Current PhD students
(Currently on maternity leave)
Main supervisor: Marianne S. Andersen
Project:
”Cortisol in cognition, psychological health and body composition. Programming and pharmacological effects of glucocorticoids”
Project: Home-based intervention with semaglutide treatment of neuroleptic-related prediabetes (HISTORI)
Background and Aim
Individuals with schizophrenia have a 2- to 3-fold higher mortality rate than the general population, with approximately one-third of the excess mortality attributed to type 2 diabetes (T2DM) and cardiovascular disease (CVD). Lifestyle interventions have generally failed to prevent the development of metabolic syndrome (MetS) and prediabetes in this population.
This study aims to evaluate whether once-weekly treatment with the GLP-1 receptor agonist (GLP-1Ra) semaglutide can prevent the progression of prediabetes, MetS, and deterioration of mental health.
Methods
HISTORI is a multicenter, double-blind, randomized, placebo-controlled trial (1:1 ratio) involving 154 adults (aged 18–60 years, BMI > 27 kg/m²) with schizophrenia receiving second-generation antipsychotic treatment. The study was conducted in mental health facilities across the Region of Southern Denmark and the Region of Zealand.
Collaborators
- Ashok A. Ganeshalingam (PhD student)
- Nicolai Gundtoft Uhrenholt (PhD student)
- Professor Niels Bilenberg (Psychiatry)
- Professor Sidse Arnfred (Psychiatry)
- Professor Peter Gæde (Endocrinology)
- Professor Jan Frystyk (Principal Investigator)
Funding
The study is supported by the Novo Nordisk Foundation with a grant exceeding DKK 8.5 million.
Project Status
All 154 participants have completed treatment and one-year follow-up. Data analysis is underway to assess the long-term effects of trial participation. The first publication, focusing on HbA1c, MetS, and mental health outcomes, was submitted in January 2025.
The primary study objective was to demonstrate an HbA1c reduction of more than 0.2% after 30 weeks of treatment, which was successfully achieved.
Main supervisor: Marianne S. Andersen
Project:
“Metabolic and physical fitness signatures in offspring of mothers with and without Polycystic Ovary Syndrome”
Status of projects:
The Odense Child Cohort (OCC)
Published: Project 1 (P1): Higher maternal cortisol associated with lower blood pressure in offspring from 3 months to 5 years of age in the Odense Child Cohort. Published in Hypertension. DOI: 10.1161/HYPERTENSIONAHA.122.20265
Submitted: Project 2 (P2): Diurnal urinary aldosterone excretion and potassium intake during pregnancy are associated with higher blood pressure in early childhood. Submitted to JAHA.
Ongoing: Project 3 (P3): Progesterone, potassium and sodium intakes, in pregnancy as predictors of maternal blood pressure.
The Double Edge Study
Accepted: Project 4 (P4): Changes in adrenal function and insufficiency symptoms after cessation of prednisolone. A Double Edge Study. Accepted for publication in JAMA Network Open. DOI: 10.1001/jamanetworkopen.2025.1029
Ongoing: Project 5 (P5): Aldosterone concentrations were lower in patients with suppressed ACTH after prednisolone therapy compared to patients with normal ACTH levels, irrespective of blood pressure.
Background and findings
P1: Physiological GC has maturing and programming effects in the prenatal life including offspring blood pressure (OBP). In our study of 1,317 mother-child pairs, we found that maternal cortisol levels were associated with lower OBP up to 5 years of age and that the inverse relationship was stronger among boys.
P2: The mineralocorticoid receptor agonist aldosterone, along with potassium and sodium, plays a crucial role in feto-placental growth and programming of OBP. High potassium and low sodium intakes are generally recommended in adults with normal renal function. Our data suggested a positive association between maternal aldosterone, potassium intake and OBP. Progesterone, a partial mineralocorticoid receptor antagonist, is positively correlated with aldosterone and is 10-fold more accessible than free aldosterone. The difference in concentration and accessibility may theoretically influence the observed positive association between aldosterone and OBP, as well as the lack of association between sodium and OBP.
