Neglecting Bone Health: A Critical Gap in Management of Muscle Spasticity with Botulinum Toxin in Spinal Cord Injury.

Neuromuscular inhibitors have been quickly advanced from being used only for aesthetic purposes to being used as a treatment for musculoskeletal pain and muscle spasticity. This phenomenon stems from the diminished force exerted by muscles, which are essential for bone remodeling. In this context, it is hypothesized that botulinum toxin (BTX) might exert a direct influence on bone resorption. Although such treatments have the potential to provide patients with significant relief, bone loss occurring due to elective muscle paralysis has yet to be examined in clinical trials. The disuse model resulting from spinal cord injury, characterized by the absence of ground reaction and muscle forces, provides an ideal context for exploring the skeletal ramifications of intramuscular BTX injection. This approach enables an investigation into the intricate interplay between muscle and bone, encompassing the impact of spasticity on bone preservation, the potential positive and negative outcomes of BTX on bone metabolism, and the involvement of the autonomic nervous system in bone remodeling regulation. This paper presents a narrative review of research findings on the disturbance of the typical balance between muscles and bones caused by acute muscle paralysis from BTX, resulting in osteopenia and bone resorption.

Simulation of the bone remodelling microenvironment by calcium compound-loaded hydrogel fibrous membranes for in situ bone regeneration.

The endowment of guided bone regeneration (GBR) membranes with the ability to activate the endogenous regenerative capability of bone to regenerate bone defects is of clinical significance. Herein we explored the preparation of the calcium compound (CC) (calcium sulfate (CaSL), calcium hydrophosphate (CaHP), or tricalcium phosphate (TCaP)) loaded ultrathin silk fibroin (SF)/gelatin (G) fibre membranes via electrospinning as the GBR membranes to regenerate the calvarial bone defects. The in vitro experiments demonstrated that the CaSL-loaded ultrathin fibrous membranes could simulate optimally the bone remodelling microenvironment in comparison with the CaHP- and TCaP-loaded fibrous membranes, displaying the highest activity to regulate the migration, proliferation, and differentiation of mesenchymal stem cells (MSCs). Also, the in vivo experiments demonstrated that the CaSL-loaded fibrous membranes presented the highest intrinsic osteoinduction to guide in situ regeneration of bone. Furthermore, the in vivo experiments demonstrated that the as-prepared composite fibrous membranes possessed good degradability. In summary, our results suggested that the CaSL-loaded fibrous membranes with high intrinsic osteoinduction and good degradability have potential to translate into clinical practice.

Pro-Osteogenic Effect of the Nutraceutical BlastiMin Complex® in Women with Osteoporosis or Osteopenia: An Open Intervention Clinical Trial.

Osteoporosis is a chronic disease that affects millions of patients worldwide and is characterized by low bone mineral density (BMD) and increased risk of fractures. Notably, natural molecules can increase BMD and exert pro-osteogenic effects. Noteworthily, the nutraceutical BlastiMin Complex® (Mivell, Italy, European Patent Application EP4205733A1) can induce differentiation of human bone marrow mesenchymal stem cells (BM-MSCs) in osteoblasts and can exert in vitro pro-osteogenic and anti-inflammatory effects. Thus, the purpose of this study was to verify the effects of BlastiMin Complex® on bone turnover markers (BTMs) and BMD in patients with senile and postmenopausal osteopenia or osteoporosis. The efficacy of BlastiMin Complex® on BTMs in serum was evaluated through biochemical assays. BMD values were analyzed by dual-energy X-ray absorptiometry (DXA) and Radiofrequency Echographic Multi Spectrometry (R.E.M.S.) techniques, and the SNPs with a role in osteoporosis development were evaluated by PCR. Clinical data obtained after 12 months of treatment showed an increase in bone turnover index, a decrease in C-reactive protein levels, and a remarkable increase in P1NP levels, indicating the induction of osteoblast proliferation and activity in the cohort of 100% female patients recruited for the study. These findings show that the nutraceutical BlastiMin Complex® could be used as an adjuvant in combination with synthetic drugs for the treatment of osteoporosis pathology.

