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Abstract Background Low back pain (LBP) affects a significant proportion of the adult population. Potent anti-resorptive drugs such as intravenous zoledronic acid have been demonstrated to reduce Modic changes (MCs) upon magnetic resonance imaging (MRI) of the spine and concomitantly decrease associated LBP. It is uncertain whether oral alendronic acid has a similar effect. Methods 82 subjects were recruited in this case-control study. Treatment subjects (n = 41) received oral alendronic acid treatment for at least 1-year and were matched by gender and age (± 2) to control subjects (n = 41) not receiving any anti-osteoporotic medication. The prevalence, type, and extent of MCs were quantified upon T1 and T2-weighted MRIs of the lumbosacral spine. Results Treatment subjects received oral alendronic acid for 124.0 ± 62.1 weeks at the time of MRI assessment and exhibited a lower prevalence of MCs over the lumbosacral spine (18/41 vs. 30/41, p

Myopenia is a condition marked by progressive decline of muscle mass and strength and is associated with aging or obesity. It poses the risk of falling, with potential bone fractures, thereby also increasing the burden on family and society. Skeletal muscle wasting is characterized by a reduced number of myoblasts, impaired muscle regeneration and increased muscle atrophy markers (Atrogin-1, MuRF-1). Endothelin-1 (ET-1) is a potent vasoconstrictor peptide. Increased circulating levels of ET-1 is noted with aging and is associated with muscular fibrosis and decline of strength. However, the regulatory mechanism controlling its effect on myogenesis and atrophy remains unknown. In the present study, the effects of ET-1 on myoblast proliferation, differentiation and development were investigated in C2C12 cells and in ET-1-infused mice. The results show that ET-1, acting via ETB receptors, reduced insulin-stimulated cell proliferation, and also reduced MyoD, MyoG and MyHC expression in the differentiation processes of C2C12 myoblasts. ET-1 inhibited myoblast differentiation through ETB receptors and the p38 mitogen-activated protein kinase (MAPK)-dependent pathway. Additionally, ET-1 decreased MyHC expression in differentiated myotubes. Inhibition of proteasome activity by MG132 ameliorated the ET-1-stimulated protein degradation in differentiated C2C12 myotubes. Furthermore, chronic ET-1 infusion caused skeletal muscle atrophy and impaired exercise performance in mice. In conclusion, ET-1 inhibits insulin-induced cell proliferation, impairs myogenesis and induces muscle atrophy via ETB receptors and the p38 MAPK-dependent pathway. [ABSTRACT FROM AUTHOR]

Vitamin D, an essential micronutrient crucial for skeletal integrity and various non-skeletal physiological functions, exhibits limited bioavailability and stability in vivo. This study is focused on the development of polyethylene glycol (PEG)-grafted phospholipid micellar nanostructures co-encapsulating vitamin D3 and conjugated with alendronic acid, aimed at active bone targeting. Furthermore, these nanostructures are rendered optically traceable in the UV–visible region of the electromagnetic spectrum via the simultaneous encapsulation of vitamin D3 with carbon dots, a newly emerging class of fluorescents, biocompatible nanoparticles characterized by their resistance to photobleaching and environmental friendliness, which hold promise for future in vitro bioimaging studies. A systematic investigation is conducted to optimize experimental parameters for the preparation of micellar nanostructures with an average hydrodynamic diameter below 200 nm, ensuring colloidal stability in physiological media while preserving the optical luminescent properties of the encapsulated carbon dots. Comprehensive chemical-physical characterization of these micellar nanostructures is performed employing optical and morphological techniques. Furthermore, their binding affinity for the principal inorganic constituent of bone tissue is assessed through a binding assay with hydroxyapatite nanoparticles, indicating significant potential for active bone-targeting. These formulated nanostructures hold promise for novel therapeutic interventions to address skeletal-related complications in cancer affected patients in the future. [ABSTRACT FROM AUTHOR]

Background: Low back pain (LBP) affects a significant proportion of the adult population. Potent anti-resorptive drugs such as intravenous zoledronic acid have been demonstrated to reduce Modic changes (MCs) upon magnetic resonance imaging (MRI) of the spine and concomitantly decrease associated LBP. It is uncertain whether oral alendronic acid has a similar effect. Methods: 82 subjects were recruited in this case-control study. Treatment subjects (n = 41) received oral alendronic acid treatment for at least 1-year and were matched by gender and age (± 2) to control subjects (n = 41) not receiving any anti-osteoporotic medication. The prevalence, type, and extent of MCs were quantified upon T1 and T2-weighted MRIs of the lumbosacral spine. Results: Treatment subjects received oral alendronic acid for 124.0 ± 62.1 weeks at the time of MRI assessment and exhibited a lower prevalence of MCs over the lumbosacral spine (18/41 vs. 30/41, p < 0.001) as compared to control subjects. Amongst both groups, type 2 MCs were predominant. Quantification of type 2 MCs in treatment subjects revealed a significant reduction in area (113 ± 106 mm2 vs. 231 ± 144 mm2, p < 0.01) and volume (453 ± 427 mm3 vs. 925 ± 575 mm3, p < 0.01) affected by type 2 MCs in comparison to matched controls. Conclusion: Oral alendronic acid may be useful in the treatment of MC-associated LBP in patients with concomitant osteoporosis. [ABSTRACT FROM AUTHOR]

Pretargeting, which is the separation of target accumulation and the administration of a secondary imaging agent into two sequential steps, offers the potential to improve image contrast and reduce radiation burden for nuclear imaging. In recent years, the tetrazine ligation has emerged as a promising approach to facilitate covalent pretargeted imaging due to its unprecedented kinetics and bioorthogonality. Pretargeted bone imaging with TCO-modified alendronic acid (Aln-TCO) is an attractive model that allows the evaluation of tetrazines in healthy animals without the need for complex disease models or targeting regimens. Recent structure-activity relationship studies of tetrazines evaluated important parameters for the design of potent tetrazine-radiotracers for pretargeted imaging. However, limited information is available for 99mTc-labeled tetrazines. In this study, four tetrazines intended for labeling with fac-[99mTc(OH2)3 (CO)3]+ were synthesized and evaluated using an Aln-TCO mouse model. 3,6-bis(2-pyridyl)-1,2,4,5-Tz without additional linker showed higher pretargeted bone uptake and less background activity compared to the same scaffold with a PEG8 linker or 3-phenyl-1,2,4,5-Tz-based compounds. Additionally, improved bone/blood ratios were observed in pretargeted animals compared to animals receiving directly labeled Aln-TCO. The results of this study implicate 3,6-bis(2-pyridyl)-1,2,4,5-Tz as a promising scaffold for potential 99mTc-labeled tetrazines. [ABSTRACT FROM AUTHOR]

