Publications by authors named "Lorenz C Hofbauer"

254 Publications

New insights into the role of glycosaminoglycans in the endosteal bone microenvironment.

Biol Chem 2021 Jul 29. Epub 2021 Jul 29.

Division of Endocrinology, Diabetes, and Metabolic Bone Diseases, Department of Medicine III, Medical Center, Technische Universität Dresden, D-01307Dresden, Germany.

The bone microenvironment is a complex tissue in which heterogeneous cell populations of hematopoietic and mesenchymal origin interact with environmental cues to maintain tissue integrity. Both cellular and matrix components are subject to physiologic challenges and can dynamically respond by modifying cell/matrix interactions. When either component is impaired, the physiologic balance is lost. Here, we review the current state of knowledge of how glycosaminoglycans - organic components of the bone extracellular matrix - influence the bone micromilieu. We point out how they interact with mediators of distinct signaling pathways such as the RANKL/OPG axis, BMP and WNT signaling, and affect the activity of bone remodeling cells within the endosteal niche summarizing their potential for therapeutic intervention.
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http://dx.doi.org/10.1515/hsz-2021-0174DOI Listing
July 2021

Rodent Models of Spondyloarthritis Have Decreased White and Bone Marrow Adipose Tissue Depots.

Front Immunol 2021 2;12:665208. Epub 2021 Jun 2.

Department of Medicine III & Center for Healthy Aging, Technische Universität Dresden, Dresden, Germany.

Bone marrow adipose tissue (BMAT) has recently been recognized as a distinct fat depot with endocrine functions. However, if and how it is regulated by chronic inflammation remains unknown. Here, we investigate the amount of white fat and BMAT in HLA-B27 transgenic rats and curdlan-challenged SKG mice, two well-established models of chronic inflammatory spondyloarthritis (SpA). Subcutaneous and gonadal white adipose tissue and BMAT was reduced by 65-70% and by up to 90% in both experimental models. Consistently, B27 rats had a 2-3-fold decrease in the serum concentrations of the adipocyte-derived cytokines adiponectin and leptin as well as a 2-fold lower concentration of triglycerides. The bone marrow of B27 rats was further characterized by higher numbers of neutrophils, lower numbers of erythroblast precursors, and higher numbers of IL-17 producing CD4 T cells. IL-17 concentration was also increased in the serum of B27 rats. Using a cell culture model, we show that high levels of IL-17 in the serum of B27 rats negatively impacted adipogenesis (-76%), an effect that was reversed in the presence of neutralizing anti-IL-17 antibody. In summary, these findings show BMAT is severely reduced in two experimental models of chronic inflammatory SpA and suggest that IL-17 is involved in this process.
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http://dx.doi.org/10.3389/fimmu.2021.665208DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8207134PMC
June 2021

CHIP & HIPs: Clonal Hematopoiesis is Common in Hip Arthroplasty Patients and Associates with Autoimmune Disease.

Blood 2021 Jun 17. Epub 2021 Jun 17.

German Cancer Consortium, partner site Munich, Germany.

Clonal hematopoiesis (CH) is an age-related condition predisposing to blood cancer and cardiovascular disease (CVD). Murine models demonstrate CH-mediated altered immune function and proinflammation. Low-grade inflammation has been implicated in the pathogenesis of osteoarthritis (OA), the main indication for total hip arthroplasty (THA). THA-derived hip bones serve as a major source of 'healthy' hematopoietic cells in experimental hematology. We prospectively investigated frequency and clinical associations of CH in 200 patients without known hematologic disease undergoing THA. Prevalence of CH was 50%, including 77 patients with CH of indeterminate potential (CHIP, defined as somatic variants with allele frequencies [VAF] ≥2%), and 23 patients harboring CH with lower mutation burden (VAF 1-2%). Most commonly mutated genes were DNMT3A (29.5%), TET2 (15.0%) and ASXL1 (3.5%). CHIP significantly associated with lower hemoglobin, higher mean corpuscular volume, prior/present malignant disease, and CVD. Strikingly, we observed a previously unreported association of CHIP with autoimmune diseases (AID; multivariate adjusted odds ratio, 6.6; 95% confidence interval [1.7, 30]; p=0.0081). These findings underscore the association between CH and inflammatory diseases. Our results have considerable relevance for management of patients with OA and AID or mild anemia, and question use of hip bone-derived cells as 'healthy' experimental controls.
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http://dx.doi.org/10.1182/blood.2020010163DOI Listing
June 2021

Individualized Bone-Protective Management in Long-Term Cancer Survivors With Bone Metastases.

J Bone Miner Res 2021 Jun 16. Epub 2021 Jun 16.

Division of Endocrinology, Diabetes and Bone Diseases & Center for Healthy Ageing, Department of Medicine III, Technische Universität Dresden, Dresden, Germany.

Antiresorptive therapy is an important component of a multimodal approach to treating patients with advanced malignancies and metastatic bone disease. Over the past decade, overall survival of affected patients has improved in most cancer entities, and long-term disease control is a realistic goal in many cases. There are emerging clinical studies showing the benefits of an initial antiresorptive therapy using bisphosphonates or denosumab. However, some adverse events of these therapies, such as osteonecrosis of the jaw, correlate with the cumulative doses given, and there is an increasing clinical need for new antiresorptive concepts to treat long-term survivors. This review summarizes the clinical evidence of antiresorptive therapies across different cancers with bone involvement and presents concepts of dose-reduction protocols for long-term survivors with established metastatic bone disease. © 2021 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).
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http://dx.doi.org/10.1002/jbmr.4391DOI Listing
June 2021

The Role of Inflammation in Breast and Prostate Cancer Metastasis to Bone.

Int J Mol Sci 2021 May 11;22(10). Epub 2021 May 11.

Mildred Scheel Early Career Center, Division of Endocrinology, Diabetes, and Bone Diseases, Department of Medicine III, Technische Universität Dresden, 01159 Dresden, Germany.