Melatonin and Metformin Mitigate Doxorubicin-Induced Alveolar Bone Toxicity.

Evidence concerning the osteotoxic effects of chemotherapy (doxorubicin) has been previously described. Periodontitis also progressively increases in patients receiving chemotherapy; however, the beneficial effects of melatonin and metformin on the alleviation of doxorubicin-induced osteotoxicity have never been investigated. Therefore, we investigated the negative impact of doxorubicin on alveolar bone homeostasis and the benefits of melatonin and metformin on the attenuation of doxorubicin-induced alveolar bone toxicity. Male Wistar rats were divided into 4 groups to receive either 1 mL of normal saline solution as a control group, 3 mg/kg of doxorubicin, 3 mg/kg of doxorubicin plus 10 mg/kg of melatonin, or 3 mg/kg of doxorubicin plus 250 mg/kg of metformin. Doxorubicin treatment was given on days 0, 4, 8, 15, 22, and 29, while interventions were given daily on days 0 to 29. Following euthanasia, blood and alveolar bones were collected for evaluation of oxidative stress, bone remodeling, inflammation, microarchitecture, and periodontal condition. We found that doxorubicin increased systemic oxidative stress, decreased antioxidative capacity, increased inflammation, decreased bone formation, increased bone reabsorption, impaired microarchitecture, and impaired periodontal condition of the alveolar bone. Although cotreatment with melatonin or metformin resulted in some improvement in these parameters, cotreatment with melatonin was more effective than cotreatment with metformin in terms of decreasing oxidative stress, reducing bone resorption, and improving microarchitecture and periodontal condition. All of these findings highlight the potential for antioxidants, especially melatonin, to ameliorate doxorubicin-induced alveolar bone toxicity.

Efficacy and safety of odanacatib in the treatment of postmenopausal women with osteoporosis: a meta-analysis.

BACKGROUND: Osteoporosis, a systemic skeletal disease, seriously affects the quality of life in postmenopausal women. As one type of cathepsin K (CatK) inhibitor, odanacatib (ODN) is a fresh medication for osteoporosis. Considering the potential of ODN, we further examined the effect and safety of ODN for postmenopausal osteoporosis (PMOP) with a meta-analysis. METHODS: PubMed, EMBASE, Cochrane Library, and Web of Science were searched for eligible studies from inception to December 29th, 2023. After that, we conducted a comprehensive meta-analysis following PRISMA guidelines. Risk of bias was meticulously investigated with the Cochrane Collaboration's tool. Efficacy was assessed with bone mineral density (BMD) at different sites (lumbar spine, trochanter, radius, femoral neck) and biomarkers of bone turnover (P1NP, uNTx/Cr, s-CTx, BSAP). Safety was evaluated by analyzing total, serious, other, and skin adverse events (AEs). RESULTS: Four random clinical trials (RCTs) were involved in our research. All trials were rated as having high quality and met the eligibility criteria. In the current research, ODN was found to elevate BMD at lumbar spine, femoral neck, total hip, trochanter and forearm, while it decreased the levels of serum C-telopeptides of type I collagen (s-CTx) as well as urinary N-telopeptide/creatinine ratio (uNTx/Cr). No significant differences were observed in AEs between the ODN group and the control group. CONCLUSIONS: ODN is a promising alternative for the treatment of PMOP on account of its excellent efficacy and credible safety. Unclear links between ODN and cardiovascular AEs require further research to clarify.

Macrophage Polarization during MRONJ Development in Mice.

