Inhibition Of Bone Resorption Research Articles

Potential of 20 unexplored genes to be candidates for osteogenic regulators as novel therapeutic strategies in bone diseases

Background: Bone homeostasis is maintained by a balance between bone formation by osteoblasts and bone resorption by osteoclasts. As a therapeutic agent for osteoporosis, a strategy of suppressing bone resorption by inhibiting the function of osteoclasts is used; however, long-term use causes problems, such as decreased formation of osteoblasts and osteonecrosis of the jaw. Therefore, various growth factors and hormones have been used to promote the proliferation of osteoblasts, but the current situation is that long-term use cannot be applied owing to issues such as carcinogenic risk. To establish an appropriate osteogenesis-promoting strategy, it is essential to ensure the fate of progenitor cells in the mature osteoblasts. Purpose: To investigate potential osteogenic regulators based on published single-cell transcriptome data as an alternative approach to bone diseases treatment. Methods: a systematic review using articles through several databases with descriptions related to various genes were identified based on single-cell transcriptome data as candidates for osteogenic regulators. Results: 20 unexplored genes were identified based on single-cell transcriptome data as candidates for osteogenic regulators. Conclusions: Increasing osteoblast activity through the promotion of osteoblast differentiation shows promise as a novel approach for treating bone-formation-related diseases.

Targeting Bone Marrow Microenvironment for Treatment of High-Risk B-Cell Acute Lymphoblastic Leukemia

Introduction B-cell acute lymphoblastic leukemia (B-ALL) is the most common form of cancer in children, accounting for approximately 20% of all pediatric cancers. Although treatment of B-ALL represents one of the success stories of modern medicine with 5-year survival rates approaching 90%, some children continue to have a dismal prognosis, particularly those with high-risk genetic alterations in their ALL cells or those who relapse. The leukemia microenvironment is an attractive novel therapeutic target, especially for children with high-risk leukemia as dose-limiting toxicities of conventional chemotherapeutic agents have prevented further improvements in survival. Aims In this study, we investigate whether therapeutically targeting the bone marrow (BM) osteoclasts can improve treatment outcome for B-ALL and the mechanisms of crosstalk between osteoclasts and leukemia cells. Methods We have established syngeneic and patient-derived xenograft (PDX) models for high-risk B- ALL that recapitulate the clinical symptoms of bone loss. For in vitro experiments, leukemia cells were cultured with osteoclast-derived conditioned media (CM) for 3 days. Results To evaluate the therapeutic potential of targeting osteoclasts during leukemia development, we administered zoledronic acid (2ug 5 days/week for 2 weeks), a bisphosphonate inhibitor of osteoclastic bone resorption, alone and in combination with imatinib (100mg/kg daily for 28 days) or dasatinib (10mg/kg daily for 28 days) in our BCR-ABL1 + B-ALL syngeneic mouse model. We showed that zoledronic acid treatment significantly reversed leukemia-induced bone loss by attenuating osteoclast activity. Zoledronic acid alone was found to enhance event-free survival in leukemia-bearing mice and further improvement was shown in combination with imatinib (p<0.05) or dasatinib (p<0.01). In addition, we administered zoledronic acid alone and in combination with vincristine, dexamethasone, and L-asparaginase (VXL) in a relapsed B-ALL PDX model. We further demonstrated that zoledronic acid alone or in combination with VXL improved survival compared to mice treated with vehicle (p<0.001) or VXL alone (p<0.01), respectively. In the clinical setting, we assessed the feasibility and safety of incorporating zoledronic acid early into leukemia therapy in three children with B-ALL. The patients were undergoing induction or consolidation chemotherapy and were administered zoledronic acid at the same time. Zoledronic acid was well tolerated without any significant adverse effects, indicating the feasibility of safely administering zoledronic acid in combination with chemotherapy in children with ALL. To gain mechanistic insight into the effect of osteoclasts on leukemia cells, we compared the molecular profile of the leukemia cells cultured with CM and control media using RNA sequencing. There were 30 differentially expressed genes identified at the 5% false discovery rate with a log fold-change value ≥1 or ≤-1. KEGG pathway analysis revealed a significant difference in cell cycle pathway in leukemia cells cultured with CM compared to control. Biological process analysis showed a positive regulation of B-cell proliferation and negative regulation of lymphocyte apoptotic process in leukemia cells cultured with CM compared to control. To functionally examine the effect of osteoclasts on leukemia cells, we showed that osteoclast-derived CM significantly increased B-ALL cell proliferation, as demonstrated by increased cell number (p<0.001), as well as reduced cell percentages in G0/G1 phases and increased S+G2/M phases (p<0.05) via cell cycle analyses. Using annexin V and DAPI staining, we further demonstrated that there were more live cells and less apoptotic and dead cells when the leukemia cells were cultured with CM compared to control (p<0.001). Together, our findings suggest that soluble factors produced by osteoclasts promote leukemia cell proliferation and survival. Conclusion Our study reveals osteoclasts play a role in leukemogenesis and leukemia-induced bone loss, and that targeting osteoclasts can provide dual clinical benefit in terms of bone health and improved survival for children with high-risk B-ALL.