Introduction: Heterotopic ossification (HO) is a complex pathology often observed in combat injured casualties who have sustained severe, high energy polytraumatic extremity injuries. Once HO has developed, prophylactic therapies are limited outside of surgical excision. Tourniquet-induced ischemia injury (IR) exacerbates trauma-mediated musculoskeletal tissue injury, inflammation, osteogenic progenitor cell development and HO formation. Others have shown that focal adhesion kinase-2 (FAK2) plays a key role in regulating early inflammatory signaling events. Therefore, we hypothesized that targeting FAK2 prophylactically would mitigate extremity trauma induced IR inflammation and HO formation. Methods: We tested whether the continuous infusion of a FAK2 inhibitor (Defactinib, PF-573228; 6.94 µg/kg/min for 14 days) can mitigate ectopic bone formation (HO) using an established blast-related extremity injury model involving femoral fracture, quadriceps crush injury, three hours of tourniquetinduced limb ischemia, and hindlimb amputation through the fracture site. Tissue inflammation, infiltrating cells, osteogenic progenitor cell content were assessed at POD-7. Micro-computed tomography imaging was used to quantify mature HO at POD-56. Results: In comparison to vehicle control-treated rats, FAK2 administration resulted in no marked wound healing complications or weight loss. FAK2 treatment decreased HO by 43%. At POD-7, marked reductions in tissue proinflammatory gene expression and assayable osteogenic progenitor cells were measured, albeit no significant changes in expression patterns of angiogenic, chondrogenic and osteogenic genes. At the same timepoint, injured tissue from FAK-treated rats had fewer infiltrating cells. Additionally, gene expression analyses of tissue infiltrating cells resulted in a more measurable shift from an M1 inflammatory to an M2 antiinflammatory macrophage phenotype in the FAK2 inhibitor-treated group. Discussion: Our findings suggest that FAK2 inhibition may be a novel strategy to dampen trauma-induced inflammation and attenuate HO in patients at high risk as a consequence of severe musculoskeletal polytrauma. [ABSTRACT FROM AUTHOR]

Background: Deferoxamine (DFO) angiogenesis induction potential has been demonstrated in earlier studies, but not in the osteonecrosis of the femoral head (ONFH). In this study, we evaluated the outcome of ONFH treated with combined core decompression and local DFO administration loaded on Polylactic Glycolic Acid (PLGA). Patients and methods: In a pilot experimental study, six patients (10 hips) with early-stage non-traumatic ONFH were treated by core decompression, and concurrent injection of local DFO loaded on PLGA scaffold into the subchondral femoral head. Outcome measures were evaluated before the surgery and 12 and 24 months after the surgery and included visual analog scale (VAS) for pain, modified Merle d'Aubigné-Postel (MAP) score for hip function by MRI, and rate of osteonecrosis assessed by the modified. Results: The mean MPA score was 14.7 ± 1.16 before the surgery and 16.7 ± 1.41 one year after the surgery (P = 0.004). The mean VAS for pain was 4.7 ± 1.25 before the surgery and 1.8 ± 1.03 one year after the surgery (P = 0.005). The mean Kerboul angle was 219 ± 58.64 before the operation and 164.6 ± 41.82 one year after the operation (P < 0.001). Osteonecrosis progression or collapse was not seen in any of the patients at the final follow-up. No postoperative side effect attributed to the DFO was noticed, as well. Conclusion: In short-term follow-up, combined core decompression and local DFO administration not only prevent the progression of ONFH but also reduces the rate of osteonecrosis significantly. However, future controlled studies are required to confirm the present results. Trial registration: IRCT20161121031003N3, 16/04/2019. [ABSTRACT FROM AUTHOR]

Introduction: Femur head necrosis (FHN) is a challenging clinical disease with unclear underlying mechanism, which pathologically is associated with disordered metabolism. However, the disordered metabolism in cancellous bone of FHN was never analyzed by gas chromatography-mass spectrometry (GC-MS). Objectives: To elucidate altered metabolism pathways in FHN and identify putative biomarkers for the detection of FHN. Methods: We recruited 26 patients with femur head necrosis and 22 patients with femur neck fracture in this study. Cancellous bone tissues from the femoral heads were collected after the surgery and were analyzed by GC-MS based untargeted metabolomics approach. The resulting data were analyzed via uni- and multivariate statistical approaches. The changed metabolites were used for the pathway analysis and potential biomarker identification. Results: Thirty-seven metabolites distinctly changed in FHN group were identified. Among them, 32 metabolites were upregulated and 5 were downregulated in FHN. The pathway analysis showed that linoleic acid metabolism were the most relevant to FHN pathology. On the basis of metabolites network, L-lysine, L-glutamine and L-serine were deemed as the junctions of the whole metabolites. Finally, 9,12-octadecadienoic acid, inosine, L-proline and octadecanoic acid were considered as the potential biomarkers of FHN. Conclusion: This study provides a new insight into the pathogenesis of FHN and confirms linoleic acid metabolism as the core. [ABSTRACT FROM AUTHOR]

Carbon nanotubes (CNTs) are applied in a drug delivery system, which can be reacted with different structures such biomolecules. Bones have vital functions and are the locations of biochemical reactions in cells that might be exposed various diseases. As different metal ions are integral components of bone tissue with different functions in the physiological cellular medium as well as in bone treatment, they can be used differently as a basis or as a supplement for various materials in the field of bone repair. Therefore, this research aims to represent the recent progress in conjugated bisphosphonate (BP)-divalent transition metal ions of Mn2+, Fe2+, and Co2+ with an emphasis on the properties of interaction with a (6, 6) armchair carbon nanotube as a nanocarrier to exhibit the potential biomedical application of drug delivery. In this article, “CNT” linked to “BP“ of alendronic acid, ibandronic acid, neridronic acid, and pamidronic acid, which are chelated to transition metal cations of Mn2+, Fe2+, and Co2+, was investigated based on DFT insights for obtaining the electron charge density. Transition metals chelating with phosphonate groups, which are large with six O atoms with negative charges, are active in generating chelated complexes with the bisphosphonates [BPs- Mn2+/Fe2+/Co2+] through the status of drug design. In this work, B3LYP/6-311+G(d,p)/lanl2dz we have estimated the susceptibility of CNT for conjugating alendronic acid, ibandronic acid, neridronic acid, and pamidronic acid, which are chelated to transition metal cations of Mn2+, Fe2+, and Co2+ through NMR, NQR, IR, UV-VIS spectroscopy, and HOMO-LUMO analysis. Finally, the obtained results have confirmed that the possibility of applying CNT and BPs of alendronic acid, ibandronic acid, neridronic acid, and pamidronic acid becomes suitable in transition metal chelating for delivery application. The calculated HOMO–LUMO energy gaps for BPs of alendronic acid, ibandronic acid, neridronic acid, and pamidronic acid at the B3LYP/6-311+G (d,p) level have revealed that the energy gap reflects the chemical activity of the molecule.

To evaluate the histological adverse effects of alendronate administered systemically and topically in combination with orthodontic movement by intense force. Thirty-six 24-week-old female Wistar rats, ovariectomized, were used and divided into three groups (n = 12/group): control, locally treated with saline (0.07 ml/kg/week) (group 1) and experimental, treated with alendronic acid systemically (0.07 mg/kg/week) (group 2) and locally (7 mg/kg/week) (group 3). At 14 days, an orthodontic anchor was installed in the right first molar, and a force of 144 cN was applied for 28 days. The samples were processed for histological evaluation. Descriptive statistics, Shapiro-Wilk tests, one-way ANOVA with Bonferroni correction, one-way repeated measures ANOVA and chi-square tests were performed. All tests were statistically significant at p <0.05. The adverse events found in all groups were inflammation and osteoclastic activity. In the bisphosphonate-treated groups, there were statistically significant differences (p = 0.005) in the osteoclastic activity between the two hemiarcates. All rats in group 2 presented paralytic ileus. Compared to local administration, systemic treatment with alendronic acid produces more adverse effects, such as inflammation, fibrinoid necrosis, and osteoclastic activity. During the application of intense forces, it was not possible to show that there is necrosis associated with bisphosphonates. [ABSTRACT FROM AUTHOR]