Macrophages are important regulators of bone remodeling, and M1 polarization is observed in the setting of medication-related osteonecrosis of the jaws (MRONJ). Here, we characterize the phenotype of macrophages during early stages of MRONJ development in zoledronate (ZA)-treated mice with periodontal disease and explore the role of rosiglitazone, a drug that has been reported to lower the M1/M2 macrophage ratio, in MRONJ burden. Mice received ZA, and experimental periodontal disease (EPD) was induced around their second left maxillary molar. The mice were euthanized 1, 2, or 4 wk later. Micro-computed tomography and histologic and immunohistochemical analyses were carried out. In a separate experiment, mice were treated with ZA in the absence or presence of rosiglitazone, EPD was induced for 5 wk, and the MRONJ burden was assessed. An M1 predilection was noted in ZA versus vehicle (Veh) mice at 1, 2, or 4 wk after ligature placement. M1 cells were found to be positive for MMP-13, and their presence coincided with disruption of the surrounding collagen network in ZA mice. Rosiglitazone caused a reversal in the M1/M2 polarization in Veh and ZA mice. Rosiglitazone did not cause significant radiographic changes 5 wk after EPD in Veh or ZA animals. Importantly, percentage osteonecrosis and bone exposure were decreased in the rosiglitazone-treated versus nontreated ZA sites 5 wk after EPD. Our data point to an important role of M1 macrophage polarization with an overexpression of MMP-13 in the early phases of MRONJ development and provide insight into the use of interventional approaches promoting an M2 phenotype as a preventative means to alleviate MRONJ burden.

Effects of coenzyme Q10 on orthodontic tooth movement and alveolar bone remodeling in rats.

OBJECTIVES: To evaluate the effects of coenzyme Q10 (CoQ10) on alveolar bone remodeling and orthodontic tooth movement (OTM). MATERIALS AND METHODS: An orthodontic appliance was placed in 42 female Sprague‒Dawley rats were divided into two groups: the orthodontic force (OF) group (n = 21) and the OF + CoQ10 (CoQ10) treatment group (n = 21). Each group was divided into 3 subgroups, and the rats were sacrificed on days 3, 7 and 14. The rats in CoQ10 and OF groups were administered 100 mg/kg b.w./day CoQ10 (in 1 mL/b.w. soybean oil) and 1 mL b.w./day soybean oil, respectively, by orogastric gavage. The OTM was measured at the end of the experiment. The osteoclast, osteoblast and capillary numbers; vascular endothelial growth factor (VEGF), receptor activator nuclear kappa B ligand (RANKL) and osteoprotegrin (OPG) levels in tissue; and total antioxidant status (TAS) and total oxidant status (TOS) in blood were determined. RESULTS: Compared with the OF group, the CoQ10 treatment group exhibited decreased orthodontic tooth movement and osteoclast and capillary numbers. Indeed, the levels of VEGF and RANKL decreased, while the levels of OPG increased except on day 7. Additionally, the CoQ10 treatment group exhibited lower TOS and higher TAS on days 7 and 14 (p < 0.05). Histological findings showed that the morphology of osteoblasts changed in the CoQ10 group; however, there was no significant difference in the number of osteoblasts between the groups (p > 0.05). CONCLUSION: Due to its effect on oxidative stress and inflammation, CoQ10 regulates bone remodeling by inhibiting osteoclast differentiation, promoting osteoblast differentiation and reducing the amount of OTM. CLINICAL RELEVANCE: Considering that OTM may be slowed with the use of CoQ10, topics such as orthodontic treatment duration, orthodontic force activation and appointment frequency should be considered in treatment planning. It is predicted that the use of CoQ10 will support the effectiveness of treatment in clinical applications such as preventing relapse in orthodontic treatment by regulating bone modulation and anchorage methods that suppress/optimize unwanted tooth movement.

A prospective study of vitamin D, proinflammatory cytokines, and risk of fragility fractures in women on aromatase inhibitors for breast cancer.

