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Special Issue "Osteoporosis"

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Endocrinology and Metabolism".

Deadline for manuscript submissions: closed (15 May 2021).

Special Issue Editor

Dr. Alberto Falchetti
E-Mail Website
Guest Editor
Centro Hercolani and Villa Alba (GVM), 40123 Bologna and EndOsMet, Villa Donatello Private Hospital, 50132 Florence, Italy
Interests: osteoporosis; metabolic bone diseases; parathyroid diseases; multiple endocrine neoplasia; genetic diseases of bone
Special Issues and Collections in MDPI journals

Special Issue Information

Dear Colleagues,

Osteoporosis still represents a pathological condition that remains largely underdiagnosed and undertreated mainly due to the low frequency of screening and to the controversies in BMD testing standards. Testosterone, estrogens, SHBG, and FSH levels interact in determining the bone mass accrual, BMD maintenance, and lifetime decrease.

As a general example of this, in recent decades, the global rise of obesity and sedentary lifestyles, together with an aging population, lead to increased incidence and prevalence of type 2 diabetes, a known major cause of disability, socioeconomic costs, and increased risk of all-cause mortality. Fragility fractures are increasingly recognized as an important complication of T2DM. Osteoporosis is often an underdiagnosed T2DM related complication.

Appropriate early diagnosis of osteoporosis is mandatory in order to start adequate treatment of these subjects, representing a very important step in clinical practice as it may impact on mortality more than in women.

This Specail Issue aims to update the pathophysiology and preclinical approach to osteoporosis, overall fracture risk, including human affected by dysmetabolism, systemic disorders, with or without type 2 diabetes, to move the field forward and suggest how to decrease the fracture rate in the specific clinical scenario.

We welcome both original research and review articles.

Dr. Alberto Falchetti
Guest Editor

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Keywords

  • osteoporosis
  • fractures in T2DM
  • preclinical and instrumental diagnostic tools of bone fragility
  • pathogenesis of bone fragility, in general and according to a specific clinical scenario
  • biomarkers predictive of bone mass reduction as also of bone fragility
  • prevention of fractures
  • the role of antidiabetic drugs on bone health and fracture rate
  • the effects of antiosteoporotic drugs, in general and according to a specific clinical scenario

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Published Papers (9 papers)