P3: Progesterone is essential for achieving and maintaining a healthy pregnancy and increases throughout pregnancy. This may contribute to feto-placental growth and maternal blood pressure (BP), and high dietary sodium and low potassium intakes may affect this relationship adversely.
P4: Glucocorticoid (GC) therapy is widely used in patients with polymyalgia rheumatic (PMR) or giant cell arteritis (GCA) and GC-induced adrenal insufficiency (GIAI) may occur, however, GC withdrawal syndrome (GWS) is more prevalent and patients with GWS may have clinical symptoms corresponding to adrenal insufficiency (fatigue, symptoms, emotions and miscellaneuos). Only 1.9% exhibited GIAI after prednisolone therapy, diagnosed by low cortisol response to the short synacthen test, while 34% reported symptoms attributable to adrenal insufficiency. In our study, the symptomatic group had lower basal cortisol levels compared with the asymptomatic group.
P5: Previous or ongoing low-dose prednisolone therapy suppresses adrenocorticotropic hormone (ACTH) in patients with PMR or GCA and may lower aldosterone levels and increase BP compared to patients with normal ACTH levels.
Clinical perspectives
P1: Endogenous cortisol in late pregnancy was associated with lower OBP. It is unknown if low normal BP is beneficial or a risk factor.
P2: Higher maternal aldosterone or more maternal potassium intake during pregnancy were associated with higher OBP, but within normal range, in young children and girls were more susceptible to maternal potassium intake. The planned follow-up period in the OCC will clarify the maturing effects of higher maternal cortisol, aldosterone, potassium and sodium intakes on OBP, and if low normal OBP or high normal OBP is beneficial for the children’s cardiovascular risk later in life.
P3: Ongoing
P4: Our data support a higher prevalence of GWS that is not captured by biomedical testing and the risk of GIAI after prednisolone therapy is low
P5: Ongoing
Project: Thromboembolism in Anorexia Nervosa (TEAN)
Background:
Sudden death due to thromboembolic events in patients with anorexia nervosa is well known. However, the incidence of thromboembolic events and the hemostatic balance in patients with AN are sparsely investigated. The TEAN-study is a PhD project, and adopts a multi-omnics approach, integrating register-based and case-control methodologies examining the incidence, risk factors, and clinical implications of thromboembolism in anorexia nervosa.
The first sub study investigates the incidence of thromboembolism in 12,000 patients with anorexia nervosa compared to a 1:5 age – and gender matched control group in the Danish health care registries. The results show a seven-fold increased risk of thromboembolism in patients with anorexia nervosa. The next sub study explores the hemostatic balance in anorexia nervosa and the results will help guide clinical management as to whether this patient group should receive thromboembolic prophylactic intervention. As per the beginning of 2025, the study has finished inclusion, data have been analyzed and are currently being written into a manuscript.
New collaborations have been fostered and the project has evolved during the project period. The project has been expanded to include both the use of artificial intelligence, clinical pharmacology and pharmacoepidemiology.
Main supervisor:
Professor, MD, PhD René Klinkby Støving, Research Unit of Medical Endocrinology, Odense University Hospital
Collaborators:
Else Marie Bladbjerg, professor, Thrombosis Research, Department of Clinical Biochemistry, Esbjerg Hospital
Rasmus Søgaard Hansen, MD, PhD and Pernille Just Vinholt, MD, PhD, professor, Department of Clinical Biochemistry, Odense University Hospital
Ulrik Sprogøe, MD, PhD, associate professor, Department of Clinical Immunology, Odense University Hospital
Jesper Hallas, professor, and Julie Rudbeck Krumborg, MD, PhD student, Clinical Pharmacology, Pharmacy and Environmental Medicine, Department of Public Health, University of Southern Denmark, Odense, Denmark
Pia Veldt Larsen, PhD, Mental Health Services, Region of Southern Denmark, Denmark
Jan Magnus Sjögren, MD, associate professor, Institute of Clinical Science, Department of Psychiatry, Umeå University, Umeå, Sweden
Project: The effect of oral Semaglutide on bone turnover in patients with type 2 diabetes: a randomized placebo-controlled clinical trial – (SOBER II)
Status: Ongoing, 17 % of participants enrolled.