BACKGROUND: Vitamin D is critical to bone health by regulating intestinal absorption of calcium, whereas proinflammatory cytokines, including IL-1, IL-6, IL-12, and TNF-α, are known to increase bone resorption. We hypothesized that vitamin D and these cytokines at the time of breast cancer diagnosis were predictive for fragility fractures in women receiving aromatase inhibitors (AIs). METHODS: In a prospective cohort of 1,709 breast cancer patients treated with AIs, we measured the levels of 25-hydroxyvitamin D (25OHD), IL-1ß, IL-6, IL-12, and TNF-α from baseline blood samples. The associations of these biomarkers were analyzed with bone turnover markers (BALP and TRACP), bone regulatory markers (OPG and RANKL), bone mineral density (BMD) close to cancer diagnosis, and risk of fragility fractures during a median of 7.5 years of follow up. RESULTS: Compared to patients with vitamin D deficiency, patients with sufficient levels had higher bone turnover, lower BMD, and higher fracture risk; the latter became non-significant after controlling for covariates including BMD and no longer existed when patients taking vitamin D supplement or bisphosphonates or with history of fracture or osteoporosis were excluded. There was a non-significant trend of higher levels of IL-1ß and TNF-α associated with higher risk of fracture (highest vs. lowest tertile, IL-1ß: adjusted HR=1.37, 95% CI=0.94-1.99; TNF-α: adjusted HR=1.38, 95% CI=0.96-1.98). CONCLUSIONS: Our results do not support proinflammatory cytokines or vitamin D levels as predictors for risk of fragility fractures in women receiving AIs for breast cancer.

Influence of Menstrual Cycle and Oral Contraceptive Phases on Bone (re)modelling Markers in Response to Interval Running.

To explore how sex hormone fluctuations may affect bone metabolism, this study aimed to examine P1NP and ß-CTX-1 concentrations across the menstrual and oral contraceptive (OC) cycle phases in response to running. 17ß-oestradiol, progesterone, P1NP and ß-CTX-1 were analysed pre- and post-exercise in eight eumenorrheic females in the early-follicular, late-follicular, and mid-luteal phases, while 8 OC users were evaluated during the withdrawal and active pill-taking phases. The running protocol consisted of 8 × 3min treadmill runs at 85% of maximal aerobic speed. 17ß-oestradiol concentrations (pg·ml-1) were lower in early-follicular (47.22 ± 39.75) compared to late-follicular (304.95 ± 235.85;p = < 0.001) and mid-luteal phase (165.56 ± 80.6;p = 0.003) and higher in withdrawal (46.51 ± 44.09) compared to active pill-taking phase (10.88 ± 11.24;p < 0.001). Progesterone (ng·ml-1) was higher in mid-luteal (13.214 ± 4.926) compared to early-follicular (0.521 ± 0.365; p < 0.001) and late-follicular phase (1.677 ± 2.586;p < 0.001). In eumenorrheic females, P1NP concentrations (ng·ml-1) were higher in late-follicular (69.97 ± 17.84) compared to early-follicular (60.96 ± 16.64;p = 0.006;) and mid-luteal phase (59.122 ± 11.77;p = 0.002). ß-CTX-1 concentrations (ng·ml-1) were lower in mid-luteal (0.376 ± 0.098) compared to late-follicular (0.496 ± 0.166; p = 0.001) and early-follicular phase (0.452 ± 0.148; p = 0.039). OC users showed higher post-exercise P1NP concentrations in withdrawal phase (61.75 ± 8.32) compared to post-exercise in active pill-taking phase (45.45 ± 6;p < 0.001). Comparing hormonal profiles, post-exercise P1NP concentrations were higher in early-follicular (66.91 ± 16.26;p < 0.001), late-follicular (80.66 ± 16.35;p < 0.001) and mid-luteal phases (64.57 ± 9.68;p = 0.002) to active pill-taking phase. These findings underscore the importance of studying exercising females with different ovarian hormone profiles, as changes in sex hormone concentrations affect bone metabolism in response to running, showing a higher post-exercise P1NP concentrations in all menstrual cycle phases compared with active pill-taking phase of the OC cycle.

Osteogenic effect of an adiponectin-derived short peptide that rebalances bone remodeling: a potential disease-modifying approach for postmenopausal osteoporosis therapy.

