whole blood. DBS are created by spotting 3x75µL onto a cotton filter paper of the same type used in 2006-2007. The cards are left overnight at ambient temperatures then transferred to -20C for long term storage. DNA is be extracted from two 3.2mm disks excised from the DBS card, then purified using magnetic silica beads. Finally, concentrations are measured using intercalating dyes.

All hair samples (minimum 20 mg per participant) will be encoded so that all samples are pseudonymised, and the key is under special protection and only with access for authorized personnel. All hair samples will be used in the analyses, and then discarded.

Eligibility criteria: Inclusion Criteria:

* Individuals (n = 2000) born in Denmark in 2006 or 2007
* Are 18 years old and alive at the time of the clinical examination

Exclusion Criteria:

* Pregnancy or lactation
* No DBS samples available
* Lack of consent to use DBS samples or national health registries
* Emigration or disappearance

Primary outcomes:
measure: Bone Mineral Density of Spine, Hip and Whole-body
timeFrame: Baseline
measure: Bone Mineral Density of Spine, Hip and Whole-body
timeFrame: 2 years
measure: Bone Area of Spine, Hip and Whole-body
timeFrame: Baseline
measure: Bone Area of Spine, Hip and Whole-body
timeFrame: 2 years
measure: Bone Mineral Content of Spine, Hip and Whole-body
timeFrame: Baseline
measure: Bone Mineral Content of Spine, Hip and Whole-body
timeFrame: 2 years
Secondary outcomes:
measure: Total Body Lean Mass
timeFrame: Baseline
measure: Total Body Lean Mass
timeFrame: 2 years
measure: Total Body Fat Mass
timeFrame: Baseline
measure: Total Body Fat Mass
timeFrame: 2 years
measure: High-Resolution Peripheral Quantitative Computed Tomography of The Distal Radius and Tibia
timeFrame: Baseline
measure: High-Resolution Peripheral Quantitative Computed Tomography of The Distal Radius and Tibia
timeFrame: 2 years
measure: Body Weight
timeFrame: Baseline
measure: Body Weight
timeFrame: 2 years
measure: Height
timeFrame: Baseline
measure: Height
timeFrame: 2 years
measure: Body Mass Index
timeFrame: Baseline
measure: Body Mass Index
timeFrame: 2 years
measure: Waist Circumference
timeFrame: Baseline
measure: Waist Circumference
timeFrame: 2 years
measure: Hip Circumference
timeFrame: Baseline
measure: Hip Circumference
timeFrame: 2 years
measure: Waist-Hip Ratio
timeFrame: Baseline
measure: Waist-Hip Ratio
timeFrame: 2 years
measure: Endocrine Status
timeFrame: Baseline
measure: Endocrine Status and Bone Markers of Bone Metabolism
timeFrame: Baseline
measure: Hair Cortisol Concentrations
timeFrame: Baseline
measure: Blood Pressure
timeFrame: Baseline
measure: Blood Pressure
timeFrame: 2 years
Other outcomes:
measure: Self-reported Stress
timeFrame: Baseline
measure: Self-reported Sleep
timeFrame: Baseline
measure: Self-reported Hearing
timeFrame: Baseline
Locations:
city: Aalborg
country: Denmark
facility: Aalborg University Hospital, Department of Endocrinology
city: Aarhus
country: Denmark
facility: Aarhus University Hospital, Department of Endocrinology
city: Copenhagen
country: Denmark
facility: Rigshospitalet, Department of Clinical Biochemistry and Endocrinology
city: Frederiksberg
country: Denmark
facility: Bispebjerg and Frederiksberg Hospital, EEK, Parker Institute
city: Holbæk
country: Denmark
facility: Holbæk Hospital, Department of Medicine
city: Hvidovre
country: Denmark
facility: Hvidovre Hospital, Department of Endocrinology
city: Køge
country: Denmark
facility: Zealand University Hospital, Department of Medicine
city: Odense
country: Denmark
facility: Odense University Hospital, Department of Endocrinology
city: Odense
country: Denmark
facility: University of Southern Denmark, Department of Clinical Research
Study officials:
affiliation: OPEN, University of Southern Denmark, Odense and Department of Medicine 1, Holbæk Hospital, Holbæk
name: Bo Abrahamsen, MD, PhD
role: STUDY_CHAIR
affiliation: OPEN, Department of Clinical Research, University of Southern Denmark and Odense University Hospital
name: Katrine H Rubin, MHS, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Department of Clinical Medicine and Department of Endocrinology and Diabetes, Aarhus University
name: Bente Langdahl, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Faculty of Medicine, Aalborg University and Department of Endocrinology, Aalborg University Hospital
name: Peter Vestergaard, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: The Parker Institute, Frederiksberg Hospital, Frederiksberg
name: Berit L Heitmann, DMD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: The Parker Institute, Frederiksberg Hospital, Frederiksberg
name: Mina N Händel, Msc, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Department of CIinical Medicine, Endocrinology, Zealand University Hospital, Køge
name: Charlotte L Tofteng, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Department of Endocrinology, Amager and Hvidovre Hospital, Hvidovre
name: Pernille Bach-Mortensen, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Department of Endocrinology, Odense University Hospital, Odense
name: Pernille Hermann, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Department of Clinical Biochemistry and Centre of Diagnostic Investigation,Rigshospitalet Copenhagen
name: Niklas R Jørgensen, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Danish Center for Neonatal Screening, Statens Serum Institut, Copenhagen
name: Jonas Bybjerg-Grauholm, MSE
role: PRINCIPAL_INVESTIGATOR
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