Background: People with Type 2 diabetes (T2D) have a higher fracture risk despite normal bone density. Glucagon like peptide 1 (GLP-1), an incretin hormone, acutely reduces bone resorption. However, long-term treatment with GLP-1 receptor agonists (GLP-1RA), a treatment used for T2D and obesity, increased bone formation in one trial (Liraglutide) but increased bone resorption in another trial (Semaglutide). The aim of this trial is to investigate if semaglutide, a long-acting GLP1RA, improves bone formation and strength in men and women aged 50-85 years with T2D and low bone mass. Treatment involves oral administration of semaglutide once daily or matching placebo for 52 weeks.
Clinical perspectives: If effective in improving bone formation and strength, semaglutide could be targeted to patients with T2D with osteoporosis/a previous fracture. Further, semaglutide was recently approved for obesity treatment, and current obesity treatment include bariatric surgery, which causes bone loss and increase fracture risk. Thus, even neutral effects on bone would favour semaglutide over surgical treatment of obesity in patients at risk of osteoporosis and/or fractures.
Project: SHORT-term effects of GLucagon-like peptide One on BonE (SHORT GLOBE)
Status: 2 out of 12 participants completed the trial. Expected LPLV end of October 2025.
Background: Glucagon-like peptide 1 (GLP-1), secreted postprandially, has emerged as a potential regulator of bone remodeling. Short-term GLP-1 exposure (two hours) in vivo led to an 80% reduction in the bone resorption marker Collagen I, cross-linked C-terminal telopeptide (CTX) in bone marrow serum from healthy young males. In contrast, preliminary data from our group have shown that three-days exposure to GLP-1 in-vitro increases the activity of both osteoclasts and osteoblasts. The in vitro findings have not been corroborated by physiological studies. As such, the understanding of the relevance of GLP-1 to human bone physiology currently only covers acute effects. Furthermore, a clinical trial conducted on non-diabetic individuals undergoing long-term treatment with the GLP-1 receptor agonist (GLP-1RA), semaglutide, demonstrated an increase in the bone resorption marker CTX. The discrepancy between immediate effects observed in vivo and longer-term effects seen in the clinical trial underscores the need to clarify the effect of extended GLP-1 exposure in vivo.
Clinical perspectives: This study will elucidate the sub-acute impact of GLP-1 on human bone formation and resorption uncovering the relevance of GLP-1 to human bone physiology. If GLP-1 increases bone formation and enhances overall bone turnover, GLP-1 based pharmaceuticals may benefit patients with low bone turnover, such as patients with type 2 diabetes.
Title: ISWI-mediated chromatin remodeling directing stromal cell differentiation
Status: Ongoing
Background: Lineage determination of stromal progenitors is a complex mechanism involving activation of differentiation-selective gene programs and repression of genes important for multipotency. An important regulator of gene expression is chromatin accessibility which is modulated by chromatin remodeling complexes. Based on the ATP-ase subunit there are four distinct chromatin remodeling complexes, of which SWI/SNF has been reported to be pro-adipogenic and INO80 to be pro-osteogenic, while the function of imitation switch (ISWI) during stromal cell differentiation has not been reported. Due to its ubiquitous expression, we question if ISWI contributes to chromatin remodeling during stromal cell differentiation and in turn affects linage specification.
Material and methods: I compared in vitro differentiation potential of human stromal progenitors exposed to pharmacologic or genetic inhibition of SMARCA5, the ATPase subunit of ISWI, using ED2-AD101, siRNA mediated knockdown and stable CRISPR-Cas9 knockout. Furthermore, RNA-seq, DNase-seq and ChIP-seq of ISWI, H3K27ac and MED1 were performed to test genome wide association of ISWI with lineage-selective change in gene expression and enhancer activity.