Adiponectin, an adipokine, regulates metabolic processes, including glucose flux, lipid breakdown, and insulin response, by activating adiponectin receptors 1 and 2 (AdipoR1 and AdipoR2). We have previously shown that globular adiponectin (gAd), an endogenous form of adiponectin, has osteoanabolic and anti-catabolic effects in rodent models of postmenopausal osteopenia. Moreover, we reported the identification of a 13-mer peptide (ADP-1) from the collagen domain of adiponectin, which exhibited significant adiponectin-mimetic properties. Since the clinical development of gAd is constrained by its large size, here, we investigated the osteogenic property of ADP-1. ADP-1 induced osteoblast differentiation more potently than gAd. ADP-1 elicited osteoblast differentiation through two downstream pathways that involved the participation of adiponectin receptors. Firstly, it enhanced mitochondrial biogenesis and OxPhos, leading to osteoblast differentiation. Secondly, it activated the Akt-glycogen synthase kinase 3ß-Wnt pathway, thereby increasing osteoblast differentiation. Additionally, ADP-1 suppressed the production of receptor-activator of nuclear kappa B ligand from osteoblasts, enabling it to act as a dual-action molecule (suppressing osteoclast function besides promoting osteoblast function). In osteopenic ovariectomized rats, ADP-1 increased bone mass and strength and improved trabecular integrity by stimulating bone formation and inhibiting bone resorption. Furthermore, by increasing ATP-producing intermediates within the tricarboxylic acid cycle in bones, ADP-1 likely fueled osteoblast function. Given its dual-action mechanism and high potency, ADP-1 offers a unique opportunity to address the unmet clinical need to reset the aberrant bone remodeling in osteoporosis to normalcy, potentially offering a disease-modifying impact.

Prevention of bone dehiscence associated with orthodontic tooth movement by prophylactic injection of bone anabolic agents in mice.

Although bone dehiscence may occur during orthodontic tooth movement into the narrow alveolar ridge, a non-invasive prevention method is yet to be fully established. We show for the first time prevention of bone dehiscence associated with orthodontic tooth movement by prophylactic injection of bone anabolic agents in mice. In this study, we established a bone dehiscence mouse model by applying force application and used the granular type of scaffold materials encapsulated with bone morphogenetic protein (BMP)-2 and OP3-4, the receptor activator of NF-κB ligand (RANKL)-binding peptide, for the prophylactic injection to the alveolar bone. In vivo micro-computed tomography revealed bone dehiscence with decreased buccal alveolar bone thickness and height after force application, whereas no bone dehiscence was observed with the prophylactic injection after force application, and alveolar bone thickness and height were kept at similar levels as those in the control group. Bone histomorphometry analyses revealed that both bone formation and resorption parameters were significantly higher in the injection with force application group than in the force application without the prophylactic injection group. These findings suggest that the prophylactic local delivery of bone anabolic reagents can prevent bone dehiscence with increased bone remodelling activity.

Skeletal fluorosis: an uncommon cause, yet a rescue treatment?

PURPOSE: Skeletal fluorosis (SF) results from chronic exposure to fluoride (F-) causing excessive aberrantly mineralized brittle bone tissue, fractures, and exostoses. There is no established treatment other than avoiding the source of F-. Still, excess F- can persist in bone for decades after exposure ceases. CASE PRESENTATION: A 50-year-old woman presented with multiple, recurrent, low AQ2 trauma fractures yet high radiologic bone mineral density. Serum F- was elevated, and osteomalacia was documented by non-decalcified transiliac biopsy. She reported intermittently "huffing" a keyboard cleaner containing F- (difluoroethane) for years. Following cessation of her F- exposure, we evaluated the administration of the parathyroid hormone analog, abaloparatide, hoping to increase bone remodeling and diminish her skeletal F- burden. CONCLUSION: Due to the prolonged half-life of F- in bone, SF can cause fracturing long after F- exposure stops. Anabolic therapy approved for osteoporosis, such as abaloparatide, may induce mineralized bone turnover to replace the poorly mineralized osteomalacic bone characteristic of SF and thereby diminish fracture risk. Following abaloparatide treatment for our patient, there was a decrease in bone density as well as a reduction in F- levels.

The effect of romosozumab on bone mineral density depending on prior treatment: a prospective, multicentre cohort study in Switzerland.