Effects of denosumab on bone mineral density around proximal femoral prosthesis after total hip replacement in postmenopausal osteoporotic patients

To evaluate the effect of denosumab on bone mineral density around proximal femoral prosthesis after total hip arthroplasty(THA) in the postmenopausal osteoporotic patients. Fifty-four consecutive patients underwent unilateral primary THA were included in this retrospective study. Twenty-five patients received denosumab for osteoporosis as the treatment group, and the twenty-nine without denosumab were the control group. At 1 week, 3month, 6 months, and 12 months after THA, bone turnover markers and proximal femoral periprosthetic bone mineral density (BMD) were measured. At 3, 6 and 12 months after operation, the level of TRACP-5b in the control group was significantly higher than that in the treatment group (P<0.05);the level of bone-specific alkaline phosphatase (BALP) between two groups showed significant difference in 12 months after operation (control group was higher than treatment group, P<0.05). The BMD of Gruen 1 and Gruen 7 decreased at 3, 6 and 12 months after operation compared with 1 week after operation. Comparing the treatment group and the control group, the differences of the the decrease of BMD in Gruen 1 and Gruen 7 were no significant at 3 months after surgery. In Gruen 1, Gruen 7 at 6 months after operation and Gruen 1, Gruen 7 at 12 months after operation, the decrease of BMD in the control group was significantly higher than that in the treatment group(P<0.05). It is suggested that desudumab could inhibit the loss of BMD after 6 months, and continuously show a protective effect on bone mass at 12 months after operation. After THA in postmenopausal patients with osteoporotic femoral neck fracture, Desuzumab can reduce the loss of BMD around the proximal femoral prosthesis and effectively inhibit bone resorption.

Bisphosphonates and Their Connection to Dental Procedures: Exploring Bisphosphonate-Related Osteonecrosis of the Jaws.

Bisphosphonates are widely used to treat osteoporosis and malignant tumors due to their effectiveness in increasing bone density and inhibiting bone resorption. However, their association with bisphosphonate-related osteonecrosis of the jaws (BRONJ) following invasive dental procedures poses a significant challenge. This review explores the functions, mechanisms, and side effects of bisphosphonates, emphasizing their impact on dental procedures. Dental patients receiving bisphosphonate treatment are at higher risk of BRONJ, necessitating dentists' awareness of these risks. Topical bisphosphonate applications enhance dental implant success, by promoting osseointegration and preventing osteoclast apoptosis, and is effective in periodontal treatment. Yet, systemic administration (intravenous or intraoral) significantly increases the risk of BRONJ following dental procedures, particularly in inflamed conditions. Prevention and management of BRONJ involve maintaining oral health, considering alternative treatments, and careful pre-operative and post-operative follow-ups. Future research could focus on finding bisphosphonate alternatives with fewer side effects or developing combinations that reduce BRONJ risk. This review underscores the need for further exploration of bisphosphonates and their implications in dental procedures.