Current results: In vitro experiments showed decreased osteogenic potential for stromal progenitor cells upon CRISPR-Cas9 mediated knockout, transient siRNA knockdown and pharmacological inhibition of SMARCA5. Furthermore, a correlation between change in ISWI binding and accessibility of chromatin (DNase-seq) during differentiation was found. Enrichment analysis showed that gene induction during osteoblast differentiation as well as adipocyte differentiation was associated with nearby gain in ISWI binding (+/- 50,000 bp from TSS).
Clinical perspectives: In vitro inhibition of ISWI activity has shown to affect the differentiation potential of stromal progenitor cells. Recapitulating similar effects on bone and fat formation in vivo and understanding the molecular mechanism, will provide a new drug target for diseases with defective osteoblast and adipocyte formation such as osteoporosis and obesity.
Title: Rapamycin alleviates bone loss in ovariectomized mice – Insights from a study in mice with heterogeneous background.
Status: Ongoing
Background and aim: Aging is the most significant risk factor for skeletal fragility and osteoporosis, yet no preventive strategies are currently available. Rapamycin, through its inhibition of mTOR (the mechanistic target of rapamycin), extends both lifespan and healthspan by counteracting age-related degenerative changes. However, its effects on musculoskeletal health remain unknown. This study investigates in genetically heterogenous UM-HET3 mice the impact of Rapamycin-enriched diet on bone phenotype following ovariectomy.
Materials and methods: Female HET3 mice were ovariectomized (OVX) or sham operated then fed 14 ppm Rapamycin or control diets for 4 and 8 weeks following the surgery. Microarchitecture and strength of long bones were evaluated by µCT and 3-point bending mechanical testing respectively. Bone resorption and senescence were analyzed by histology. RNA sequencing was performed on bone tissues.
Current results: OVX led to a significant reduction of 36.4% of BV/TV (trabecular bone volume) while animals fed rapamycin diet only lose 19.1% (OVX-RAPA vs OVX-CTL) mainly by maintaining their trabecular number only -2% in OVX-RAPA as compared to -21.1% in OVX-CTL. OVX led to impaired cortical bone (+21.9% porosity and -7.2% Co-Th in OVX-CTL as compared to SHAM-CTL). This impairment was exacerbated in OVX-RAPA (+48.8% porosity and -10.2% Co.Th) as compared to OVX-CTL, however bone strength parameters were unchanged between groups as tested by 3 point bending. Glucose tolerance was unchanged following OVX even though pancreas presented a 100% increase of their b-cell mass. Both RAPA groups exhibited a significant glucose intolerance as evaluated by GTT, fasted blood glucose level and AUC. Interestingly, their b-cell mass % was comparable to that of the SHAM-CTL group. RNA sequencing revealed that rapamycin enhanced expression of genes related to bone formation and autophagy. Rapamycin-enriched diet in UM-HET3 ovariectomized mice shows a positive effect on long bone trabecular parameters. Even though those mice present an impaired glucose metabolism and cortical parameters, the overall bone strength is unchanged. Further interventions with intermittent dosing are needed.
Clinical perspectives: Rapamycin has been extensively characterized and it is right to assume that low dose of this drug would be devoid of side-effects and a much safer alternative to hormone replacement therapies used to treat osteoporosis. This project might provide evidence that it is possible to improve bone loss experienced by post-menopausal women using highly cost-effective and safe measures. Additionally, the use of Rapamycin might improve bone aging phenotype and more broadly could alleviate age-induced changes.
Project: Pregnancy loss: the possible link to polycystic ovary syndrome and uterine malformations.
Status: The project started in 2024, and is expected to finish in 2026. Research participants are still undergoing enrollment in this project. Current status is (February 2025) 2950/3000 expected inclusions.