This multicentre, prospective cohort study measured the effect of romosozumab for 12 months on bone mineral density, taking into account prior therapies. Prior antiresorptive therapy blunted the BMD response to romosozumab, and the duration was correlated with BMD changes at both the lumbar spine and total hip. INTRODUCTION: In Switzerland, romosozumab is administered to high-risk osteoporosis patients. Our study aimed to assess the effect of romosozumab on bone mineral density (BMD), taking into account prior therapies. METHODS: This multicentre, prospective cohort study measured the effect of romosozumab for 12 months in patients in a nationwide Swiss osteoporosis registry. BMD and bone turnover marker (P1NP and CTX) changes were measured and compared between pre-treated and treatment naïve patients. RESULTS: Ninety-nine patients (92 women and 7 men, median age 71 years [65, 76]) were enrolled from January 2021 to December 2023. Among them, 22 had no prior treatment before romosozumab, while 77 had previous therapy (including 23 with a history of prior teriparatide therapy), with a median duration of 6 years [4, 11] of cumulative antiresorptive treatment. Over 12 months, romosozumab led to BMD changes of 10.3% [7.5, 15.5] at the lumbar spine, 3.1% [1.1, 5.8] at the total hip and 3.1% [0.5, 5.3] at the femoral neck, indicating notable variability. Significantly lower BMD responses were observed in pre-treated patients, with the duration of prior antiresorptive therapy inversely associated with BMD increases at the lumbar spine and hip. Other predictors of BMD changes at the total hip included baseline T-scores at the hip, body mass index and baseline CTX level, while the BMD response at the lumbar spine was associated with the lumbar spine T-score at baseline, age and baseline CTX level. CONCLUSION: Prior antiresorptive therapy blunted the BMD response to romosozumab, and the duration was correlated with BMD changes at both the lumbar spine and total hip.

Bone effects of metformin monotherapy and its combination with teneligliptin: A 12-week follow-up study in patients with type 2 diabetes mellitus.

AIMS: The skeletal effects of metformin monotherapy and in combination with teneligliptin are not well illustrated in patients with T2DM. To address this, we conducted an observational study to evaluate the effect of these oral hypoglycemic agents on bone turnover markers. METHODS: We recruited patients with T2DM and first-ever prescribed metformin monotherapy or metformin combined with teneligliptin from a tertiary care teaching hospital in New Delhi, North India. Both bone formation and resorption markers, IL-6 and PTD, were estimated along with glycated hemoglobin at baseline and 12 weeks. RESULTS: In both groups, hbA1c levels decreased significantly from baseline to 12 weeks. In the metformin-treated group, ß-CTX, sRANKL, IL-6, and PTD decreased significantly, and no significant changes were observed in P1NP, OC, BAP, or OPG at 12 weeks from baseline. In the metformin + teneligliptin group, BAP, ß-CTX, sRANKL, IL-6, and PTD decreased significantly, and no significant changes were observed in P1NP, OC, or OPG after 12 weeks from baseline. CONCLUSIONS: The positive bone outcome of metformin or teneligliptin was linked to bone resorption rather than bone formation and was independent of changes in HbA1c or PTD. However, these results must be confirmed with well-designed RCTs with more extended follow-up periods.

A p38 MAP kinase inhibitor suppresses osteoclastogenesis and alleviates ovariectomy-induced bone loss through the inhibition of bone turnover.

Inhibition of excessive osteoclastic activity is an efficient therapeutic strategy for many bone diseases induced by increased bone resorption, such as osteoporosis. BMS-582949, a clinical p38α inhibitor, is a promising drug in Phase II studies for treating rheumatoid arthritis. However, its function on bone resorption is largely unknown. In this study, we find that BMS-582949 represses RANKL-induced osteoclast differentiation in a dose-dependent manner. Moreover, BMS-582949 inhibits osteoclastic F-actin ring formation and osteoclast-specific gene expression. Mechanically, BMS-582949 treatment attenuates RANKL-mediated osteoclastogenesis through mitogen-activated protein kinases (MAPKs) and protein kinase B (AKT) signaling pathways without disturbing nuclear factor-κB (NF-κB) signaling. Interestingly, BMS-582949 impairs osteoclastic mitochondrial biogenesis and functions, such as oxidative phosphorylation (OXPHOS). Furthermore, BMS-582949 administration prevents bone loss in ovariectomized mouse mode by inhibiting both bone resorption and bone formation in vivo. Taken together, these findings indicate that BMS-582949 may be a potential and effective drug for the therapy of osteolytic diseases.