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Research

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Article
Bone Status in a Mouse Model of Experimental Autoimmune-Orchitis
Int. J. Mol. Sci. 2021, 22(15), 7858; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22157858 - 23 Jul 2021
Viewed by 432
Abstract
Investigations in male patients with fertility disorders revealed a greater risk of osteoporosis. The rodent model of experimental autoimmune-orchitis (EAO) was established to analyze the underlying mechanisms of male infertility and causes of reduced testosterone concentration. Hence, we investigated the impact of testicular [...] Read more.
Investigations in male patients with fertility disorders revealed a greater risk of osteoporosis. The rodent model of experimental autoimmune-orchitis (EAO) was established to analyze the underlying mechanisms of male infertility and causes of reduced testosterone concentration. Hence, we investigated the impact of testicular dysfunction in EAO on bone status. Male mice were immunized with testicular homogenate in adjuvant to induce EAO (n = 5). Age-matched mice were treated with adjuvant alone (adjuvant, n = 6) or remained untreated (control, n = 7). Fifty days after the first immunization specimens were harvested. Real-time reverse transcription-PCR indicated decreased bone metabolism by alkaline phosphatase and Cathepsin K as well as remodeling of cell-contacts by Connexin-43. Micro computed tomography demonstrated a loss of bone mass and mineralization. These findings were supported by histomorphometric results. Additionally, biomechanical properties of femora in a three-point bending test were significantly altered. In summary, the present study illustrates the induction of osteoporosis in the investigated mouse model. However, results suggest that the major effects on bone status were mainly caused by the complete Freund’s adjuvant rather than the autoimmune-orchitis itself. Therefore, the benefit of the EAO model to transfer laboratory findings regarding bone metabolism in context with orchitis into a clinical application is limited. Full article
(This article belongs to the Special Issue Osteoporosis)
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Article
Loss of Wnt16 Leads to Skeletal Deformities and Downregulation of Bone Developmental Pathway in Zebrafish
Int. J. Mol. Sci. 2021, 22(13), 6673; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22136673 - 22 Jun 2021
Viewed by 581
Abstract
Wingless-type MMTV integration site family, member 16 (wnt16), is a wnt ligand that participates in the regulation of vertebrate skeletal development. Studies have shown that wnt16 can regulate bone metabolism, but its molecular mechanism remains largely undefined. We obtained the wnt16 [...] Read more.
Wingless-type MMTV integration site family, member 16 (wnt16), is a wnt ligand that participates in the regulation of vertebrate skeletal development. Studies have shown that wnt16 can regulate bone metabolism, but its molecular mechanism remains largely undefined. We obtained the wnt16−/− zebrafish model using the CRISPR-Cas9-mediated gene knockout screen with 11 bp deletion in wnt16, which led to the premature termination of amino acid translation and significantly reduced wnt16 expression, thus obtaining the wnt16−/− zebrafish model. The expression of wnt16 in bone-related parts was detected via in situ hybridization. The head, spine, and tail exhibited significant deformities, and the bone mineral density and trabecular bone decreased in wnt16−/− using light microscopy and micro-CT analysis. RNA sequencing was performed to explore the differentially expressed genes (DEGs). Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis found that the down-regulated DEGs are mainly concentrated in mTOR, FoxO, and VEGF pathways. Protein–protein interaction (PPI) network analysis was performed with the detected DEGs. Eight down-regulated DEGs including akt1, bnip4, ptena, vegfaa, twsg1b, prkab1a, prkab1b, and pla2g4f.2 were validated by qRT-PCR and the results were consistent with the RNA-seq data. Overall, our work provides key insights into the influence of wnt16 gene on skeletal development. Full article
(This article belongs to the Special Issue Osteoporosis)
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Article
Is the Jaw Bone Micro-Structure Altered in Response to Osteoporosis and Bisphosphonate Treatment? A Micro-CT Analysis
Int. J. Mol. Sci. 2021, 22(12), 6559; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22126559 - 18 Jun 2021
Viewed by 492
Abstract
The aim of the study was to quantify the micro-architectural changes of the jaw bone in response to ovariectomy, exposed or not to bisphosphonate treatment. A total of 47 Wistar rats were ovariectomized (OVX) or sham-operated (shOVX) and exposed to osteoporosis preventive treatment [...] Read more.
The aim of the study was to quantify the micro-architectural changes of the jaw bone in response to ovariectomy, exposed or not to bisphosphonate treatment. A total of 47 Wistar rats were ovariectomized (OVX) or sham-operated (shOVX) and exposed to osteoporosis preventive treatment for eight weeks either with bisphosphonates (alendronate, ALN; group OVX-ALN) three days/week at a dose of 2 mg/kg or with saline solution (untreated control condition; group OVX). The bone morphometric parameters of the trabecular jaw bone were assessed using ex vivo micro-computed tomography. The regions of interest investigated in the maxilla were the inter-radicular septum of the second molar and the tuber. The regions quantified in the mandible included the three molar regions and the condyle. A one-way analysis of variance followed by pairwise comparison using Tukey’s HSD and the Games–Howell test was conducted to explore significant differences between the groups. In the maxilla, OVX decreased the bone volume in the inter-radicular septum of the second molar. Bisphosphonate treatment was able to prevent this deterioration of the jaw bone. The other investigated maxillary regions were not affected by (un)treated ovariectomy. In the mandible, OVX had a significant negative impact on the jaw bone in the buccal region of the first molar and the inter-radicular region of the third molar. Treatment with ALN was able to prevent this jaw bone loss. At the condyle site, OVX significantly deteriorated the trabecular connectivity and shape, whereas preventive bisphosphonate treatment showed a positive effect on this trabecular bone region. No significant results between the groups were observed for the remaining regions of interest. In summary, our results showed that the effects of ovariectomy-induced osteoporosis are manifested at selected jaw bone regions and that bisphosphonate treatment is capable to prevent these oral bone changes. Full article
(This article belongs to the Special Issue Osteoporosis)
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Article
The Impact of the “Osteo” Component of Osteosarcopenia on Fragility Fractures in Post-Menopausal Women
Int. J. Mol. Sci. 2021, 22(10), 5256; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22105256 - 17 May 2021
Viewed by 657
Abstract
Osteosarcopenia, the coexistence of bone and muscle loss, is common in older adults, but its definition lacks international consensus. This cross-sectional study (n = 1199 post-menopausal women) aimed to determine the association between osteosarcopenia and fragility fractures and to investigate the impact [...] Read more.
Osteosarcopenia, the coexistence of bone and muscle loss, is common in older adults, but its definition lacks international consensus. This cross-sectional study (n = 1199 post-menopausal women) aimed to determine the association between osteosarcopenia and fragility fractures and to investigate the impact of the definition of the “osteo” component. Bone mineral density and bone microarchitecture were measured by dual-energy X-ray absorptiometry and the trabecular bone score (TBS), respectively. The “osteo” component of osteosarcopenia was classified as osteoporosis (T-score ≤ −2.5 SD), osteopenia/osteoporosis (T-score < −1 SD), and high-fracture-risk osteopenia (−2.5 SD < T-score < −1 SD)/osteoporosis (T-score ≤ −2.5 SD). The Fracture Risk Assessment Tool was used to identify high-fracture-risk osteopenia. Altogether, 30.3%, 32.2%, 14.4%, and 23.1% of participants had osteosarcopenia, osteoporosis alone, sarcopenia alone, and neither condition, respectively. The odds ratios between osteosarcopenia and fragility fractures were 3.70 (95% CI: 1.94–7.04) for osteosarcopenia, 2.48 (95% CI: 1.30–4.71) for osteoporosis alone, and 1.87 (95% CI: 0.84–4.14) for sarcopenia alone. Women with osteosarcopenia also had lower TBS, indicating worse bone microarchitecture. In conclusion, women with osteosarcopenia were more likely to have previously sustained a fracture compared to those without osteosarcopenia, with sarcopenia alone, and with osteoporosis alone. The relationship between osteosarcopenia and fracture risk may be best identified when considering high-fracture-risk osteopenia and osteoporosis. Full article
(This article belongs to the Special Issue Osteoporosis)
Article
3D Environment Is Required In Vitro to Demonstrate Altered Bone Metabolism Characteristic for Type 2 Diabetics
Int. J. Mol. Sci. 2021, 22(6), 2925; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22062925 - 13 Mar 2021
Cited by 1 | Viewed by 944
Abstract
A large British study, with almost 3000 patients, identified diabetes as main risk factor for delayed and nonunion fracture healing, the treatment of which causes large costs for the health system. In the past years, much progress has been made to treat common [...] Read more.
A large British study, with almost 3000 patients, identified diabetes as main risk factor for delayed and nonunion fracture healing, the treatment of which causes large costs for the health system. In the past years, much progress has been made to treat common complications in diabetics. However, there is still a lack of advanced strategies to treat diabetic bone diseases. To develop such therapeutic strategies, mechanisms leading to massive bone alterations in diabetics have to be well understood. We herein describe an in vitro model displaying bone metabolism frequently observed in diabetics. The model is based on osteoblastic SaOS-2 cells, which in direct coculture, stimulate THP-1 cells to form osteoclasts. While in conventional 2D cocultures formation of mineralized matrix is decreased under pre-/diabetic conditions, formation of mineralized matrix is increased in 3D cocultures. Furthermore, we demonstrate a matrix stability of the 3D carrier that is decreased under pre-/diabetic conditions, resembling the in vivo situation in type 2 diabetics. In summary, our results show that a 3D environment is required in this in vitro model to mimic alterations in bone metabolism characteristic for pre-/diabetes. The ability to measure both osteoblast and osteoclast function, and their effect on mineralization and stability of the 3D carrier offers the possibility to use this model also for other purposes, e.g., drug screenings. Full article
(This article belongs to the Special Issue Osteoporosis)
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Review