Tumor metastasis to bone is a common event in multiple forms of malignancy. Inflammation holds essential functions in homeostasis as a defense mechanism against infections and is a strategy to repair injured tissue and to adapt to stress conditions. However, exaggerated and/or persistent (chronic) inflammation may eventually become maladaptive and evoke diseases such as autoimmunity, diabetes, inflammatory tissue damage, fibrosis, and cancer. In fact, inflammation is now considered a hallmark of malignancy with prognostic relevance. Emerging studies have revealed a central involvement of inflammation in several steps of the metastatic cascade of bone-homing tumor cells through supporting their survival, migration, invasion, and growth. The mechanisms by which inflammation favors these steps involve activation of epithelial-to-mesenchymal transition (EMT), chemokine-mediated homing of tumor cells, local activation of osteoclastogenesis, and a positive feedback amplification of the protumorigenic inflammation loop between tumor and resident cells. In this review, we summarize established and evolving concepts of inflammation-driven tumorigenesis, with a special focus on bone metastasis.
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http://dx.doi.org/10.3390/ijms22105078DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8151893PMC
May 2021

Skeletal endocrinology: where evolutionary advantage meets disease.

Bone Res 2021 May 28;9(1):28. Epub 2021 May 28.

Department of Medicine III & Center for Healthy Aging, Technische Universität Dresden, Dresden, Germany.

The regulation of whole-body homeostasis by the skeleton is mediated by its capacity to secrete endocrine signaling molecules. Although bone-derived hormones confer several adaptive benefits, their physiological functions also involve trade-offs, thus eventually contributing to disease. In this manuscript, we discuss the origins and functions of two of the best-studied skeletal mediators, fibroblast growth factor 23 and osteocalcin, in an evolutionary context. Moreover, we provide a theoretical framework seeking to explain the broad involvement of these two hormones in amniote physiology as well as their potential to fuel the development and progression of diseases. Vice versa, we outline which perturbations might be amenable to manipulation of these systems and discuss limitations and ongoing challenges in skeletal endocrine research. Finally, we summarize unresolved questions and potential future studies in this thriving field.
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http://dx.doi.org/10.1038/s41413-021-00149-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8163738PMC
May 2021

Erwiderung auf den Leserbrief zum Beitrag: „Testosteronmangel im Alter – was ist zu tun“.

Dtsch Med Wochenschr 2021 May 19. Epub 2021 May 19.

Bereich Endokrinologie, Diabetes und Knochenstoffwechselerkrankungen und Zentrum für gesundes Altern, Medizinische Klinik und Poliklinik III, Universitätsklinikum Carl Gustav Carus der Technischen Universität Dresden.

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http://dx.doi.org/10.1055/a-1423-2691DOI Listing
May 2021

Luspatercept restores SDF-1-mediated hematopoietic support by MDS-derived mesenchymal stromal cells.

Leukemia 2021 May 17. Epub 2021 May 17.

German Consortium for Cancer Research (DKTK, Site Dresden), DKFZ, Heidelberg, Germany.

The bone marrow microenvironment (BMME) plays a key role in the pathophysiology of myelodysplastic syndromes (MDS), clonal blood disorders affecting the differentiation, and maturation of hematopoietic stem and progenitor cells (HSPCs). In lower-risk MDS patients, ineffective late-stage erythropoiesis can be restored by luspatercept, an activin receptor type IIB ligand trap. Here, we investigated whether luspatercept can modulate the functional properties of mesenchymal stromal cells (MSCs) as key components of the BMME. Luspatercept treatment inhibited Smad2/3 phosphorylation in both healthy and MDS MSCs and reversed disease-associated alterations in SDF-1 secretion. Pre-treatment of MDS MSCs with luspatercept restored the subsequent clonogenic potential of co-cultured HSPCs and increased both their stromal-adherence and their expression of both CXCR4 and ß3 integrin. Luspatercept pre-treatment of MSCs also increased the subsequent homing of co-cultured HSPCs in zebrafish embryos. MSCs derived from patients who had received luspatercept treatment had an increased capacity to maintain the colony forming potential of normal but not MDS HSPCs. These data provide the first evidence that luspatercept impacts the BMME directly, leading to a selective restoration of the ineffective hematopoiesis that is a hallmark of MDS.
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http://dx.doi.org/10.1038/s41375-021-01275-5DOI Listing
May 2021

Tumor- and osteoclast-derived NRP2 in prostate cancer bone metastases.

Bone Res 2021 May 14;9(1):24. Epub 2021 May 14.

Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA.

Understanding the role of neuropilin 2 (NRP2) in prostate cancer cells as well as in the bone microenvironment is pivotal in the development of an effective targeted therapy for the treatment of prostate cancer bone metastasis. We observed a significant upregulation of NRP2 in prostate cancer cells metastasized to bone. Here, we report that targeting NRP2 in cancer cells can enhance taxane-based chemotherapy with a better therapeutic outcome in bone metastasis, implicating NRP2 as a promising therapeutic target. Since, osteoclasts present in the tumor microenvironment express NRP2, we have investigated the potential effect of targeting NRP2 in osteoclasts. Our results revealed NRP2 negatively regulates osteoclast differentiation and function in the presence of prostate cancer cells that promotes mixed bone lesions. Our study further delineated the molecular mechanisms by which NRP2 regulates osteoclast function. Interestingly, depletion of NRP2 in osteoclasts in vivo showed a decrease in the overall prostate tumor burden in the bone. These results therefore indicate that targeting NRP2 in prostate cancer cells as well as in the osteoclastic compartment can be beneficial in the treatment of prostate cancer bone metastasis.
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http://dx.doi.org/10.1038/s41413-021-00136-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8121836PMC
May 2021

Soluble Neuropilin-1 is an independent marker of poor prognosis in early breast cancer.

J Cancer Res Clin Oncol 2021 Aug 21;147(8):2233-2238. Epub 2021 Apr 21.

Department of Gynecology and Obstetrics, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.