This study aims to compare the anti-osteoporotic drugs alendronic acid (ALN) and flufenamic acid (FA) alone impregnate into nanoparticles of mesoporous bioactive glass (nMBG), which further composites calcium phosphate cement (CPC) and investigates their in vitro performance. The drug release, physicochemical properties, and biocompatibility of nMBG@CPC composite bone cement are tested, and the effect of the composites on improving the proliferation and differentiation efficiency of mouse precursor osteoblasts (D1 cells) is also investigated. Drug release shows that FA impregnates nMBG@CPC composite, a large amount of FA is released rapidly within 8 h, gradually reaching a stable release within 12 h, followed by a slow and sustained release within 14 days, and then reaches a plateau within 21 days. The release phenomenon confirms that the drug-impregnated nBMG@CPC composite bone cement effectively achieves slow drug delivery. The working time and setting time of each composite are within 4–10 min and 10–20 min, respectively, meeting the operational requirements of clinical applications. The addition of nMBG nanoparticles in the CPC matrix did not prevent the aggregation phenomenon under microstructural observation, thus resulting in a decrease in the strength of the nMBG@CPC composite. However, after 24 h of immersed reaction, the strength of each 5 wt.% nMBG impregnated with different concentrations of FA and ALN is still greater than 30 MPa, which is higher than the general trabecular bone strength. The drug-impregnated nMBG@CPC composites did not hinder the product formation and exhibit biocompatibility. Based on the proliferation and mineralization of D1 cells, the combination of nMBG with abundant FA and ALN in CPC is not conducive to the proliferation of D1 cells. However, when D1 cells are contact cultured for 21 days, alkaline phosphatase (ALP) enzyme activity shows higher ALP secretion from drug-impregnated nMBG@CPC composites than drug-free composites. Accordingly, this study confirms that nMBG can effectively impregnate the anti-osteoporosis drugs FA and ALN, and enhance the mineralization ability of osteoblasts. Furthermore, drug-impregnated nMBG applications can be used alone or in combination with CPC as a new option for osteoporotic bone-filling surgery. [ABSTRACT FROM AUTHOR]

Bone fracture healing is a complex physiologic process that involves changes in the expression of several thousand genes. Long noncoding RNAs (lncRNAs) may have critical biological roles in this process. The objectives of the present study were to determine whether BMSC-derived exosomal lncTUG1 can enhance osteogenic differentiation and thereby promoting bone fracture recovery and to investigate its potential mechanisms of action. Bone marrow mesenchymal stromal cells were isolated from mice and cultured for the following experiments. After adipogenic and osteogenic differentiation induction, Oil Red O, alizarin red S, and alkaline phosphatase staining solutions were applied to confirm the formation of lipid droplets and calcium nodules. Western blotting analyses, real-time reverse transcription PCR assays, luciferase reporter were performed to confirm relative RNA and protein expressions and luciferase activities of transfected cells. RNA pull-down and RNA immunoprecipitation assays were also carried to verify the interaction between lncTUG1 and miR-22-5p. Additionally, a mouse model of closed femoral fractures was generated to evaluate the in vivo effect of increased lncTUG1 on fracture healing. BMSC-derived exosomal lncTUG1 enhanced the activity of osteoblasts. Overexpression of miR-22-5p reversed the osteopromoting effect of increased lncTUG1. The knockdown of Anxa8 reversed the osteogenic effect of miR-22-5p inhibitors, indicating an interaction between Anxa8 and miR-22-5p. Upregulation of lncTUG1 could promote the fracture recovery in vivo. In conclusion, the present study highlights the functional importance of BMSC-derived exosomal lncTUG1 in the process of bone fracture recovery. [ABSTRACT FROM AUTHOR]

Atypical femoral fracture (AFF) is a rare complication related to the use of bisphosphonates (BPs). Herein, we analyzed the risk factors and onset patterns of AFF using the Japanese Adverse Drug Event Report database and reported the findings. First, the independent risk factors for AFF were gender (female), high body mass index, and medical history of osteoporosis, arthritis, and systemic lupus erythematosus (SLE). Drug-related risk factors for AFF included BPs (i.e., alendronic acid, ibandronic acid, etidronic acid, zoledronic acid, minodronic acid, risedronic acid), denosumab, prednisolone, lansoprazole, rabeprazole, exemestane, letrozole, eldecalcitol, and menatetrenone. Therefore, it appears that AFF is influenced by a combination of patient backgrounds and drugs, and that the risk of developing AFF is particularly high in patients with fragile bones (e.g., osteoporosis, arthritis, and SLE). Second, in the analysis of AFF onset patterns, the onset of AFF from BPs and denosumab took a long time (>1 year) to develop. Analysis using a Weibull distribution showed wear-out failure-type AFF onset for BPs and denosumab, and both osteoporosis and cancer patients with long-term administration of these drugs showed a tendency to have an increased risk of onset. AFF developed earlier in osteoporosis patients with long-term administration of BPs and denosumab than in cancer patients. [ABSTRACT FROM AUTHOR]

Endothelial impairment and dysfunction are closely related to the pathogenesis of steroid-associated osteonecrosis of the femoral head (SONFH). Recent studies have showed that hypoxia inducible factor-1α (HIF-1α) plays a crucial role in endothelial homeostasis maintenance. Dimethyloxalylglycine (DMOG) could suppress HIF-1 degradation and result in nucleus stabilization by repressing prolyl hydroxylase domain (PHD) enzymatic activity. Our results showed that methylprednisolone (MPS) remarkably undermined biological function of endothelial progenitor cells (EPC) by inhibiting colony formation, migration, angiogenesis, and stimulating senescence of EPCs, while DMOG treatment alleviated these effects by promoting HIF-1α signaling pathway, as evidenced by senescence-associated β-galactosidase (SA-β-Gal) staining, colony-forming unit, matrigel tube formation, and transwell assays. The levels of proteins related to angiogenesis were determined by ELISA and Western blotting. In addition, active HIF-1α bolstered the targeting and homing of endogenous EPCs to the injured endothelium in the femoral head. Histopathologically, our in vivo study showed that DMOG not only alleviated glucocorticoid-induced osteonecrosis but also promoted angiogenesis and osteogenesis in the femoral head as detected by microcomputed tomography (Micro-CT) analysis and histological staining of OCN, TRAP, and Factor Ⅷ. However, all of these effects were impaired by an HIF-1α inhibitor. These findings demonstrate that targeting HIF-1α in EPCs may constitute a novel therapeutic approach for the treatment of SONFH. [ABSTRACT FROM AUTHOR]

Carbon nanotubes (CNTs) are applied in a drug delivery system, which can be reacted with different structures such biomolecules. Bones have vital functions and are the locations of biochemical reactions in cells that might be exposed various diseases. As different metal ions are integral components of bone tissue with different functions in the physiological cellular medium as well as in bone treatment, they can be used differently as a basis or as a supplement for various materials in the field of bone repair. Therefore, this research aims to represent the recent progress in conjugated bisphosphonate (BP)-divalent transition metal ions of Mn2+, Fe2+, and Co2+ with an emphasis on the properties of interaction with a (6, 6) armchair carbon nanotube as a nanocarrier to exhibit the potential biomedical application of drug delivery. In this article, "CNT" linked to "BP" of alendronic acid, ibandronic acid, neridronic acid, and pamidronic acid, which are chelated to transition metal cations of Mn2+, Fe2+, and Co2+, was investigated based on DFT insights for obtaining the electron charge density. Transition metals chelating with phosphonate groups, which are large with six O atoms with negative charges, are active in generating chelated complexes with the bisphosphonates [BPs- Mn2+/Fe2+/Co2+] through the status of drug design. In this work, B3LYP/6-311+G(d,p)/lanl2dz we have estimated the susceptibility of CNT for conjugating alendronic acid, ibandronic acid, neridronic acid, and pamidronic acid, which are chelated to transition metal cations of Mn2+, Fe2+, and Co2+ through NMR, NQR, IR, UV-VIS spectroscopy, and HOMO-LUMO analysis. Finally, the obtained results have confirmed that the possibility of applying CNT and BPs of alendronic acid, ibandronic acid, neridronic acid, and pamidronic acid becomes suitable in transition metal chelating for delivery application. The calculated HOMO–LUMO energy gaps for BPs of alendronic acid, ibandronic acid, neridronic acid, and pamidronic acid at the B3LYP/6-311+G (d,p) level have revealed that the energy gap reflects the chemical activity of the molecule. [ABSTRACT FROM AUTHOR]