Systemic Convergent Multitarget Interactions of Plant Polyphenols Revealed by Affinity-Based Protein Profiling of Bone Cells Using C-Glucosidic Vescal(ag)in-Bearing Chemoproteomic Probes.

The ellagitannins vescalagin and vescalin, known as actin-dependent inhibitors of osteoclastic bone resorption, were mounted onto chemical probes to explore their interactions with bone cell proteins by means of affinity-based chemoproteomics and bioinformatics. The chemical reactivity of the pyrogallol units of these polyphenols toward oxidation into electrophilic ortho-quinones was exploited using NaIO4 to promote the covalent capture of target proteins, notably those expressed at lower abundance and those interacting with polyphenols at low-to-moderate levels of affinity. Different assays revealed the multitarget nature of both ellagitannins, with 100-370 statistically significant proteins captured by their corresponding probes. A much higher number of proteins were captured from osteoclasts than from osteoblasts. Bioinformatic analyses unveiled a preference for the capture of proteins having phosphorylated ligands and GTPase regulators and enabled the identification of 33 potential target proteins with systemic relevance to osteoclast differentiation and activity, as well as to the regulation of actin dynamics.

Ginsenoside compound-K attenuates OVX-induced osteoporosis via the suppression of RANKL-induced osteoclastogenesis and oxidative stress

Osteoporosis (OP), a systemic and chronic bone disease, is distinguished by low bone mass and destruction of bone microarchitecture. Ginsenoside Compound-K (CK), one of the metabolites of ginsenoside Rb1, has anti-aging, anti-inflammatory, anti-cancer, and hypolipidemic activities. We have demonstrated CK could promote osteogenesis and fracture healing in our previous study. However, the contribution of CK to osteoporosis has not been examined. In the present study, we investigated the effect of CK on osteoclastogenesis and ovariectomy (OVX)-induced osteoporosis. The results showed that CK inhibited receptor activator for nuclear factor-κB ligand (RANKL)-mediated osteoclast differentiation and reactive oxygen species (ROS) activity by inhibiting the phosphorylation of NF-κB p65 and oxidative stress in RAW264.7 cells. In addition, we also demonstrated that CK could inhibit bone resorption using bone marrow-derived macrophages. Furthermore, we demonstrated that CK attenuated bone loss by suppressing the activity of osteoclast and alleviating oxidative stress in vivo. Taken together, these results showed CK could inhibit osteoclastogenesis and prevent OVX-induced bone loss by inhibiting NF-κB signaling pathway.Graphical