Background: Neuropilin-1 (NRP-1) is a transmembrane protein that acts as a multifunctional non-tyrosine kinase receptor with an established role in development and immunity. NRP-1 also regulates tumor biology, and high expression levels of tissue NRP-1 have been associated with a poor prognosis. Recently, ELISA-based quantification of soluble NRP-1 (sNRP-1) has become available, but little is known about the prognostic value of sNRP-1 in malignancies.

Materials And Methods: We measured sNRP-1 in the serum of 509 patients with primary early breast cancer (BC) at the time of diagnosis using ELISA.

Results: Mean serum values of sNRP-1 were 1.88 ± 0.52 nmol/l (= 130.83 ± 36.24 ng/ml). SNRP-1 levels weakly correlated with age, and were higher in peri- and postmenopausal patients compared to premenopausal patients, respectively (p < 0.0001). Low levels of sNRP-1 were associated with a significant survival benefit compared to high sNRP-1 levels at baseline (p = 0.005; HR 1.94; 95%CI 1.23-3.06). These findings remained significant after adjustment for tumor stage including lymph node involvement, grading, hormone receptor, HER2 status, and age (p = 0.022; HR 1.78; 95%CI 1.09-2.91).

Conclusion: Our findings warrant further investigations into the prognostic and therapeutic potential of sNRP-1 in BC.
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http://dx.doi.org/10.1007/s00432-021-03635-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8236462PMC
August 2021

Novel approaches to target the microenvironment of bone metastasis.

Nat Rev Clin Oncol 2021 Aug 19;18(8):488-505. Epub 2021 Apr 19.

Department of Tumor Biology, Center of Experimental Medicine, University Cancer Center Hamburg (UCCH), University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Bone metastases are a frequent and severe complication of advanced-stage cancers. Breast and prostate cancers, the most common malignancies in women and men, respectively, have a particularly high propensity to metastasize to bone. Conceptually, circulating tumour cells (CTCs) in the bloodstream and disseminated tumour cells (DTCs) in the bone marrow provide a snapshot of the dissemination and colonization process en route to clinically apparent bone metastases. Many cell types that constitute the bone microenvironment, including osteoblasts, osteocytes, osteoclasts, adipocytes, endothelial cells, haematopoietic stem cells and immune cells, engage in a dialogue with tumour cells. Some of these cells modify tumour biology, while others are disrupted and out-competed by tumour cells, thus leading to distinct phases of tumour cell migration, dormancy and latency, and therapy resistance and progression to overt bone metastases. Several current bone-protective therapies act by interrupting these interactions, mainly by targeting tumour cell-osteoclast interactions. In this Review, we describe the functional roles of the bone microenvironment and its components in the initiation and propagation of skeletal metastases, outline the biology and clinical relevance of CTCs and DTCs, and discuss established and future therapeutic approaches that specifically target defined components of the bone microenvironment to prevent or treat skeletal metastases.
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http://dx.doi.org/10.1038/s41571-021-00499-9DOI Listing
August 2021

Mice lacking DKK1 in T cells exhibit high bone mass and are protected from estrogen-deficiency-induced bone loss.

iScience 2021 Mar 23;24(3):102224. Epub 2021 Feb 23.

Department of Medicine III, Division of Endocrinology, Diabetes and Bone Diseases, Technische Universität Dresden, Dresden 01307, Germany.

The Wnt inhibitor Dickkopf-1 (DKK1) is a negative regulator of bone formation and bone mass and is dysregulated in various bone diseases. How DKK1 contributes to postmenopausal osteoporosis, however, remains poorly understood. Here, we show that mice lacking DKK1 in T cells are protected from ovariectomy-induced bone loss. Ovariectomy activated CD4+ and CD8+ T cells and increased their production of DKK1. Co-culture of activated T cells with osteoblasts inhibited Wnt signaling in osteoblasts, leading to impaired differentiation. Importantly, DKK1 expression in T cells also controlled physiological bone remodeling. T-cell-deficient knock-out mice had a higher bone mass with an increased bone formation rate and decreased numbers of osteoclasts compared with controls, a phenotype that was rescued by adoptive transfer of wild-type T cells. Thus, these findings highlight that T cells control bone remodeling in health and disease via their expression of DKK1.
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http://dx.doi.org/10.1016/j.isci.2021.102224DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7961106PMC
March 2021

Relevant genetic variants are common in women with pregnancy and lactation-associated osteoporosis (PLO) and predispose to more severe clinical manifestations.

Bone 2021 06 12;147:115911. Epub 2021 Mar 12.

Department of Osteology and Biomechanics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. Electronic address:

Pregnancy and lactation-associated osteoporosis (PLO) is a rare skeletal disorder characterized by early-onset osteoporosis typically manifestating with vertebral compression fractures or transient osteoporosis of the hip. We hypothesized that genetic variants may play a role in the development of PLO. This study aimed to analyze the presence of genetic variants and a potential association with the clinical presentation in PLO. 42 women with PLO were included from 2013 to 2019 in a multicenter study in Germany. All cases underwent comprehensive genetic analysis based on a custom-designed gene panel including genes relevant for skeletal disorders. The skeletal status was assessed using dual-energy X-ray absorptiometry (DXA). Subgroups were further analyzed by serum bone turnover markers (n = 31) and high-resolution peripheral computed tomography (HR-pQCT; n = 23). We detected relevant genetic variants in 21 women (50%), with LRP5, WNT1 and COL1A1/A2 being the most commonly involved genes. The mean number of vertebral compression fractures was 3.3 ± 3.4 per case with a significantly higher occurrence in the subgroup with genetic variants (4.8 ± 3.7 vs. 1.8 ± 2.3, p = 0.02). Among the total cohort, DXA Z-scores were significantly lower at the lumbar spine compared to the femoral neck (p = 0.002). HR-pQCT revealed a pronounced reduction of trabecular and cortical thickness, while trabecular number was within the reference range. Eighteen women (43%) received a bone-specific therapy (primarily teriparatide). Overall, a steep increase in bone mass (+37.7%) was observed after 3 years. In conclusion, pregnancy and lactation represent skeletal risk factors, which may unmask hereditary bone disorders leading to PLO. These cases were affected more severely. Nevertheless, a timely diagnosis and adequate treatment can ensure a substantial recovery potential even without specific therapy. Patients with genetically induced low bone turnover (e.g.; LRP5, WNT1) may especially benefit from osteo-anabolic medication.
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http://dx.doi.org/10.1016/j.bone.2021.115911DOI Listing
June 2021

From Pharmacology to Physiology: Endocrine Functions of μ-Opioid Receptor Networks.