Two Weeks of Continuous Opioid Treatment in an Adenine-Induced Mouse Model of Chronic Kidney Disease Exacerbates the Bone Inflammatory State and Increases Osteoclasts.

Patients with chronic kidney disease (CKD) report high pain levels, but reduced renal clearance eliminates many analgesic options; therefore, 30-50% of CKD patients have chronic opioid prescriptions. Opioid use in CKD is associated with higher fracture rates. Opioids may directly alter bone turnover directly through effects on bone cells and indirectly via increasing inflammation. We hypothesized that continuous opioid exposure would exacerbate the high bone turnover state of CKD and be associated with elevated measures of inflammation. Male C57Bl/6J mice after 8 weeks of adenine-induced CKD (AD) and non-AD controls (CON) had 14-day osmotic pumps (0.25-µL/hr release) containing either saline or 50-mg/mL oxycodone (OXY) surgically implanted in the subscapular region. After 2 weeks, all AD mice had elevated blood urea nitrogen, parathyroid hormone, and serum markers of bone turnover compared to controls with no effect of OXY. Immunohistochemical staining of the distal femur showed increased numbers of osteocytes positive for the mu opioid and for toll-like receptor 4 (TLR4) due to OXY. Osteocyte protein expression of tumor necrosis factor-α (TNF-α) and RANKL were higher due to both AD and OXY so that AD + OXY mice had the highest values. Trabecular osteoclast-covered surfaces were also significantly higher due to both AD and OXY, resulting in AD + OXY mice having 4.5-fold higher osteoclast-covered surfaces than untreated CON. These data demonstrate that opioids are associated with a pro-inflammatory state in osteocytes which increases the pro-resorptive state of CKD.

From Bone Remodeling to Wound Healing: An miR-146a-5p-Loaded Nanocarrier Targets Endothelial Cells to Promote Angiogenesis.

Wound healing is a complex challenge that demands urgent attention in the clinical realm. Efficient angiogenesis is a pivotal factor in promoting wound healing. microRNA-146a (miR-146a) inhibitor has angiogenic potential in the periodontal ligament. However, free microRNAs (miRNAs) are poorly delivered into cells due to their limited tissue specificity and low intracellular delivery efficiency. To address this hurdle, we developed a nanocarrier for targeted delivery of the miR-146a inhibitor into endothelial cells. It is composed of a polyethylenimine (PEI)-modified mesoporous silica nanoparticle (MSN) core and a pentapeptide (YIGSR) layer that recognizes endothelial cells. In vitro, we defined that the miR-146a inhibitor and adiponectin (ADP) can modulate angiogenesis and the remodeling of periodontal tissues by activating the ERK and Akt signaling pathways. Then, we confirm the specificity of YIGSR to endothelial cells, and importantly, the nanocarrier effectively delivers the miR-146a inhibitor into endothelial cells, promoting angiogenesis. In a C57 mouse skin wound model, the miR-146a inhibitor is successfully delivered into endothelial cells at the wound site using the nanocarrier, resulting in the formation of new blood vessels with strong CD31 expression. Additionally, no significant differences are found in the expression levels of inflammatory markers interleukin-6 and tumor necrosis factor-α. This outcome not only brings new strategies for angiogenesis but also exhibits broader implications for bone remodeling and wound healing. The breakthrough holds significance for future research and clinical interventions.

The clinical assessment of changes in bone density in rheumatoid arthritis patients': Role of DEXA scan and bone turnover biomarkers.