PSVI-8 Bisphosphonate Pharmacokinetics in Juvenile Horses

Abstract Bisphosphonates alter bone metabolism via inhibition of osteoclastic bone resorption. Although bisphosphonates are beneficial to treat bone disease, extra-label use in healthy juvenile horses may interfere with normal bone metabolism. The objective was to determine plasma pharmacokinetics of the bisphosphonate clodronate disodium (CD) following a single intramuscular dose to better define the time course of CD in juvenile horses. Ten yearling Quarter Horses (334 ± 18 kg, 504 ± 13 d of age) were used to test the hypothesis that juvenile horses would have faster clearance rate of CD compared with previously published data in adult horses. Horses were placed in individual stalls, jugular intravenous catheters were inserted, and an initial blood sample (0 h) was collected. Horses were administered CD intramuscularly at 1.8 mg/kg BW per label. Plasma samples were collected at 0.5, 1, 3, 6, 12, 24, 48, and 72 h post-administration. Plasma concentration of clodronate was determined by liquid chromatography tandem mass spectrometry. Pharmacokinetic parameters were calculated using a two-compartment model. Blood chemistry parameters [blood urea nitrogen (BUN), creatinine, alkaline phosphatase (ALKP), aspartate aminotransferase (AST), gamma glutamyl transferase (GGT), and creatine kinase (CK)] were determined via a commercial laboratory. Included blood chemistry parameters were analyzed for an effect of time using PROC Mixed of SAS. Clodronate was detected in plasma up to 72 h post-administration. Maximum plasma concentration (43,971 ± 25,920 ng/mL) was reached at 0.5 h post-administration. Analysis revealed bicompartmental kinetics with distribution and terminal half-lives of 1.9 ± 0.4 h and 24.4 ± 4.3 h, respectively. Area under the curve to last sample was 22,755 ± 11,426 ng*h/mL and extrapolated to infinity was 26,778 ± 12,465 ng*h/mL. Blood chemistry parameters varied over time within normal ranges. Markers of renal function, BUN and creatinine, decreased from h 0 to h 72 (P &amp;lt; 0.01). Liver function markers ALKP and AST were not affected by CD treatment (P &amp;gt; 0.27). However, GGT and CK changed over time (P &amp;lt; 0.01), with GGT greater at 48 h than other time points, and CK increasing from 0.5 to 24 h before decreasing by 72 h but remaining above baseline. Plasma clodronate concentrations were greater in juvenile horses than previously reported in mature horses (Krueger et al., 2020, Equine Vet J.; Knych et al., 2022, Equine Vet J.). Further, the observed bicompartmental kinetics differed from the linear kinetics previously reported in mature horses whereby juvenile horses from the current study had greater exposure to CD over time as indicated by a longer terminal half-life. Moreover, the single intramuscular dose of CD (1.8 mg/kg BW) did not cause markers of kidney or liver function to deviate from normal ranges in juvenile Quarter Horses.

Efficacy of iguratimod on mineral and bone disorders after kidney transplantation: a preliminary study

Background Iguratimod has been shown to promote bone formation and inhibit bone resorption in rheumatoid arthritis patients. We aimed to explore its effect on bone metabolism and vascular calcification (VC) in kidney transplant recipients (KTRs). Methods A post hoc analysis was conducted among the subjects in our previous randomized clinical trial (NCT02839941). Forty-three KTRs completing bone metabolism 52 weeks after enrollment were selected for this analysis, among whom 27 patients received VC examinations. In the iguratimod group, iguratimod (25 mg twice daily) was added adjuvant to the traditional triple regimen. At the 52-week follow-up, the following parameters were assessed: serum calcium, phosphorus, 25-hydroxyvitamin D, intact parathyroid hormone (iPTH), bone alkaline phosphatase (BALP), osteocalcin, type I collagen N-terminal peptide (NTx), type I collagen C-terminal peptide (CTx), bone mineral density (BMD) of the femoral neck and lumbar spine, coronary artery calcification (CAC) and thoracic aortic calcification (TAC). Bone metabolic and VC indices were compared between the two groups using the independent samples t test and Wilcoxon nonparametric test. Results At 52 weeks after enrollment, the iguratimod group had lower osteocalcin (p = 0.010), BALP (p = 0.015), NTx (p = 0.007), CTx (p = 0.012), CAC (p = 0.080) and TAC scores (p = 0.036) than the control group. There was no significant difference in serum calcium, phosphorus, 25-hydroxyvitamin D, iPTH and BMD between the groups. Iguratimod could reduce bone turnover markers (BTMs) at both high and low iPTH levels. The adverse effect of iguratimod was mild and tolerable. Conclusion Iguratimod is safe, can reduce BTMs and may could attenuate VC in the first year after KT.

Effects of bisphosphonates and treadmill exercise on bone and kidney in adenine-induced chronic kidney disease rats.