Trends Endocrinol Metab 2021 05 3;32(5):306-319. Epub 2021 Mar 3.

Department of Medicine III and Center for Healthy Aging, Technische Universität Dresden, Dresden, Germany.

The steady rise in opioid users and abusers has uncovered multiple detrimental health consequences of perturbed opioid receptor signaling, thereby creating the need to better understand the biology of these systems. Among endogenous opioid networks, μ-receptors have received special attention due to their unprecedented biological complexity and broad implications in homeostatic functions. Here, we review the origin, molecular biology, and physiology of endogenous opioids with a special focus on μ-opioid receptor networks within the endocrine system. Moreover, we summarize the current evidence supporting an involvement of the latter in regulating distinct endocrine functions. Finally, we combine these insights to present an integrated perspective on μ-opioid receptor biology and provide an outlook on future studies and unresolved questions in this field.
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http://dx.doi.org/10.1016/j.tem.2021.02.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8035298PMC
May 2021

High stroma-derived WNT5A is an indicator for low-risk prostate cancer.

FEBS Open Bio 2021 Apr 11;11(4):1186-1194. Epub 2021 Mar 11.

Division of Endocrinology, Diabetes, and Bone Diseases, Department of Medicine III and University Center for Healthy Aging, Technische Universität Dresden, Germany.

Prostate cancer (PCa) is a major cause of cancer-related death in men. Tumor-derived protein derived from Wnt5A gene (WNT5A) plays an important role in primary and metastatic PCa. Surrounding stroma cells also produce WNT5A, which may modulate the biology of PCa. Here, we assessed the role of stroma-derived WNT5A (stWNT5A) in primary PCa. A tissue microarray of samples obtained from 400 patients who underwent radical prostatectomy and control samples from 41 patients with benign prostate hyperplasia (BPH) was immunohistochemically assessed for expression of stWNT5A. The cores were scored for staining intensity: 0 (no staining), 1 (weak), 2 (moderate), or 3 (strong) and the stained stromal surface area: 0 (0%), 1 (1-25%), 2 (26-50%), 3 (51-75%), or 4 (76-100%). Gleason Score (GS) and TNM-stage were assessed by stratifying the cohort into high-risk (≥ pT3, pN1, GS ≥ 8) and non-high-risk patients. Ki67 and TUNEL assays were performed to assess proliferation and apoptosis. Expression of stWNT5A in BPH and tumor-free control samples was 1.2-fold higher compared to tumor samples (P < 0.001). Non-high-risk patients had a higher stWNT5A score than high-risk patients (P < 0.05). stWNT5A expression was not correlated with overall and cancer-specific survival. Proliferation (r  = 0.038, P < 0.001) and apoptosis (r  = 0.277, P < 0.001) negatively correlated with stWNT5A expression. In summary, we show that expression of stWNT5A is higher in benign tissue and non-high-risk PCa. Stroma-derived Wnt signaling and tumor-derived Wnt may differentially impact on tumor behavior. Future studies are warranted to dissect the Wnt profile in tumor vs. surrounding stroma tissues.
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http://dx.doi.org/10.1002/2211-5463.13131DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8016115PMC
April 2021

Late-onset hypogonadism: Clinical evidence, biological aspects and evolutionary considerations.

Ageing Res Rev 2021 05 18;67:101301. Epub 2021 Feb 18.

Department of Medicine III & Center for Healthy Aging, Technische Universität Dresden, Dresden, Germany.

The growing life expectancy in modern societies has raised scientific interest in identifying medical interventions to alleviate age-associated pathologies such as vascular calcification, cognitive decline, sarcopenia, osteoporosis and sexual dysfunction. Although no such single treatment has thus far been established in humans, some clinicians and patients have set their hopes on testosterone replacement therapy (TRT) as a potential "fountain of youth" for aging men. While TRT has proven effective in ameliorating distinct symptoms of late-onset hypogonadism (LOH), its safety remains to be demonstrated. Besides humans, multiple other species exhibit age-related reductions in circulating testosterone levels, raising the question whether such changes are an inherent, pathological feature of growing organismal age or rather reflect an adaptive response. In this manuscript, we apply key principles of evolutionary medicine to testosterone biology and LOH to provide a novel perspective on these two fields. Additionally, we discuss insightful data derived from the animal kingdom to illustrate the plasticity of individual testosterone trajectories across the lifespan, outline cost-benefit-considerations of TRT in LOH and highlight potential caveats of such therapies.
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http://dx.doi.org/10.1016/j.arr.2021.101301DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8043243PMC
May 2021

[Testosterone deficiency in the ageing male].

Dtsch Med Wochenschr 2021 Feb 29;146(3):141-145. Epub 2021 Jan 29.

Bereich Endokrinologie, Diabetes und Knochenstoffwechselerkrankungen und Zentrum für gesundes Altern, Medizinische Klinik und Poliklinik III, Universitätsklinikum Carl Gustav Carus der Technischen Universität Dresden.