In addition to generalised of bone loss and a higher fracture risk, rheumatoid arthritis (RA) causes periarticular bone erosions. Improvements in bone density/erosion and turnover may not go hand in hand with a positive clinical response to biological anti-inflammatory drugs assesed by disease activity score 28 (DAS28) in RA patients. This study aimed to understand how biologic anti-inflammatory drugs affect bone density, erosion, and turnover in RA patients. We examined bone mineral density (BMD) and bone turnover biomarkers. The study population consisted of 62 RA patients, 49 (79%) of whom were female and 13 (21%) of whom were male. The patients ranged in age from 40 to 79 years old. The patients' BMD was measured using a DEXA scan, and their plasma levels of bone turnover biomarkers CTX and osteocalcin were quantified utilizing an ELISA. BMD of the hip and lumbar spine in responder patients rose after therapy by 0.001g/cm2 (0.11 percent, p0.001 vs. before treatment) and 0.0396g/cm2 (3.96 percent, p0.001 vs. before treatment), respectively. Clinically non-responder patients' DAS28 revealed minor reductions in hip BMD values of -0.008g/cm2 (-0.78 percent, p0.001 vs. before therapy), as well as an improvement in lumbar spine BMD of 0.03g/cm2 (3.03 percent, p0.001 vs. before treatment). After 12 weeks of therapy, the CTX levels in responder patients dropped from 164 125 pg/ml to 131 129 pg/ml. Osteocalcin levels in non-responder patients increased substantially from 11.6 ng/ml to 14.9 ng/ml after 12 weeks of therapy compared to baseline (p = 0.01). Treatment with biologic anti-inflammatory medicines decreases widespread bone loss in RA patients' hip and lumbar spine. The beneficial effects of therapy on BMD were not associated with changes in disease activity of RA patients. Changes in plasma levels of bone turnover biomarkers such as sCTX and osteocalcin confirmed the treatment's beneficial effects.

Nutraceuticals and Functional Foods: A Comprehensive Review of Their Role in Bone Health.

Bone health is the result of a tightly regulated balance between bone modeling and bone remodeling, and alterations of these processes have been observed in several diseases both in adult and pediatric populations. The imbalance in bone remodeling can ultimately lead to osteoporosis, which is most often associated with aging, but contributing factors can already act during the developmental age, when over a third of bone mass is accumulated. The maintenance of an adequate bone mass is influenced by genetic and environmental factors, such as physical activity and diet, and particularly by an adequate intake of calcium and vitamin D. In addition, it has been claimed that the integration of specific nutraceuticals such as resveratrol, anthocyanins, isoflavones, lycopene, curcumin, lutein, and ß-carotene and the intake of bioactive compounds from the diet such as honey, tea, dried plums, blueberry, and olive oil can be efficient strategies for bone loss prevention. Nutraceuticals and functional foods are largely used to provide medical or health benefits, but there is an urge to determine which products have adequate clinical evidence and a strong safety profile. The aim of this review is to explore the scientific and clinical evidence of the positive role of nutraceuticals and functional food in bone health, focusing both on molecular mechanisms and on real-world studies.

A Multifunctional Tissue-Engineering Hydrogel Aimed to Regulate Bacterial Ferroptosis-Like Death and Overcoming Infection Toward Bone Remodeling.

Infection is the most common complication after orthopedic surgery and can result in prolonged ailments such as chronic wounds, enlarged bone defects, and osteomyelitis. Iron, which is essential for bacterial metabolism and immune cell functions, is extremely important. Bacteria harness iron from nearby cells to promote biofilm formation, ensuring their survival. Iron deficiency within the infection microenvironment (IME) consequently hampers macrophage function, enabling further dissemination of the infection and hindering macrophage polarization to the M2 phenotype. Therefore, a novel approach is proposed to regulate macrophage polarization, aiming to restore the inflammatory immune environment. A composite hydrogel derived from natural polymers is developed to address infections and manage iron metabolism in macrophages. This IME-responsive hydrogel, named FCL-ECMH, is synthesized by encapsulating vermiculite functional core layers within a decellularized extracellular matrix hydrogel. It is noteworthy that FCL-ECMH can produce reactive oxygen species within the IME. Supplementary photothermal treatment enhances bacterial iron uptake, leading to ferroptosis-like death. This process also rejuvenates the iron-enriched macrophages around the IME, thereby enhancing their antibacterial and tissue repair functions. In vivo experiments confirmed the antibacterial and repair-promoting capabilities of FCL-ECMH, indicating its potential for clinical applications.