Background: Zinc sulfate is an inorganic compound used as a nutritional supplement, and it is known to aid in enhancing anti-inflammatory properties. Recurrent aphthous stomatitis is a commonest oral mucosal conditions characterized by painful recurring ulcers. Many current studies focus on establishing Zinc sulfate's potency against Recurrent aphthous stomatitis and its other uses in dentistry as it has anti-inflammatory activity with minimal adverse effects. Aim: To determine the effectiveness of zinc sulfate in the treatment of recurrent aphthous stomatitis. Materials and methods: A systematic review of clinical trials using zinc sulfate as an effective agent against Recurrent aphthous stomatitis. Various databases were searched and obtained a total of 112 articles, among which three studies were included. A systematic review was performed using PubMed, Scholar, Wiley, Cochrane and Science direct. From the total 112 articles that appeared from various sources, 109 articles were screened, and three studies were related to the research topic. This article was reported according to the systematic review guidelines. Result: Three studies were included in the systematic review, of which all are clinical trials showed that Zinc sulfate had a crucial role in reducing inflammation and improving oral hygiene status. The P-value of the three articles selected are 0.001, 0.0001 and > 0.05. Conclusion: With a comparative analysis between the existing related articles about the effectiveness of zinc sulfate in treating the recurrent aphthous stomatitis, the sequel of the effectiveness of zinc sulfate in the treatment of recurrent aphthous stomatitis have to be given. [ABSTRACT FROM AUTHOR]

This Viewpoint discusses the ongoing lawsuit between plaintiffs who had been affected by atypical femoral fractures while receiving alendronate and the drug manufacturer. [ABSTRACT FROM AUTHOR]

Murine models of long-bone fracture, stress fracture, and cortical defect are used to discern the cellular and molecular mediators of intramembranous and endochondral bone healing. Previous work has shown that Osterix (Osx+) and Dentin Matrix Protein-1 (DMP1+) lineage cells and their progeny contribute to injury-induced woven bone formation during femoral fracture, ulnar stress fracture, and tibial cortical defect repair. However, the contribution of preexisting versus newly-derived Osx+ and DMP1+ lineage cells in these murine models of bone injury is unclear. We addressed this knowledge gap by using male and female 12-week-old, tamoxifen-inducible Osx Cre_ERT2 and DMP1 Cre_ERT2 mice harboring the Ai9 TdTomato reporter allele. To trace pre-existing Osx+ and DMP1+ lineage cells, tamoxifen (TMX: 100 mg/kg gavage) was given in a pulse manner (three doses, 4 weeks before injury), while to label pre-existing and newly-derived lineage Osx+ and DMP1+ cells, TMX was first given 2 weeks before injury and continuously (twice weekly) throughout healing. TdTomato positive (TdT+) cell area and cell fraction were quantified from frozen histological sections of injured and uninjured contralateral samples at times corresponding with active woven bone formation in each model. We found that in uninjured cortical bone tissue, Osx Cre_ERT2 was more efficient than DMP1 Cre_ERT2 at labeling the periosteal and endosteal surfaces, as well as intracortical osteocytes. Pulse-labeling revealed that pre-existing Osx+ lineage and their progeny, but not pre-existing DMP1+ lineage cells and their progeny, significantly contributed to woven bone formation in all three injury models. In particular, these pre-existing Osx+ lineage cells mainly lined new woven bone surfaces and became embedded as osteocytes. In contrast, with continuous dosing, both Osx+ and DMP1+ lineage cells and their progeny contributed to intramembranous woven bone formation, with higher TdT+ tissue area and cell fraction in Osx+ lineage versus DMP1+ lineage calluses (femoral fracture and ulnar stress fracture). Similarly, Osx+ and DMP1+ lineage cells and their progeny significantly contributed to endochondral callus regions with continuous dosing only, with higher TdT+ chondrocyte fraction in Osx+ versus DMP1+ cell lineages. In summary, pre-existing Osx+ but not DMP1+ lineage cells and their progeny make up a significant amount of woven bone cells (particularly osteocytes) across three preclinical models of bone injury. Therefore, Osx+ cell lineage modulation may prove to be an effective therapy to enhance bone regeneration. [ABSTRACT FROM AUTHOR]

Objective: The osteoclastic bone resorption inhibitors might have positive effect in preventing femoral head collapse in patients with osteonecrosis of the femoral head (ONFH). However, as a novel osteoclastic inhibitor, whether denosumab can prevent collapse in steroid‐induced ONFH remains unknown. This study aims to evaluate the treatment effect of denosumab and the potential protective mechanism. Methods: This was a retrospective study. A total of 161 patients with steroid‐induced ONFH who underwent denosumab treatment were reviewed, and 209 untreated patients were selected as controls. Their clinical characteristics and radiological exam results were obtained. Patients were treated with 60 mg denosumab every 6 months for 2 years. The primary outcome was the incidence of femoral head collapse at 2 years after the initial diagnosis of ONFH. Secondary outcomes included the Harris hip score, progression of osteosclerosis, increase in necrotic area, bone marrow oedema relief, and bone mineral density increase in the femoral head. The Mann–Whitney U test and chi‐square tests were performed to identify the differences between the continuous and categorical variables, respectively. A multivariate logistic regression model was built to identify the factors associated with the treatment effect of denosumab. Results: The incidence of femoral head collapse was 42.24% (68/161) in the denosumab group and 54.07% (113/209) in the control group (χ2 = 5.094, p = 0.024; relative risk = 0.787, 95% CI = 0.627–0.973). The excellent‐good rates of the Harris hip score were 63.98% (103/161) in the denosumab group and 44.98% (94/209) in the control group (χ2 = 13.186, p < 0.001). The incidence of osteosclerosis progression in the denosumab group was 55.28% (89/161), which was significantly higher than that in the control group (43.54%, 91/209, χ2 = 5.016, p = 0.025). Meanwhile, a significant increase in bone mineral density was identified in 29.19% (47/161) and 7.18% (15/209) of patients in the denosumab and control groups, respectively (χ2 = 31.600, p < 0.001). The osteoclastic cytoplasm expression of LC3‐II was more positive in the control group than in the denosumab group (immunohistochemistry scoring: 3.58 ± 2.27 vs 6.33 ± 2.64, Z = −2.684, p = 0.007). A total of three independent factors were considered to be associated with the positive treatment effect of denosumab, the time of first denosumab administration (OR = 2.010, 95% CI = 1.272–3.177), osteosclerosis (OR = 1.583, 95% CI = 1.024–2.445), and the necrotic area before denosumab administration (medium necrotic area: OR = 2.084, 95% CI = 1.245–3.487; large necrotic area: OR = 2.211, 95% CI = 1.255–3.893). Conclusions: The current study demonstrated that denosumab had a positive effect on preventing femoral head collapse in patients with steroid ONFH. This effect might be closely associated with the inhibition of osteoclasts and their autophagy. [ABSTRACT FROM AUTHOR]