Over the past years, a growing demand for testosterone replacement therapy in aging men has been noted in the US as well as in Europe. The current evidence for detrimental consequences of low testosterone in old men is largely based on retrospective studies. On the other hand, prospective placebo-controlled randomized trials investigating clinically relevant endpoints are limited. Clinical benefits of testosterone replacement therapy in ageing men include improved sexual function and libido, increase in muscle mass and -function, as well as bone mass accrual. Whether testosterone supplementation in ageing men confers an altered risk for cardiovascular disease and/or prostate cancer remains unclear. Ongoing clinical trials (e. g. TRAVERSE trial, NCT03 518 034) will help to resolve these questions.
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http://dx.doi.org/10.1055/a-1240-9784DOI Listing
February 2021

Role of osteogenic Dickkopf-1 in bone remodeling and bone healing in mice with type I diabetes mellitus.

Sci Rep 2021 Jan 21;11(1):1920. Epub 2021 Jan 21.

Department of Medicine III and Center for Healthy Aging, Medical Faculty, Technische Universität Dresden, Fetscherstr. 74, 01307, Dresden, Germany.

Type 1 diabetes mellitus (T1DM) is associated with low bone mass and a higher risk for fractures. Dickkopf-1 (Dkk1), which inhibits Wnt signaling, osteoblast function, and bone formation, has been found to be increased in the serum of patients with T1DM. Here, we investigated the functional role of Dkk1 in T1DM-induced bone loss in mice. T1DM was induced in 10-week-old male mice with Dkk1-deficiency in late osteoblasts/osteocytes (Dkk1;Dmp1-Cre, cKO) and littermate control mice by 5 subsequent injections of streptozotocin (40 mg/kg). Age-matched, non-diabetic control groups received citrate buffer instead. At week 12, calvarial defects were created in subgroups of each cohort. After a total of 16 weeks, weight, fat, the femoral bone phenotype and the area of the bone defect were analyzed using µCT and dynamic histomorphometry. During the experiment, diabetic WT and cKO mice did not gain body weight compared to control mice. Further they lost their perigonadal and subcutaneous fat pads. Diabetic mice had highly elevated serum glucose levels and impaired glucose tolerance, regardless of their Dkk1 levels. T1DM led to a 36% decrease in trabecular bone volume in Cre- negative control animals, whereas Dkk1 cKO mice only lost 16%. Of note, Dkk1 cKO mice were completely protected from T1DM-induced cortical bone loss. T1DM suppressed the bone formation rate, the number of osteoblasts at trabecular bone, serum levels of P1NP and bone defect healing in both, Dkk1-deficient and sufficient, mice. This may be explained by increased serum sclerostin levels in both genotypes and the strict dependence on bone formation for bone defect healing. In contrast, the number of osteoclasts and TRACP 5b serum levels only increased in diabetic control mice, but not in Dkk1 cKO mice. In summary, Dkk1 derived from osteogenic cells does not influence the development of T1DM but plays a crucial role in T1DM-induced bone loss in male mice by regulating osteoclast numbers.
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http://dx.doi.org/10.1038/s41598-021-81543-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7820472PMC
January 2021

Emerging Players in Prostate Cancer-Bone Niche Communication.

Trends Cancer 2021 02 24;7(2):112-121. Epub 2020 Oct 24.

Department of Medicine III and Center for Healthy Aging, Technische Universität Dresden, Dresden, Germany. Electronic address:

Patients with advanced prostate cancer (PCa) frequently develop skeletal metastases that are associated with fractures, disability, and increased mortality. Within the bone metastatic niche, mutual interactions between tumor cells and osteoblasts have been proposed as major contributors of osteotropism by PCa. Here, we highlight the emerging role of PCa-derived extracellular vesicles (EVs) in reprogramming osteoblasts and support of premetastatic niche formation. We also develop the concept of cancer-associated osteoblasts (CAOs) and outline the potential of PCa cells to acquire an osteoblastic phenotype, termed osteomimicry, as two strategies that PCa utilizes to create a favorable protected niche. Finally, we delineate future research that may help to deconstruct the complexity of PCa osteotropism.
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http://dx.doi.org/10.1016/j.trecan.2020.09.006DOI Listing
February 2021

Aberrant Bone Homeostasis in AML Is Associated with Activated Oncogenic FLT3-Dependent Cytokine Networks.

Cells 2020 11 9;9(11). Epub 2020 Nov 9.

Institute of Molecular Cell Biology, Center for Molecular Biomedicine (CMB), Jena University Hospital, 07745 Jena, Germany.

Acute myeloid leukaemia (AML) is a haematopoietic malignancy caused by a combination of genetic and epigenetic lesions. Activation of the oncoprotein FLT3 ITD (Fms-like tyrosine kinase with internal tandem duplications) represents a key driver mutation in 25-30% of AML patients. FLT3 is a class III receptor tyrosine kinase, which plays a role in cell survival, proliferation, and differentiation of haematopoietic progenitors of lymphoid and myeloid lineages. Mutant FLT3 ITD results in an altered signalling quality, which causes cell transformation. Recent evidence indicates an effect of FLT3 ITD on bone homeostasis in addition to haematological aberrations. Using gene expression data repositories of FLT3 ITD-positive AML patients, we identified activated cytokine networks that affect the formation of the haematopoietic niche by controlling osteoclastogenesis and osteoblast functions. In addition, aberrant oncogenic FLT3 signalling of osteogenesis-specific cytokines affects survival of AML patients and may be used for prognosis. Thus, these data highlight the intimate crosstalk between leukaemic and osteogenic cells within the osteohaematopoietic niche.
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http://dx.doi.org/10.3390/cells9112443DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7697865PMC
November 2020

The Bone Morphogenetic Protein Pathway: The Osteoclastic Perspective.

Front Cell Dev Biol 2020 16;8:586031. Epub 2020 Oct 16.

Department of Medicine III, Technische Universität Dresden, Dresden, Germany.