The increasing prevalence of osteoporosis and chronic kidney disease (CKD) due to the aging of society has highlighted the need for development of effective treatments for elderly patients. This study examined whether the combination of treadmill exercise therapy and alendronate (ALN) can improve bone mineral density (BMD) and bone strength without worsening renal function in adenine-induced CKD model rats. 8-week-old male Wistar rats (n = 70) were divided into experimental groups based on the treatment protocol, i.e., non-CKD (control), vehicle only (CKD), ALN only, exercise only, and combined ALN plus exercise. A 0.75% adenine diet was used to induce CKD. Groups were killed at either 20 or 30weeks of age. Comprehensive assessments included serum and urine biochemistry tests, renal histology, bone histomorphometry, BMD measurement, micro-computed tomography examinations, and biomechanical testing. Blood biochemistry tests, urine analyses and histological evaluations of the kidney demonstrated that ALN treatment did not worsen renal function or kidney fibrosis in moderate-stage CKD model rats. Both ALN and treadmill exercise significantly suppressed bone resorption (p < 0.05-p < 0.01). Moreover, ALN monotherapy and combined ALN and treadmill exercise significantly improved BMD of the lumbar spine and femur, bone microstructure, and trabecular bone strength (p < 0.05-p < 0.01). Treadmill exercise was also shown to decrease cortical porosity at the mid-diaphysis of the femur and improve kidney fibrosis. The combination of ALN and treadmill exercise is effective in improving BMD, the microstructure of trabecular and cortical bone, and bone strength, without compromising renal function in adenine-induced CKD model rats.

Osteoprotective effect by interleukin-4 (IL-4) on lipoprotein-induced periodontitis

Lipoproteins are immunostimulatory bacterial components suggested to participate in inflammation-induced bone loss in periodontal disease through stimulation of osteoclast differentiation. Toll-like receptor 2 activation by Pam2CSK4 (PAM2), known to mimic bacterial lipoproteins, was previously shown to enhance periodontal bone resorption in mice. The anti-inflammatory cytokine interleukin-4 (IL-4) is a known inhibitor of RANKL-induced bone resorption in vitro. Here, we have investigated whether IL-4 could decrease PAM2-induced periodontal bone loss and osteoclastogenesis in vivo. In a model of periodontitis induced by gingival injections of PAM2 in mice, concomitant injections of IL-4 reduced bone loss. Histologically, IL-4 reduced the recruitment of inflammatory cells and the formation of TRAP+ osteoclasts stimulated by PAM2. Mouse bone marrow macrophages (BMMs) and neonatal calvarial osteoblasts were used to assess the effect of IL-4 on PAM2-induced osteoclastogenesis in vitro. In RANKL-primed BMMs stimulated by PAM2 Nfatc1, Ctsk, and Acp5 gene expression was up-regulated and resulted in robust formation of TRAP+ multinucleated osteoclasts, effects which were impaired by IL-4. These effects were mediated by impairment in PAM2-induced c-fos expression. In primary calvarial osteoblast cultures, IL-4 decreased PAM2-induced Tnfsf11 (encoding RANKL) mRNA and enhanced Tnfrsf11b (encoding OPG) expression. Our data demonstrate that the osteoprotective effect by IL-4 on lipoprotein-induced periodontal disease occurs through the inhibition of osteoclastogenesis by three mechanisms, one by acting directly on osteoclast progenitors, another by acting indirectly through decreasing the expression of osteoclast-regulating cytokines in osteoblasts and a third by decreasing inflammation.

Effect of Liraglutide on Osteoporosis in a Rat Model of Type 2 Diabetes Mellitus: A Histological, Immunohistochemical, and Biochemical Study.