Introduction: Osteoarthritis is a chronic degenerative process of multifactor etiology, still largely unexplained. The activity of antioxidant enzymes and concentration of lipid peroxidation products in synovial membrane can be indirectly inferred from its oxidation-reduction status. The role of synovial membrane in the pathogenesis of osteoarthritis is relatively poorly understood, probably due to the difficulties in the acquisition of the material. Aim of the research: We sought to understand the association between osteoarthritis development and the activities of several antioxidant enzymes and levels of selected oxidative stress biomarkers in synovial membranes of osteoarthritic patients. Material and methods: The synovial tissue samples were collected from 67 patients. Of these patients, 48 underwent endoprosthetic total hip replacement due to osteoarthritis (the examined group), while 19 underwent surgical repair of a traumatic femoral neck fracture (the control group). Homogenates of synovial membrane were prepared according to our published method. The biochemical analysis included: activity of copper-zinc superoxide dismutase (CuZn-SOD), glutathione peroxidase (GPx), glutathione reductase (GR), catalase (CAT), concentrations of protein, malondialdehyde (MDA), thiol groups, and total oxidant status (TOS). Results: When comparing the examined group with the control group, the activity of CuZn-SOD was significantly elevated and the activity of GPx and the level of thiol groups were significantly decreased, whereas the activities of GR, CAT, the levels of protein, MDA, and TOS remained unaltered. Conclusions: Osteoarthritis is associated with oxidative stress and altered activities of the antioxidant enzymes in synovial membrane. However, lipid peroxidation seems not to be important for the etiology and development of osteoarthritis. [ABSTRACT FROM AUTHOR]

Acid attacks are on the rise, and they cause extensive and deep burns, especially on the face. The treatments used to improve the aesthetic, functional and social impact of non-acid scars do not always prove useful for acid scars. This article reports the case of a woman with an extended, mature, acid facial scar, caused by sulfuric acid assault, treated with a recent new procedure that combines the application of vacuum and electromagnetic fields. Before and after the treatment, the aesthetic appearance, and motor function of the face and neck were evaluated, as well as the level of hydration, the amount of sebum, the elasticity, and the pH of the skin. The improvements highlighted after the treatment of the aesthetic and functional characteristics of the face and neck, and of the physical parameters of the skin seemed to indicate that this particular treatment induces tissue regeneration, even in the nerve component. However, it is evident that the rehabilitation pathways of facial wounds and scars must be personalized, and must include continuous psychological support for the patient. [ABSTRACT FROM AUTHOR]

Steroid-induced osteonecrosis of femoral head (SANFH) involves impaired differentiation of bone marrow mesenchymal stem cells (BMSC), the mechanism of which is regulated by multiple microRNAs. Studies have shown that miR-145 is a key regulatory molecule of BMSC cells, but its mechanism in steroid-induced femur head necrosis remains unclear. The present study mainly explored the specific mechanism of miR-145 involved in SANFH. In this study dexamethasone, a typical glucocorticoid, was used to induce osteogenic differentiation of BMSC cells. Western blot, qPCR, CCK8 and flow cytometry were used to investigate the effects of miR-145 on the proliferation and differentiation of BMSC. The relationship between miR-145 and GABA Type A Receptor Associated Protein Like 1(GABARAPL1) was identified using dual luciferase reports and the effects of the two molecules on BMSC were investigated in vitro. The results showed that miR-145 was up-regulated in SANFH patients, while GABARAPL1 was down-regulated. Inhibition of miR-145 can improve apoptosis and promote proliferation and activation of BMSC. GABARAPL1 is a downstream target gene of miR-145 and is negatively regulated by miR-145. In conclusion, miR-145 regulates the proliferation and differentiation of glucocorticoid-induced BMSC cells through GABARAPL1 and pharmacologically inhibit targeting miR-145 may provide new aspect for the treatment of SANFH. [ABSTRACT FROM AUTHOR]

Bone resorption inhibitors, such as bisphosphonates (BP) and denosumab, are frequently used for the management of osteoporosis. Although both drugs reduce the risk of osteoporotic fractures, they are associated with a serious side effect known as medication-related osteonecrosis of the jaw (MRONJ). Sclerostin antibodies (romosozumab) increase bone formation and decrease the risk of osteoporotic fractures: however, their anti-resorptive effect increases ONJ. Thus, this study aimed to elucidate the role of sclerostin deletion in the development of MRONJ. Sclerostin knockout (Sost Δ26/Δ26 ) mice were used to confirm the development of ONJ by performing tooth extractions. To confirm the role of sclerostin deficiency in a more ONJ-prone situation, we used the BP-induced ONJ model in combination with severe periodontitis to evaluate the development of ONJ and bone formation in wild-type (WT) and Sost Δ26/Δ26 mice. Wound healing assay using gingival fibroblasts with or without sclerostin stimulation and tooth extraction socket healing were evaluated in the WT and Sost Δ26/Δ26 mice. ONJ was not detected in the extraction socket of Sost Δ26/Δ26 mice. Moreover, the incidence of ONJ was significantly lower in the Sost Δ26/Δ26 mice treated with BP compared to that of the WT mice. Osteogenic proteins, osteocalcin, and runt-related transcription factor 2, were expressed in the bone surface in Sost Δ26/Δ26 mice. Recombinant sclerostin inhibited gingival fibroblast migration. The wound healing rate of the extraction socket was faster in Sost Δ26/Δ26 mice than in WT mice. Sclerostin deficiency did not cause ONJ and reduced the risk of developing BP-induced ONJ. Enhanced bone formation and wound healing were observed in the tooth extraction socket. The use of romosozumab (anti-sclerostin antibody) has proven to be safe for surgical procedures of the jaw. • Tooth extraction did not induce osteonecrosis of the jaw (ONJ) in Sost knockout mice. • Development of bisphosphonate-induced ONJ was reduced in Sost knockout mice. • Gingival wound healing and bone formation in tooth extraction sockets were enhanced in Sost knockout mice. [ABSTRACT FROM AUTHOR]

Objective: To study the relationship between vascular endothelial cells (VEC) and autophagy, and its regulatory mechanism in steroid‐induced avascular necrosis of the femoral head (SANFH). Methods: In cell experiment, VEC were isolated and cultured from the femoral head of Sprague–Dawley rats and divided into three groups: blank control group (Ctrl), methylprednisolone group (MP), and methylprednisolone+mTOR‐shRNA group (MP + shmTOR). The autophagy formation was observed by transmission electron microscope. The mRNA expression of PI3K, Akt, mTOR, Beclin1 and MAP1LC3 was detected by RT‐PCR and the protein expression was detected by Western blot and immunofluorescence. Expression of the damage marker 6‐keto‐PGF1α was detected by the ELISA method. In vivo experiment, after establishing the model, the grouping method was the same as cell experiment. Autophagosomes were observed by same method, and the expression of related factors was detected by the same method in cell experiment. Results: In the cell experiment, autophagosomes in the MP group were significantly lower than in the Ctrl group, and the autophagosomes in the MP + shmTOR group were intermediate between two groups (P < 0.05). The mRNA expression levels of PI3K, Akt and mTOR in the MP group were significantly higher than in the Ctrl group, while the MP+ shmTOR group presented intermediate levels between these groups (average gray value were 3837.90, 2996.30, 3005.60, F = 428.64, P < 0.05). MRNA expression levels of Beclin1 and MAP1LC3 in the MP group were significantly lower than that in Ctrl group (P < 0.05). The content of 6‐keto‐PGF1α in the MP + shmTOR group was higher than in the Ctrl group and lower than in the MP group at the evaluated time intervals (average absorbance value were 104.98, 206.83, 145.91, F = 352.83, P < 0.01). In vivo experiment, the content of 6‐Keto‐PGF1α in the hormone group increased as time went on; the mTOR‐si group was higher than that in control group, but lower than that in the hormone group (P < 0.01). The mRNA expressions of Beclin1 and MAP1LC3 in the control group were higher than those in the hormone group, while the mRNA expressions of PI3K, Akt and mTOR were lower than those in the mTOR‐si group (P < 0.05). Conclusion: The steroid inhibited the physiological protective effect of autophagy on SANFH by increasing the expression of PI3K/Akt/mTOR signaling pathway related factors and decreasing the expression of Beclin1 and MAP1LC3 in the femoral head VEC. [ABSTRACT FROM AUTHOR]