Bone health crucially relies on constant bone remodeling and bone regeneration, both tightly controlled processes requiring bone formation and bone resorption. Plenty of evidence identifies bone morphogenetic proteins (BMP) as major players in osteoblast differentiation and thus, bone formation. However, in recent past years, researchers also increasingly reported on the pivotal role of these multi-functional growth factors in osteoclast formation and activity. This review aims to summarize the current knowledge of BMP signaling within the osteoclast lineage, its role in bone resorption, and osteoblast-osteoclast coupling. Furthermore, subsequent clinical implications for recombinant BMP therapy will be discussed in view of recent preclinical and clinical studies.
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http://dx.doi.org/10.3389/fcell.2020.586031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7597383PMC
October 2020

Effect of Vitamin D Supplementation, Omega-3 Fatty Acid Supplementation, or a Strength-Training Exercise Program on Clinical Outcomes in Older Adults: The DO-HEALTH Randomized Clinical Trial.

JAMA 2020 11;324(18):1855-1868

Department of Biostatistics, Harvard T. H. Chan School of Public Health, Boston, Massachusetts.

Importance: The benefits of vitamin D, omega-3 fatty acids, and exercise in disease prevention remain unclear.

Objective: To test whether vitamin D, omega-3s, and a strength-training exercise program, alone or in combination, improved 6 health outcomes among older adults.

Design, Setting, And Participants: Double-blind, placebo-controlled, 2 × 2 × 2 factorial randomized clinical trial among 2157 adults aged 70 years or older who had no major health events in the 5 years prior to enrollment and had sufficient mobility and good cognitive status. Patients were recruited between December 2012 and November 2014, and final follow-up was in November 2017.

Interventions: Participants were randomized to 3 years of intervention in 1 of the following 8 groups: 2000 IU/d of vitamin D3, 1 g/d of omega-3s, and a strength-training exercise program (n = 264); vitamin D3 and omega-3s (n = 265); vitamin D3 and exercise (n = 275); vitamin D3 alone (n = 272); omega-3s and exercise (n = 275); omega-3s alone (n = 269); exercise alone (n = 267); or placebo (n = 270).

Main Outcomes And Measures: The 6 primary outcomes were change in systolic and diastolic blood pressure (BP), Short Physical Performance Battery (SPPB), Montreal Cognitive Assessment (MoCA), and incidence rates (IRs) of nonvertebral fractures and infections over 3 years. Based on multiple comparisons of 6 primary end points, 99% confidence intervals are presented and P < .01 was required for statistical significance.

Results: Among 2157 randomized participants (mean age, 74.9 years; 61.7% women), 1900 (88%) completed the study. Median follow-up was 2.99 years. Overall, there were no statistically significant benefits of any intervention individually or in combination for the 6 end points at 3 years. For instance, the differences in mean change in systolic BP with vitamin D vs no vitamin D and with omega-3s vs no omega-3s were both -0.8 (99% CI, -2.1 to 0.5) mm Hg, with P < .13 and P < .11, respectively; the difference in mean change in diastolic BP with omega-3s vs no omega-3s was -0.5 (99% CI, -1.2 to 0.2) mm Hg; P = .06); and the difference in mean change in IR of infections with omega-3s vs no omega-3s was -0.13 (99% CI, -0.23 to -0.03), with an IR ratio of 0.89 (99% CI, 0.78-1.01; P = .02). No effects were found on the outcomes of SPPB, MoCA, and incidence of nonvertebral fractures). A total of 25 deaths were reported, with similar numbers in all treatment groups.

Conclusions And Relevance: Among adults without major comorbidities aged 70 years or older, treatment with vitamin D3, omega-3s, or a strength-training exercise program did not result in statistically significant differences in improvement in systolic or diastolic blood pressure, nonvertebral fractures, physical performance, infection rates, or cognitive function. These findings do not support the effectiveness of these 3 interventions for these clinical outcomes.

Trial Registration: ClinicalTrials.gov Identifier: NCT01745263.
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http://dx.doi.org/10.1001/jama.2020.16909DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7656284PMC
November 2020

Fracture risk and management of discontinuation of denosumab therapy: a systematic review and position statement by ECTS.

J Clin Endocrinol Metab 2020 10 26. Epub 2020 Oct 26.

Medical Department of Endocrinology, Aarhus University Hospital, Aarhus, Denmark.

Context: Denosumab discontinuation is characterized by an increase in bone turnover overriding pre-treatment status, a rapid bone loss in the majority and multiple vertebral fractures (VFx) in some patients.

Methods: A working group of the European Calcified Tissue Society (ECTS) performed an updated systematic review of existing literature on changes of bone turnover, bone mineral density (BMD), and fracture risk after denosumab discontinuation and provided advice on management based on expert opinion.

Results: Important risk factors for multiple VFx following denosumab cessation are prevalent VFx, longer duration off therapy, greater gain in hip BMD during therapy, and greater loss of hip BMD after therapy according to a retrospective analysis of the FREEDOM Extension Study. Case series indicate that prior bisphosphonate therapy mitigates the biochemical rebound phenomenon after denosumab discontinuation, but it is uncertain whether this attenuation prevents BMD loss and fractures. Current evidence indicates partial efficacy of subsequent antiresorptive treatment with results seemingly dependent on duration of denosumab treatment.

Conclusions: A careful assessment of indications to start denosumab treatment is advised, especially for younger patients. A case for long-term treatment with denosumab can be made for patients at high fracture risk already on denosumab treatment given the favorable efficacy and safety profile. In case of denosumab discontinuation, alternative antiresorptive treatment should be initiated 6 months after the final denosumab injection. Assessment of bone turnover markers may help define the optimal regimen, pending results of ongoing RCTs. Patients having sustained VFx should be offered prompt treatment to reduce high bone turnover.
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http://dx.doi.org/10.1210/clinem/dgaa756DOI Listing
October 2020

Skeletal health in patients following allogeneic hematopoietic cell transplantation.

Bone 2020 Oct 10:115684. Epub 2020 Oct 10.

Division of Endocrinology and Metabolic Bone Diseases, Department of Medicine III, Technische Universität Dresden, Dresden, Germany; Center for Healthy Ageing, Department of Medicine III, Technische Universität Dresden, Dresden, Germany; German Cancer Consortium (DKTK), Dresden and German Cancer Research Center (DKFZ), Heidelberg, Germany.