Diabetic osteoporosis (DOP) is a diabetic complication associated with a significant disability rate. Liraglutide, a glucagon-like peptide-1 receptor agonist, is a promising and innovative drug for type 2 diabetes mellitus (T2DM), with potential therapeutic implications for bone disorders. This investigation examined the impact of liraglutide on osteoporosis in rats with T2DM and studied the influence of vitamin D receptor Bsm1 polymorphism on liraglutide-induced outcomes. Thirty rats were divided into control, T2DM induced by a combination of a high-fat diet and 25 mg/kg streptozotocin, and T2DM-liraglutide (T2DM treated with 0.4 mg/kg/day liraglutide) groups. After 8 weeks of liraglutide treatment, femurs and blood samples were obtained from all rats for subsequent investigations. Diabetes induced a remarkable rise in the serum levels of receptor activator of nuclear factor kappa B ligand (RANKL) and C-telopeptide of type I collagen (CTX-1) associated with a remarkable decline in osteocalcin and osteoprotegerin (OPG). Impaired bone architecture was also demonstrated by light and scanning electron microscopic study. The immune expression of OPG was down-regulated, while RANKL was up-regulated. Interestingly, the administration of liraglutide ameliorated the previous changes induced by diabetes mellitus. In conclusion, liraglutide can prevent DOP, mostly due to liraglutide's ability to increase bone growth, while inhibiting bone resorption.

Selenium nanoparticles functionalized by mushroom polysaccharide-protein complex: A novel nano-mineral for managing postmenopausal osteoporosis

With an increase in aging population, osteoporosis has become one of the major public health issues nowadays, affecting over 200 million people worldwide. Since current medications are associated with various side effects, there is a clear clinical need to develop alternative therapeutics for managing osteoporosis. Selenium is an essential trace mineral, which has been proved to play important role in bone health. However, the narrow therapeutic window of selenium has greatly hindered its further development. Recently, selenium nanoparticles (SeNPs) have become a new selenium source due to its promising bioactivity and low toxicity. Nevertheless, scientific research concerning their effects on bone health is still very limited. By using the mushroom polysaccharide-protein complex isolated from Cordyceps sinensis, we have successfully prepared novel SeNPs (“Cs4-SeNPs”) with well-characterized structure and high stability. Interestingly, Cs4-SeNPs (10 μM) were found to markedly induce proliferation, differentiation, and mineralization of the pre-osteoblast murine MC3T3-E1 cells. Further mechanistic study discovered that after cellular internalization via endocytosis, Cs4-SeNPs would trigger Nox4-derived intracellular ROS generation in the MC3T3-E1 cells followed by promoting downstream BMP-2 gene transcription and activating BMP signaling via both Smad dependent and Smad independent p38 MAPK pathways. More importantly, Cs4-SeNPs (25–500 μg/kg BW/d) exhibitedpromising in vivo bone protective efficacy against OVX-induced osteoporosis by promoting bone formation, inhibiting bone resorption, and improving bone microarchitecture after oral gavage for 6 weeks. Findings of this study collectively suggested that Cs4-SeNPs is of great potential to be further developed into a safe and evidence-based nano-mineral for managing postmenopausal osteoporosis.

A review of the major considerations and predictors of osseointegrated implants

The most common bone disorder found by implant dentists is osteoporosis, which is a systemic skeletal disorder associated with aging, which is characterized by loss of bone mass, making bones fragile and more susceptible to fractures. The World Health Organisation has defined osteoporosis as a bone mineral density level greater than 2.5 standard deviations below the mean of young normal women. After 60 years of age, a third of the population have this disorder, it occurs twice as often in women than in men. It is estimated that 1.3 million fractures and 133,000 hip fractures occur every year as a result of osteoporosis. This study aimed to discuss aspects of the pharmacological action of Bisphosphonates (BP) and their influence on bone tissue when associated with treatment with dental implants. There are several types of treatments which prevent or prevent the progression of osteoporosis. So, BP, such as alendronate, are inhibitor of bone resorption. Act as controlling the development of osteoporosis by increasing the process of bone density and decreasing its reabsorption, often acting as supporting the process of osseointegration of dental implants.