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Review
Characterization of Structural Bone Properties through Portable Single-Sided NMR Devices: State of the Art and Future Perspectives
Int. J. Mol. Sci. 2021, 22(14), 7318; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22147318 - 07 Jul 2021
Viewed by 553
Abstract
Nuclear Magnetic Resonance (NMR) is a well-suited methodology to study bone composition and structural properties. This is because the NMR parameters, such as the T2 relaxation time, are sensitive to the chemical and physical environment of the 1H nuclei. Although magnetic [...] Read more.
Nuclear Magnetic Resonance (NMR) is a well-suited methodology to study bone composition and structural properties. This is because the NMR parameters, such as the T2 relaxation time, are sensitive to the chemical and physical environment of the 1H nuclei. Although magnetic resonance imaging (MRI) allows bone structure assessment in vivo, its cost limits the suitability of conventional MRI for routine bone screening. With difficulty accessing clinically suitable exams, the diagnosis of bone diseases, such as osteoporosis, and the associated fracture risk estimation is based on the assessment of bone mineral density (BMD), obtained by the dual-energy X-ray absorptiometry (DXA). However, integrating the information about the structure of the bone with the bone mineral density has been shown to improve fracture risk estimation related to osteoporosis. Portable NMR, based on low-field single-sided NMR devices, is a promising and appealing approach to assess NMR properties of biological tissues with the aim of medical applications. Since these scanners detect the signal from a sensitive volume external to the magnet, they can be used to perform NMR measurement without the need to fit a sample inside a bore of a magnet, allowing, in principle, in vivo application. Techniques based on NMR single-sided devices have the potential to provide a high impact on the clinical routine because of low purchasing and running costs and low maintenance of such scanners. In this review, the development of new methodologies to investigate structural properties of trabecular bone exploiting single-sided NMR devices is reviewed, and current limitations and future perspectives are discussed. Full article
(This article belongs to the Special Issue Osteoporosis)
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Review
18F-Sodium Fluoride PET as a Diagnostic Modality for Metabolic, Autoimmune, and Osteogenic Bone Disorders: Cellular Mechanisms and Clinical Applications
Int. J. Mol. Sci. 2021, 22(12), 6504; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22126504 - 17 Jun 2021
Viewed by 668
Abstract
In a healthy body, homeostatic actions of osteoclasts and osteoblasts maintain the integrity of the skeletal system. When cellular activities of osteoclasts and osteoblasts become abnormal, pathological bone conditions, such as osteoporosis, can occur. Traditional imaging modalities, such as radiographs, are insensitive to [...] Read more.
In a healthy body, homeostatic actions of osteoclasts and osteoblasts maintain the integrity of the skeletal system. When cellular activities of osteoclasts and osteoblasts become abnormal, pathological bone conditions, such as osteoporosis, can occur. Traditional imaging modalities, such as radiographs, are insensitive to the early cellular changes that precede gross pathological findings, often leading to delayed disease diagnoses and suboptimal therapeutic strategies. 18F-sodium fluoride (18F-NaF)-positron emission tomography (PET) is an emerging imaging modality with the potential for early diagnosis and monitoring of bone diseases through the detection of subtle metabolic changes. Specifically, the dissociated 18F- is incorporated into hydroxyapatite, and its uptake reflects osteoblastic activity and bone perfusion, allowing for the quantification of bone turnover. While 18F-NaF-PET has traditionally been used to detect metastatic bone disease, recent literature corroborates the use of 18F-NaF-PET in benign osseous conditions as well. In this review, we discuss the cellular mechanisms of 18F-NaF-PET and examine recent findings on its clinical application in diverse metabolic, autoimmune, and osteogenic bone disorders. Full article
(This article belongs to the Special Issue Osteoporosis)
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Review
Application of microRNA in Human Osteoporosis and Fragility Fracture: A Systemic Review of Literatures
Int. J. Mol. Sci. 2021, 22(10), 5232; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22105232 - 15 May 2021
Cited by 2 | Viewed by 629
Abstract
MicroRNAs (miRNAs) could serve as ideal entry points to the deregulated pathways in osteoporosis due to their relatively simple upstream and downstream relationships with other molecules in the signaling cascades. Our study aimed to give a comprehensive review of the already identified miRNAs [...] Read more.
MicroRNAs (miRNAs) could serve as ideal entry points to the deregulated pathways in osteoporosis due to their relatively simple upstream and downstream relationships with other molecules in the signaling cascades. Our study aimed to give a comprehensive review of the already identified miRNAs in osteoporosis from human blood samples and provide useful information for their clinical application. A systematic literature search for relevant studies was conducted in the Pubmed database from inception to December 2020. We set two essential inclusion criteria: human blood sampling and design of controlled studies. We sorted the results of analysis on human blood samples according to the study settings and compiled the most promising miRNAs with analyzed diagnostic values. Furthermore, in vitro and in vivo evidence for the mechanisms of the identified miRNAs was also illustrated. Based on both diagnostic value and evidence of mechanism from in vitro and in vivo experiments, miR-23b-3p, miR-140-3p, miR-300, miR-155-5p, miR-208a-3p, and miR-637 were preferred candidates in diagnostic panels and as therapeutic agents. Further studies are needed to build sound foundations for the clinical usage of miRNAs in osteoporosis. Full article
(This article belongs to the Special Issue Osteoporosis)
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Other