Background
Pregnancy loss occurs in one out of four pregnancies, and is associated with an increased risk of depression and anxiety among couples. Of the lost fetuses, 60% are aneuploid (having an incorrect number of chromosomes), while the remaining 40% are euploid (having the correct number of chromosomes) and can be considered healthy. Loss of healthy fetuses is more common among women with recurrent pregnancy loss, suggesting maternal factors as a potential cause. The purpose of the project is to investigate why women experience pregnancy loss during pregnancy. The study is unique in that chromosomal analysis of the lost fetus is performed in all participating women, enabling a focus on losses of healthy fetuses. The project’s foundation is a prospective cohort of unselected pregnancy losses (woman, man, and fetus) from gynecological departments Odense University Hospital and hospitals in the Capital Region. The project is part of the national project ’Copenhagen Odense Pregnancy Loss,’ which aims to uncover mechanisms behind pregnancy loss.
Current results: Pending
Clinical perspectives
There are two major clinical impact points of this project. Firstly the women enrolled in the study has the chance to learn if the fetus was healthy or sick and they get an evaluation of their thyroid function, early signs of type 2 diabetes and a 3D ultrasound scan of the uterus. In this way they can better the risk of another pregnancy loss in another subsequent pregnancy. Secondly the project aims at bettering the evaluation and highlighting which factors that poses a risk of euploid pregnancy loss, ultimately aiming at improving couples chance of giving birth once they are pregnant.
Project title: Insulin signaling and osteogenic potential in type 2 diabetes
Status: Completed in 2024, manuscript in preparation
Background: Greater risk of hip and non-vertebral fractures is recognized as a complication to long-standing T2D. Impaired insulin signaling in peripheral tissues precedes the development of T2D and cause dysregulation of whole-body metabolism in addition to cell type-specific changes. but whether bone cells are affected in T2D and to what extent impaired insulin signaling impacts bone formation in T2D is not known. In this study, we hypothesized that impaired insulin signaling in skeletal stem cells attenuates bone formation in individuals with T2D leading to an increased risk of fractures.
Results: By combining in vitro studies of insulin responses with single-cell transcriptomics and phosphoproteomics, we demonstrate that insulin responses in skeletal stem cells varies substantially between adult individuals with T2D, and that this variation is reflected in bone formation, thereby identifying a subgroup of individuals with T2D exhibiting low insulin signaling in their skeletal stem cells with possible increased fracture risk. Moreover, we identify a common underlying molecular profile, that attenuates the action of insulin and wnt signaling pathways in skeletal stem cells from individuals with T2D.
Clinical relevance: Improving insulin signaling in skeletal stem cells by reducing inflammation may promote bone formation and ultimately reduce fracture risk in a subgroup of individuals with T2D.
Project title: The acute effect of GLP-1 and GIP on human bone turnover
Status: Completed in 2024, manuscript in preparation
Background: Glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), are secreted postprandially and have emerged as a potential regulators of bone remodeling. Both hormones differentially target multiple tissues and are increasingly being used as pharmacological treatment options for both type 2 diabetes (T2D) and obesity, but despite a growing number of studies, the mechanism behind the effect of GLP-1 and GIP on bone remodeling remains unclear. This physiological study explores the acute differential effects between supraphysiological infusions of GLP-1, GIP and the combination on bone turnover, bone marrow metabolite profile and on stem cell properties in healthy male adults.
Results: By measuring bone turnover markers directly in the bone marrow, we find that both hormones are acutely extremely antiresorptive with CTX being suppressed by 80.0 8.9 % from baseline during infusion of GLP-1, 80.6 4.2 % from baseline during infusion of GIP and 85.0 2.8 % from baseline during infusion of GLP-1/GIP. GLP-1/GIP induce a significant increase in P1NP revealing a desired uncoupling effect of the bone remodeling process. The two hormones each induce the presence of specific metabolite profiles in the bone marrow indicating the induction of differential metabolic pathways by the hormones.
Clinical relevance: This study elucidates the acute impact of GLP-1 and GIP on bone turnover and on cellular metabolism and may help uncovering underlying molecular mechanisms with the future prospect of optimizing treatment duration in specific patient groups with low bone turnover, such as individuals with T2D.
Project title: SENolytics to Improve Osteoporosis therapy: a Randomised controlled clinical trial - The SENIOR Trial
Status of project: ongoing, recruiting participants, currently 46/120
Background: Primary osteoporosis is considered a condition occurring as response to loss of bone mass due to aging. One of the hallmarks of aging is the accumulation of cellular senescence. Studies in murine models showed that reducing cellular senescence increased bone mineral density and bone quality.