Allogeneic hematopoietic cell transplantation (HCT) is a potentially curative approach for patients with certain hematological diseases, including several forms of lymphoma and leukemia. Besides several treatment-associated risks, transplanted patients are at an increased risk of developing osteoporosis. The underlying pathophysiology is complex and includes factors influenced directly by the disease as well as applied therapies like irradiation, chemotherapy and adjuvant immunosuppressive agents. In addition, patients are prone to secondary hypogonadism, and many patients will require long-term glucocorticoid therapy to mitigate graft-versus-host reactions. All these factors contribute to bone loss, but the individual risk profile may vary greatly. This review summarizes our knowledge on bone loss following allogenic HCT and provides screening and treatment recommendations.
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http://dx.doi.org/10.1016/j.bone.2020.115684DOI Listing
October 2020

Interactions of Anemia, FGF-23, and Bone in Healthy Adults-Results From the Study of Health in Pomerania (SHIP).

J Clin Endocrinol Metab 2021 Jan;106(1):e288-e299

Department of Medicine III and Center for Healthy Aging, Dresden Technical University Medical Center, Dresden, Germany.

Context: Osteoporosis and anemia are among the most common diseases in the aging population with an increasing prevalence worldwide.

Objective: As the bone-derived hormone fibroblast growth factor 23 (FGF-23) was recently reported to regulate erythropoiesis, we examined age-related associations between hemoglobin levels and bone quality, bone turnover, and FGF-23 concentrations.

Design: We used data from more than 5000 adult subjects who participated in the population-based cohorts of the Study of Health in Pomerania (SHIP and SHIP-Trend). Bone quality was assessed by quantitative ultrasound at the heel, bone turnover by measurement of carboxy-terminal telopeptide of type I collagen (CTX), and intact amino-terminal propeptide of type I procollagen (P1NP) serum concentrations, respectively. Anemia was defined as hemoglobin <13 g/dL in men and <12 g/dL in women. Carboxy-terminal FGF-23 levels were measured in plasma in a subset of 852 subjects.

Results: Anemic subjects had poorer bone quality, higher fracture risk, and lower serum levels of P1NP than nonanemic individuals. Linear regression models revealed positive associations between hemoglobin and bone quality in subjects aged 40 or above and inverse associations with CTX in subjects aged 60 or above. Hemoglobin and FGF-23 concentrations were inversely associated, while FGF-23 was not related to bone quality or turnover.

Conclusion: Our data corroborate a close link between FGF-23 and anemia, which is related to poor bone quality in elderly people. We observed no direct association of FGF-23 with bone parameters. Further studies are needed clarifying the role of FGF-23 on bone and red blood cell production.
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http://dx.doi.org/10.1210/clinem/dgaa716DOI Listing
January 2021

Effects of androgen excess and glucocorticoid exposure on bone health in adult patients with 21-hydroxylase deficiency.

J Steroid Biochem Mol Biol 2020 11 9;204:105734. Epub 2020 Aug 9.

Medizinische Klinik and Poliklinik IV, Klinikum der Universität München, LMU München, Munich, Germany. Electronic address:

Context: This study aimed to determine the role of modifiable predictors on bone health in congenital adrenal hyperplasia (CAH).

Design: Cross-sectional, single center study, including 97 patients (N = 42 men) with classic CAH due to 21-hydroxylase deficiency (N = 65 salt wasting, N = 32 simple virilizing).

Main Outcome Measures: Treatment-related predictors of bone health.

Results: Average T scores (-0.9 ± 1.4 vs. -0.4 ± 1.4; p = 0.036) as well as Z scores (-1.0 ± 1.3 vs. -0.1 ± 1.4; p = 0.012) at the spine in patients with CAH were significantly lower in men than women. While osteoporosis was rare in women, it was documented in 9.1% of men with CAH. There was a significant positive correlation of Z scores at the spine with advancing age in women with CAH (R² = 0.178; p = 0.003). In multivariate analysis, the intake of conventional hydrocortisone (HC) instead of synthetic glucocorticoids was independently associated with a higher bone mineral density (BMD) at the hip region in both sexes. In women, there was a positive association with vitamin D concentrations. Interestingly, higher sodium levels were associated with a lower BMD independent of renin levels and fludrocortisone dosage. Neither in men nor in women, markers of androgen control were predictive for BMD at any site. Markers of bone turnover indicated low bone turnover. No pathological fractures were documented.

Conclusions: Men with CAH are particularly prone to low bone density, while women seem to be relatively protected by androgen excess compared to the general female population. The use of HC instead of synthetic GCs for hormone replacement may translate into better bone health.
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http://dx.doi.org/10.1016/j.jsbmb.2020.105734DOI Listing
November 2020

Increased FGF-23 levels are linked to ineffective erythropoiesis and impaired bone mineralization in myelodysplastic syndromes.

JCI Insight 2020 08 6;5(15). Epub 2020 Aug 6.

Bone Lab Dresden, Department of Medicine III & Center for Healthy Aging, and.

Myelodysplastic syndromes (MDS) are clonal malignant hematopoietic disorders in the elderly characterized by ineffective hematopoiesis. This is accompanied by an altered bone microenvironment, which contributes to MDS progression and higher bone fragility. The underlying mechanisms remain largely unexplored. Here, we show that myelodysplastic NUP98‑HOXD13 (NHD13) transgenic mice display an abnormally high number of osteoblasts, yet a higher fraction of nonmineralized bone, indicating delayed bone mineralization. This was accompanied by high fibroblast growth factor-23 (FGF-23) serum levels, a phosphaturic hormone that inhibits bone mineralization and erythropoiesis. While Fgf23 mRNA expression was low in bone, brain, and kidney of NHD13 mice, its expression was increased in erythroid precursors. Coculturing these precursors with WT osteoblasts induced osteoblast marker gene expression, which was inhibited by blocking FGF-23. Finally, antibody-based neutralization of FGF-23 in myelodysplastic NHD13 mice improved bone mineralization and bone microarchitecture, and it ameliorated anemia. Importantly, higher serum levels of FGF‑23 and an elevated amount of nonmineralized bone in patients with MDS validated the findings. C‑terminal FGF‑23 correlated negatively with hemoglobin levels and positively with the amount of nonmineralized bone. Thus, our study identifies FGF-23 as a link between altered bone structure and ineffective erythropoiesis in MDS with the prospects of a targeted therapeutic intervention.
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http://dx.doi.org/10.1172/jci.insight.137062DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7455070PMC
August 2020

Challenges in Preventing Bone Loss Induced by Aromatase Inhibitors.