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Case Report
A Novel Germline Mutation of ADA2 Gene in Two “Discordant” Homozygous Female Twins Affected by Adenosine Deaminase 2 Deficiency: Description of the Bone-Related Phenotype
Int. J. Mol. Sci. 2021, 22(15), 8331; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22158331 - 03 Aug 2021
Viewed by 518
Abstract
Adenosine Deaminase 2 Deficiency (DADA2) syndrome is a rare monogenic disorder prevalently linked to recessive inherited loss of function mutations in the ADA2/CECR1 gene. It consists of an immune systemic disease including autoinflammatory vasculopathies, with a frequent onset at infancy/early childhood age. DADA2 [...] Read more.
Adenosine Deaminase 2 Deficiency (DADA2) syndrome is a rare monogenic disorder prevalently linked to recessive inherited loss of function mutations in the ADA2/CECR1 gene. It consists of an immune systemic disease including autoinflammatory vasculopathies, with a frequent onset at infancy/early childhood age. DADA2 syndrome encompasses pleiotropic manifestations such as stroke, systemic vasculitis, hematologic alterations, and immunodeficiency. Although skeletal abnormalities have been reported in patients with this disease, clear information about skeletal health, with appropriate biochemical-clinical characterization/management, its evolution over time and any appropriate clinical management is still insufficient. In this paper, after a general introduction shortly reviewing the pathophysiology of Ada2 enzymatic protein, its potential role in bone health, we describe a case study of two 27 year-old DADA2 monozygotic female twins exhibiting bone mineral density and bone turnover rate abnormalities over the years of their clinical follow-up. Full article
(This article belongs to the Special Issue Osteoporosis)
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