Aim: In this clinical trial we will investigate the effect of 20 weeks treatment with senolytics or antioxidant in 120 patients with increased fracture risk.
Methods: Trial participants will be randomised into one of 3 groups to receive: A) combination of 100mg Dasatinib (for 2 consecutive days every 28th day) + 1.250mg Quercetin (for 3 consecutive days every 28th day, B) 1g of nicotinamide riboside (NR), or C) Control group (no treatment).
The primary endpoint is changes in the bone turnover marker CTX measured at baseline, weeks 5, 13 and 21. Secondary endpoints are the changes in bone resorption marker tartrate resistant acid phosphatase (TRAcP) and bone formation markers (PINP, osteocalcin, and bone alkaline phosphatase). Some of the exploratory endpoints to be assessed we be Dual X-ray Scan (DXA) and HR-pQCT scans (wrist and ancles) to examine bone mineral density (BMD) and bone-architecture. The safety of senolytics will also be registered.
Current results: There are no current results.
Clinical perspectives: Targeting senescent cells to improve skeletal health and possibly other age-related complications is a novel approach for ameliorating age-relate diseases based on targeting fundamental mechanisms underlying age-related degenerative diseases. If succeeded, this opens the possibility of introducing new approaches for treatment of osteoporosis as a manifestation of the general aging process.
Project: Targeting mTOR with everolimus and/or physical training for preventing postmenopausal bone loss and accelerated skeletal aging. The RapaLoad study.
Status: Ongoing
Background:
It is estimated that women lose around 20-25% of bone mass during the 5-10 years period of postmenopausal transition and are therefore at a higher risk for developing osteoporosis and osteoporotic fragility fracture. Rapamycin, through its inhibition of mTOR (the mechanistic target of rapamycin), has been demonstrated in many preclinical animal models to extend lifespan and healthspan. Rapamycin and its analogs, including everolimus, have been used for many years at high doses as an immunosuppressant and anti-cancer drug.
Exercise training has been demonstrated to counteract age-related degenerative changes in several clinical studies. Additionally, exercise training has been shown to improve bone mass and prevent bone loss in postmenopausal women.
Aim: This study aims to determine if treatment with everolimus, exercise training, or their combination for 24 weeks enhances bone formation in healthy postmenopausal women.
Methods: A total of 136 postmenopausal women, aged 45-60 years, will be included in the trial. Participants will be randomized into one of four groups; 1) Control group (participants continue their life as usual), 2) Football fitness group (participants receive two one-hour training sessions per week for 24 weeks), 3) Everolimus group (participants receive one 5mg tablet of everolimus once a week for 24 weeks), 4) Everolimus and football fitness group (participants receive everolimus as described in group #3 and football training as described in group #2 for 24 weeks).
The primary endpoint is the percentage change in circulating levels of bone formation marker N-terminal fragment of procollagen type 1 (P1NP) at 24 weeks compared to baseline. Secondary endpoints include changes in circulating levels of CTX, TRAcP, osteocalcin and bALP, bone mineral density in the lumbar spine, total hip and femoral neck measured by DXA scan, bone microarchitecture assessed HR-qQCT, muscle function, and cardiopulmonary health.
Clinical perspectives: Postmenopausal women at risk of developing osteoporosis currently have no option for prevention. Since the aging process is the underlying mechanism of all age-related diseases, this study tests the combination of pharmacological intervention (low-dose everolimus) and non-pharmacological intervention (exercise training) for decreasing the rate of aging on musculoskeletal system and it may encourage testing this strategy for prevention of other age-related diseases.
If succeeded, this opens the possibility of introducing new approaches for preventing osteoporosis in postmenopausal women.
Main supervisor: Moustapha Kassem
Project:
“Physical training and rapamycin to enhance bone formation in aging (STRONGBONE)”
Project:
“Emotional change during hormone therapy in transgender men – investigating anxiety, depression aggression and relationships”