Diffuse sclerosing osteomyelitis (DSO) is a rare inflammatory disease of the bone with a poorly understood aetiology. We present a case of a 26‐year‐old female with DSO, who has been living with this condition for over 12 years. Many different therapies have been used to attempt to manage her symptoms. She is currently taking oral alendronic acid when she is symptomatic. This case report demonstrates the complexity of managing cases of DSO, as we focus on the multiple treatment modalities used in this case and the response to these. Many cases in literature discuss the use of intravenous bisphosphonates, however, this is linked with a higher risk of medically related osteonecrosis of the jaw. In addition to other reported case studies and research, this case provides further evidence to support the use of oral bisphosphonates in the management of DSO. [ABSTRACT FROM AUTHOR]

As of 2023, more than 200 million people worldwide are living with osteoporosis. Oral bisphosphonates (BPs) are the primary treatment but can cause gastrointestinal (GI) side effects, reducing patient compliance. Microarray (MAP) technology has the potential to overcome GI irritation by facilitating the transdermal delivery of BPs. This study examines the delivery of alendronic acid (ALN) and risedronate sodium (RDN) using dissolving and hydrogel-forming MAPs for osteoporosis treatment. In vivo testing on osteoporotic female Sprague Dawley rats demonstrated the efficacy of MAPs, showing significant improvements in mean serum and bone alkaline phosphatase levels, bone volume, and porosity compared to untreated bilateral ovariectomy (OVX) controls. Specifically, MAP treatment increased mean bone volume to 55.04 ± 2.25 % versus 47.16 ± 1.71 % in OVX controls and reduced porosity to 44.30 ± 2.97 % versus 52.84 ± 1.70 % in the distal epiphysis of the femur. In the distal metaphysis, bone volume increased to 43.32 ± 3.24 % in MAP-treated rats compared to 24.31 ± 3.21 % in OVX controls, while porosity decreased to 55.39 ± 5.81 % versus 75.69 ± 3.21 % in OVX controls. This proof-of-concept study indicates that MAP technology has the potential to be a novel, patient-friendly alternative for weekly osteoporosis management., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

The syntheses and structures of ammonium salts of the active pharmaceutical agent (4‐aminium‐1‐hydroxybutylidine)‐1,1‐bisphosphonic acid (alendronic acid, LH5) have been examined. Three deprotonation states of the parent acid were achieved i. e. LH4−, LH32− and LH23−, and crystallisation gave a total of six different structural phases including [NH4][LH4] ⋅ 2(H2O) as two polymorphs 1 a and 1 b, two hydrates of [NH4]2[LH3] ⋅ x(H2O), x=3 (2), x=6 (3), [NH4]5[LH3][LH2] ⋅ 8(H2O) (4) and [NH4]3[LH2] ⋅ 3(H2O) (5). The crystal structures obtained, along with that of the parent acid, enable a direct comparison of competing supramolecular synthons, involving phosphonate‐phosphonate O−H⋅⋅⋅O and ammonium‐phosphonate N−H⋅⋅⋅O hydrogen bonds, in a series displaying progressively decreasing P‐OH with concomitantly increasing RNH3+ moieties. Indeed, the structures show some consistent connectivity patterns of the alendronate units, which thus assemble into substructures such as 2‐D sheets (LH5 ⋅ H2O, 1 a), zig‐zag chains (2, 5) or ladder‐like arrays (3, 4). The occurrence of these motifs appears to correlate with the ionisation level of the parent acid. [ABSTRACT FROM AUTHOR]

Magnetic nanoplatelets (NPLs) based on barium hexaferrite (BaFe12O19) are suitable for many applications because of their uniaxial magneto-crystalline anisotropy. Novel materials, such as ferroic liquids, magneto-optic composites, and contrast agents for medical diagnostics, were developed by specific surface functionalization of the barium hexaferrite NPLs. Our aim was to amino-functionalize the NPLs' surfaces towards new materials and applications. The amino-functionalization of oxide surfaces is challenging and has not yet been reported for barium hexaferrite NPLs. We selected two amine ligands with two different anchoring groups: an amino-silane and an amino-phosphonate. We studied the effect of the anchoring group, backbone structure, and processing conditions on the formation of the respective surface coatings. The core and coated NPLs were examined with transmission electron microscopy, and their room-temperature magnetic properties were measured. The formation of coatings was followed by electrokinetic measurements, infrared and mass spectroscopies, and thermogravimetric analysis. The most efficient amino-functionalization was enabled by (i) amino-silanization of the NPLs precoated with amorphous silica with (3-aminopropyl)triethoxysilane and (ii) slow addition of amino-phosphonate (i.e., sodium alendronate) to the acidified NPL suspension at 80 °C. [ABSTRACT FROM AUTHOR]

Spinal cord injury (SCI) is a severe neurological complication following spinal fracture, which has long posed a challenge for clinicians. Microglia play a dual role in the pathophysiological process after SCI, both beneficial and detrimental. The underlying mechanisms of microglial actions following SCI require further exploration. The present study combined three different machine learning algorithms, namely weighted gene co-expression network analysis, random forest analysis and least absolute shrinkage and selection operator analysis, to screen for differentially expressed genes in the GSE96055 microglia dataset after SCI. It then used protein-protein interaction networks and gene set enrichment analysis with single genes to investigate the key genes and signaling pathways involved in microglial function following SCI. The results indicated that microglia not only participate in neuroinflammation but also serve a significant role in the clearance mechanism of apoptotic cells following SCI. Notably, bioinformatics analysis and lipopolysaccharide + UNC569 (a MerTK-specific inhibitor) stimulation of BV2 cell experiments showed that the expression levels of Anxa2, Myo1e and Spp1 in microglia were significantly upregulated following SCI, thus potentially involved in regulating the clearance mechanism of apoptotic cells. The present study suggested that Anxa2, Myo1e and Spp1 may serve as potential targets for the future treatment of SCI and provided a theoretical basis for the development of new methods and drugs for treating SCI. [ABSTRACT FROM AUTHOR]