J Clin Endocrinol Metab 2020 10;105(10)

Division of Endocrinology and Metabolic Bone Diseases, Department of Medicine III, Technische Universität Dresden, Dresden, Germany.

Context: Aromatase inhibitors have become a mainstay in the adjuvant treatment regimen in postmenopausal women with hormone receptor-positive breast cancer. While many of these patients have an excellent long-term prognosis, adverse effects on bone represent an emerging complication of aromatase inhibitor treatment, resulting in substantial bone loss and fragility fractures. Treatment approaches to prevent aromatase inhibitor-induced bone loss typically consist of an antiresorptive approach with bisphosphonates or the RANKL antibody denosumab. However, different guidelines vary with respect to treatment thresholds, duration, and dosing. The choice of antiresorptive regime is further complicated by comorbidities and potential disease-modifying effects of individual agents.

Objective: This review summarizes the evidence of how aromatase inhibitors affect bone health and provides an update of clinical approaches to preserve bone strength in affected women. (J Clin Endocrinol Metab XX: 0-0, 2020).
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http://dx.doi.org/10.1210/clinem/dgaa463DOI Listing
October 2020

Contributions of Dickkopf-1 to Obesity-Induced Bone Loss and Marrow Adiposity.

JBMR Plus 2020 Jun 28;4(6):e10364. Epub 2020 Apr 28.

Department of Medicine III, Center for Healthy Aging Technische Universität Dresden Dresden Germany.

Low bone strength in overweight individuals is a significant medical problem. One important determinant of mesenchymal stem cell fate into osteoblasts or adipocytes is the Wnt signaling pathway. We recently showed that Dickkopf-1 (DKK1), a potent Wnt inhibitor, is upregulated in obese mice. In this study, we investigated the role of DKK1 in the pathogenesis of obesity-induced bone loss using global and tissue-specific KO mice. Obesity was induced in 8-week-old male mice with an inducible global (Rosa26-CreERT2) or osteoprogenitor- (Osx-Cre-) specific deletion of with a high-fat diet (HFD) containing 60% fat. After 12 weeks, body weight, bone volume, bone fat mass, and bone turnover were assessed. mice experienced a similar increase in body weight and white fat pads as control mice. A HFD significantly reduced trabecular bone mass and the bone formation rate in Cre- mice and mice. Interestingly, mice were protected from HFD-induced cortical bone loss. Furthermore, a HFD was associated with increased bone marrow fat in the femur, which was less pronounced in mice. Mice with an osteoprogenitor-specific deletion showed similar results as the global knockout, showing a protection against HFD-induced cortical bone loss and an accumulation of bone marrow fat, but a similar decrease in trabecular bone volume. In summary, DKK1 appears to contribute distinctly to cortical, but not trabecular bone loss in obesity. © 2020 The Authors. published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.
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http://dx.doi.org/10.1002/jbm4.10364DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7285751PMC
June 2020

Serum Profile of microRNAs Linked to Bone Metabolism During Sequential Treatment for Postmenopausal Osteoporosis.

J Clin Endocrinol Metab 2020 08;105(8)

Department of Medicine III, Technische Universität Dresden Medical Centre, Dresden, Germany.

Context: Serum expression of microRNAs (miRs) related to bone metabolism is affected by antiosteoporotic treatment.

Objective: To investigate the effect of sequential treatments on miR expression in postmenopausal women with osteoporosis.

Design: Observational, open label, nonrandomized clinical trial.

Setting: A single-center outpatient clinic.

Patients And Interventions: Denosumab (Dmab) was administered for 12 months in 37 women who were treatment-naïve (naïve group) (n = 11) or previously treated with teriparatide (TPTD group) (n = 20) or zoledronate (ZOL group) (n = 6).

Main Outcome Measures: Relative serum expression of miRs linked to bone metabolism at 3 and 6 months of Dmab treatment.

Results: Baseline relative expression of miR-21a-5p, miR-23a-3p, miR-29a-3p, and miR-338-3p was higher in the TPTD group, while the relative expression of miR-21a-5p was lower in the ZOL group compared to the naïve group. Dmab decreased the relative expression of miR-21a-5p at 3 months (fold change [FC] 0.43, P < 0.001) and 6 months (FC 0.34, P < 0.001), and miR-338-3p and miR-2861 at 6 months (FC 0.31, P = 0.041; FC 0.52, P = 0.016, respectively) in the whole cohort. In subgroup analyses, Dmab decreased the relative expression of miR-21a-5p, miR-29a-3p, miR-338-3p, and miR-2861 at 3 months (FC 0.13, P < 0.001; FC 0.68, P = 0.044; FC 0.46, P = 0.012; and FC 0.16, P < 0.001, respectively) and 6 months (FC 0.1, P < 0.001; FC 0.52, P < 0.001; FC 0.04, P = 0.006; and FC 0.2, P < 0.001, respectively) only within the TPTD group.

Conclusions: TPTD treatment potentially affects the expression of the pro-osteoclastogenic miR-21a-5p and miRs related to the expression of osteoblastic genes RUNX2 (miR23a-3p), COL1 (miR-29a-3p), and HDAC5 (miR-2861), while sequential treatment with Dmab acts in the opposite direction.
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http://dx.doi.org/10.1210/clinem/dgaa368DOI Listing
August 2020
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