[Display omitted] • A novel binary organic phosphonic acid was firstly integrated into nanofiltration membrane. • The rejection of membrane incorporated with AA was improved, while the permeability exhibited no decline. • Mono-/divalent anion selective separation factor surpass 500 even in high saline solution up to 20 g/L. • The membrane exhibit excellent chlorine resistance and anti-fouling performance. Nanofiltration membrane (NF) have become increasingly crucial in ion separation. However, traditional polyamide (PA) NF suffers from poor selectivity for mono-/divalent anions due to weak charges and structure defects. Thus, a novel binary organic phosphonic acid, alendronic acid (AA), was firstly used as an aqueous co-monomer via interfacial polymerization (IP) to create negatively charged nanofiltration membranes with both higher charge density and pore size homogeneity for the separation of mono-/divalent anions. Both structure characterization and performance tests demonstrated the successful introduction of AA in the separation layer. Compared with pristine membrane, the NaCl/Na 2 SO 4 selectivity of membrane incorporated with AA was four times improved, while the permeability exhibited no decline. Simultaneously, the separation efficiency of Cl-/SO 4 2- was tested in NaCl/Na 2 SO 4 binary mixed solutions with varying total concentrations and different mass ratios, and the separation factor consistently exceeded 500 across a concentration range of 1 g/L to 20 g/L. Moreover, the AA-integrated membrane exhibited excellent chlorine resistance after 20000 ppm·h of chlorine treatment, which is promising for high efficiency separation of mono-/divalent anions in industrial applications. [ABSTRACT FROM AUTHOR]

Objectives: To evaluate the efficacy of resistance training (RT) combined with beta‐hydroxy‐beta‐methylbutyric acid (HMB) in the treatment of elderly patients with sarcopenia after hip replacement. Methods: From January 1, 2018 to December 31, 2018, 200 elderly patients (68 men, mean age 76.3 years and 137 women, mean age 79.1 years) who experienced femoral neck fracture with sarcopenia after hip arthroplasty were assigned to four groups: RT + HMB group, RT group, HMB group, and negative control group. Baseline data, body composition, grip strength, Barthel index (BI), Harris hip score (HHS), and visual analog scale score (VAS) were compared among the four groups before and 3 months after surgery. Results: A total of 177 participants completed the trial, including 43 in the HMB + RT group, 44 in the HMB group, 45 in the RT group, and 45 in the negative control group. At the 3‐month follow‐up, the body composition and grip strength of the HMB + RT group and RT group were significantly improved compared with those before operation. The HMB group had no significant change, while the measures in the negative control group significantly decreased. Postoperative BI and HSS did not reach pre‐injury levels in any of the four groups, but postoperative VAS score was significantly improved. However, there was no significant difference in BI, HSS, or VAS among the four groups. Conclusion: RT, with or without HMB supplementation, can effectively improve body composition and grip strength in elderly patients with sarcopenia after hip replacement at short‐term follow‐up. Simultaneously, use of exclusive HMB supplementation alone may also help to prevent decreases in muscle mass and grip strength in these patients. [ABSTRACT FROM AUTHOR]

Objective: To determine the usefulness of Serum C-terminal telopeptide cross-link of type 1 collagen (sCTX) as a preoperative marker for predicting the risk of developing medication-related osteonecrosis of the jaws (MRONJ) after invasive oral surgery in patients on antiresorptive medication. Materials and methods: Two authors independently searched four electronic databases up to March 25, 2021, for case–control studies and prospective and retrospective cohort studies that assessed preoperative sCTX levels in patients taking antiresorptive medication who underwent oral surgery procedures. The main outcome was the number of MRONJ cases in patients with an sCTX value lower and higher than 150 pg/mL. Qualitative and quantitative data was extracted in tables and the risk of bias was assessed using the QUADAS-2 tool. Estimates of diagnostic accuracy were expressed as sensitivity, specificity, negative and positive likelihood ratio (LR − and LR +), and diagnostic odds ratio (DOR), with a 95% confidence interval (95%CI). The data were combined using random-effects models based on the inverse variance method. Results: Seven studies were included in the meta-analysis. The results were as follows: sensitivity 57% (95%CI: 41–71%), specificity 72% (95%CI: 64–79%), LR + 2 (95%CI: 1.3–3.1), LR − 0.6 (95%CI: 0.4–0.9), and DOR 3.4 (95%CI: 1.5–7.7). Conclusions: The low overall performance of sCTX indicates that this parameter is not suitable for predicting MRONJ risk in patients on antiresorptive medication who need an oral surgery procedure. Clinical relevance: sCTX should not be considered a reliable preoperative marker to predict MRONJ development. [ABSTRACT FROM AUTHOR]

Aim: Noonan syndrome is an uncommon disorder which can present with developmental delay, short stature and cardiac anomalies. Oro‐facial presentation includes giant cell lesions with secondary aneurysmal bone cysts (ABC). The current case report presents an extensive mandibular ABC managed solely by oral bisphosphonates. Material and methods: This is a single retrospective case report. Results: A stark regression of the ABC was evident following the use of oral bisphosphonates with reformation of mandibular integrity. Conclusion: This case reports highlights the potential value of oral bisphosphonate to manage oral pathology such as an ABC. [ABSTRACT FROM AUTHOR]

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A new bisphosphonate-bearing acrylic monomer was synthesized with the Aza-Michael addition reaction from sodium alendronate and polyethylene glycol diacrylate. The PAN copolymer of the new monomer and acrylonitrile was heat resistant. In TGA analysis, the char yield of the copolymer at 650°C was higher than that of PAN and the commercial poly(acrylonitrile-co-methyl acrylate) while poly(acrylonitrile-co-PEGDA-Ald) copolymers started to decompose at a lower temperature. Tg of the copolymers was considerably lower than PAN. Nanofibers were produced successfully by the electrospinning method from the mixture of poly(acrylonitrile-co-PEGDA-Ald) and poly(acrylonitrile-co-methyl acrylate). The poly(acrylonitrile-co-PEGDA-Ald) was also used to extract the copper ion from water. [ABSTRACT FROM AUTHOR]

The article presents the relevance of the problem of postmenopausal osteoporosis (OP) in modern medicine, due to the social and economic consequences of fractures. The pathogenetic mechanisms of its formation are highlighted, indicating that during postmenopausal women amid estrogen deficiency, there is a violation of bone remodeling processes with increased bone resorption and decreased bone formation. Modern recommendations of the pathogenetic therapy of OP are presented, in which it is noted that the drugs of the first choice are drugs of the bisphosphonate class (BF). The ability of BF to suppress the pathological resorption of bone tissue and stimulate bone formation determines their therapeutic effect in OP. One of the drugs of the BF class is alendronate. In the treatment with alendronate, the processes of resorption by osteoclasts are suppressed and the processes of bone metabolism are restored to the premenopausal level, microarchitectural disturbances and bone loss are prevented. It has been demonstrated that the processes of bone metabolism remain stable during prolonged treatment with alendronate for 10 years, while the accumulation of the drug in the bone does not lead to excessive suppression of bone metabolism, but rather remains at the premenopausal level. The data of international and Russian randomized placebo-controlled trials (RCTs) are presented, which indicate the high effectiveness of alendronate at a dose of 70 mg 1 time / week in the treatment of primary OP in postmenopausal women: it had a positive effect on bone mineral density (BMD), reduced pain and, as a result, reduced the restriction of physical activity of patients. Quite good tolerability of the drug was noted, side effects in the treatment group were comparable to those in the placebo group. An analysis of the action of alenadronate shows that it has an aftereffect within a 12-month period after the end of treatment in relation to the BMD of the spine.

Back pain is a common clinical and socioeconomic problem. Back pain is a symptom, not a nosological form. Osteoporosis is a skeletal disease in which, despite normal bone mineralization, bone loss and bone (structure) integrity is observed. The article considers the main causes of primary and secondary osteoporosis. The main modifiable and unmodifiable risk factors for osteoporosis and fractures are presented. The main pathological conditions and diseases associated with the risk of osteoporosis are described. The problem of osteoporosis of the spine as one of the causes of mechanical painful episodes in the back of elderly patients is considered in depth. Clinical features of compression vertebral fractures in osteoporosis in women after menopause are presented. The methods of conservative treatment of osteoporosis are considered. The greatest attention is paid to such effective antiosteoporotic drugs as bisphosphonates. The data on the efficacy and tolerability of alendronic acid preparations as the most studied preparation from the group of bisphosphonates are analyzed. The information on the new medicinal form of alendronic acid – sparkling soluble tablets (Binosto) is presented.

Valproic acid is a carboxylic acid derivative commonly prescribed for several types of seizure disorders or for acute manic episodes in patients with bipolar disorder. Several cases of valproate-induced pleural effusion have been reported, although the precise pathophysiological mechanism remains unknown. To describe the presentation of pleural effusion associated with valproate use and to categorize published case reports according to clinical, immunological, and pleural effusion cell type. PubMed/MEDLINE and Embase databases were systematically searched from January 1970 until November 2020 using the following search terms: "valproic acid" OR "valproate" OR "pleural fluid" OR "exudative effusion" OR "transudative effusion" OR "valproic lung adverse events". These searches yielded 171 references of which 135 articles were considered irrelevant, leaving 36 potentially relevant references which were carefully scrutinized. Twenty-eight cases of valproate-induced pleural effusion were identified after excluding two articles reporting five patients with lung parenchymal adverse reactions to treatment with valproic acid; two articles reporting three patients in whom the pleural effusion could not be attributed to valproic acid alone; one case discussing valproate therapy and fungal pleural effusion; and one describing a patient who suffered from severe cardiac failure. There were also two cases, in an abstract form, with pericardial and pleural effusion, but without any further informative details, and, thus, they were also excluded from this survey. This was the most common type of valproate-induced pleural effusion reported in 17 out of 28 cases (60.7%), with concurrent peripheral eosinophilia in ten. Acute hypersensitivity reaction, inflammation of the pleural cavity induced by the drug, drug toxicity, and damage to mesothelial cells due to oxidants, comprise the possible pivotal mechanisms. This was reported in two cases, with concurrent pericardial effusion in one. Discontinuation of valproate led to resolution of the effusion, although the underlying pathophysiological mechanisms remain abstruse. Interestingly, a patient presented with recurrent pleural effusion characterized by transition from eosinophilic to lymphocytic predominance after readministration of valproate. Three out of 28 cases (10.7%) were characterized by neutrophilic transudative pleural effusion after long-term therapy with valproate, while concurrent pericardial effusion was also noted in two. Five patients receiving valproate therapy (17.9% out of the 28 cases) developed drug-induced lupus erythematosus with concurrent pleural effusion that was eosinophilic in three. All patients had positive antinuclear antibodies; anti-histone antibodies were positive in two. Valproate-induced pleural effusion is rare, but patients receiving treatment with valproic acid who develop respiratory symptoms should be examined for valproate-induced pleural effusion. [ABSTRACT FROM AUTHOR]

Cyclohexanone‐formaldehyde resin and acetophenone‐formaldehyde resin were in situ modified with sodium alendronate and the nanocomposites of cyclohexanone‐formaldehyde resin with sepiolite and montmorillonite by adding the nanoclay into the resin formation media. The analysis of nanocomposites of nanoclay in the resin were carried out with X‐ray diffraction. Exfoliated nanocomposites containing as much as 5 wt% sepiolite were obtained while the nanocomposites of montmorillonite were intercalated. The nanocomposites of alendronic acid‐modified ketone‐formaldehyde resin containing as much as 20 wt% sepiolite or 10 wt% montmorillonite were successfully produced in situ. Fourier transform infrared and nuclear magnetic resonance spectroscopies (NMR) were used for the structural characterization of the modified resins. The alendronic acid modified resins and their nanocomposites with the clays were used to produce reactive non‐toxic fire retardant rigid polyurethane foam. The polyurethane foam containing alendronic acid‐modified acetophenone‐formaldehyde resin had a residue of 20% in the thermogravimetric analysis and was HB‐grade in the horizontal fire test (HB) and self‐extinguished in about 3–5 s during the test. Polyurethane foams containing alendronic acid and the nanoclay with the limiting oxygen index value of 20.8 were achieved. [ABSTRACT FROM AUTHOR]

Background: Actinic keratosis (AK) occurs frequently in sun‐exposed skin while its diagnosis and treatment were still in exploration. Materials and methods: Thirty two patients with facial AK lesions were selected and examined with reflective confocal microscopy (RCM) firstly, followed by biopsy at the same site. RCM was used to observe AK lesions before 5‐aminolevulinic acid photodynamic therapy (ALA‐PDT) treatment, after the first treatment, after 4 treatments, and at 1 and 6 months follow‐up. Retrospective analysis of RCM images was performed. Results: Thirty two AK cases showed initial RCM microscopic features including disorderly arranged epidermal cells (100%), atypical keratinocytes (100%), and blurry border between the epidermis and dermis (100%). 4 patients quitted trail. After treatments, 24 cases showed basically regular arrangement of epidermal cells, absent atypical keratinocytes, and clear border between epidermis and dermis, while 4 cases improved little. At 1 and 6 months follow‐up, 23 cases remained relapse‐free while 1 case developed recurrent symptoms. Effective rate of 4 ALA‐PDT treatments for AK was 100%; recurrence and cure rates were 4.2% and 82.1%, respectively. Conclusion: ALA‐PDT is effective to treat AK, while RCM can be recommended for in vivo evaluating and monitoring the effect of ALA‐PDT on AK. [ABSTRACT FROM AUTHOR]

Management of secondary chronic osteomyelitis (SCO) of the mandible is complex and challenging condition. Antibiotics are often first line treatment but have difficulty penetrating the infected bone and surgical intervention can be extensive, disfiguring and may not provide cure. With increasing reports of successful management of primary chronic osteomyelitis with bisphosphonate therapy, it was considered a viable last line trial medication in a refractory SCO patient for whom surgery was not appropriate. The current case is the first in the literature to report successful management of SCO with oral bisphosphonates. [ABSTRACT FROM AUTHOR]

Alendronic acid is generally a well-tolerated medication, however, there are well-established adverse effects known within dentistry, such as medication-related osteonecrosis of the jaw and upper gastro-intestinal disturbances, particularly erosive oesophagitis. There is growing evidence of bisphosphonate-induced oral ulcerations and this diagnosis needs to be considered for patients presenting with unexplained oral ulceration. An 84-year-old female patient with dementia presented at our emergency dental department with severe, painful oromucosal ulceration. Haematological investigation, including Indirect-immunofluorescence demonstrated no abnormalities. Therefore, the likely diagnosis was that of chemically induced traumatic ulceration. The patient was managed through the cessation of alendronic acid, and the use of both topical and systemic corticosteroids. A 68-year-old female patient with learning difficulties presented with ulceration in the lower buccal sulcus following an urgent referral. The patients carer reported persistent difficulty in the swallowing of medicines, with medications regularly ‘pouched’ in the patients cheeks. Due to patient distress no further investigations were completed. Clinically, the lesion was characteristic of chemically induced traumatic ulceration. We therefore encouraged the continuation of liquid form alendronic acid. At a 2 week review, the ulceration had fully resolved. Alendronic acid-induced ulceration should be considered for patients presenting with oral ulceration, particularly in those with cognitive impairments. There needs to be increased awareness of alendronic acid-induced oral ulceration among prescribers, particularly in patients ‘at risk’. Alternate preparations of this medication such as dispersible tablets and an oral solution are available. [ABSTRACT FROM AUTHOR]