SAT262 Bilateral Stress Fractures Of The Femur In A Patient With HIV On Long-term Tenofovir Disoproxil Fumarate And Short-term Alendronate

Abstract Disclosure: R.J. Mahatme: None. A.D. Lindsay: None. F.S. Mirza: None. Background: Tenofovir disoproxil fumarate (TDF) is a reverse transcriptase inhibitor used for HIV treatment, which has been documented to reduce bone mineral density through enhanced osteoclastic activity, reduced osteoblastic activity, disrupted calcium absorption and renal phosphate wasting. Prolonged use of TDF increases the risk of osteoporosis and fractures. Bisphosphonates (BP) are typically used to prevent osteoporotic fractures by inhibiting bone resorption. However, BP use for more than five years, and concomitant suppression of bone remodeling may be associated with an increased risk of subtrochanteric fractures. We report a case of unusual bilateral subtrochanteric stress fractures of the femur in a patient on long term TDF for HIV, who had taken alendronate for a very short duration. Clinical Case: A 56-year-old woman presented to orthopedics in 2017 with complaint of bilateral leg/hip pain associated with weight bearing. Past medical history was significant for HIV diagnosed in 1995, osteopenia diagnosed in 2015 and fibromyalgia. The patient had been taking TDF as part of HIV therapy since 1995 and had been started on alendronate 15 months prior for osteopenia. X-ray of the hips revealed diffuse osteopenia with areas of possible stress reaction/stress fracture at the proximal third of the right femur and in the subtrochanteric left femur. Nuclear medicine bone scan showed faint foci of increased uptake in the lateral subtrochanteric regions of both proximal femora and midshaft of the right femur suggesting insufficiency fractures. The report noted that these areas were present and unchanged compared to a prior bone scan from 2011. In view of significant discomfort and risk of progression to full fracture, she underwent prophylactic intramedullary nailing of the right femur and was referred to endocrine for bone health evaluation. Endocrine evaluation showed vitamin D insufficiency and suboptimal calcium intake which were both corrected. A call to the pharmacy revealed that she had only filled 3 prescriptions of alendronate even though she was initially prescribed alendronate a year and a half prior to her presentation. Alendronate and TDF were discontinued and tenofovir alafenamide (TAF) was added to her HIV regimen due to its less deleterious effects on the skeletal system. Patient did not report significant improvement in her leg pain after the intramedullary nailing and decided to maintain a conservative approach without intervention for the left femur stress fractures. Conclusion: This is an unusual presentation of bilateral stress fractures of the femur likely related to long term TDF therapy in a relatively young postmenopausal female who had taken alendronate for less than a year of cumulative dose. This case highlights the need to use medications that have less harmful effects on the bone in adults with HIV who are also at an increased risk for low bone density and fractures. Presentation: Saturday, June 17, 2023

Aminooxyacetic acid hemihydrochloride leads to decreased intracellular ATP levels and altered cell cycle of prostate cancer cells by suppressing energy metabolism

The second most common cancer among men is prostate cancer, which is also the fifth leading reason for male cancer deaths worldwide. Bone metastases are the main factor affecting the prognosis of prostate cancer. Consequently, antitumor and anti-prostate cancer-induced bone destruction medicines are urgently needed. We previously discovered that aminooxyacetic acid hemihydrochloride (AOAA) suppressed bone resorption and osteoclast growth by decreasing adenosine triphosphate (ATP) production and limiting oxidative phosphorylation (OXPHOS). Here, we evaluated the impacts of AOAA on prostate cancer RM-1 cells in vitro. It’s found that AOAA significantly inhibited cell proliferation, migration, and invasiveness, decreased ATP levels, increased ROS, halted the cell cycle phase, and triggered apoptosis. AOAA also decreased mitochondrial membrane potential and the ability to uptake glucose, suggesting that the antitumor effects of AOAA were expressed through the inhibition of OXPHOS and glycolysis. Furthermore, we assessed the effects of AOAA in vivo using a prostate cancer-induced bone osteolysis mice model. AOAA also delayed tumor growth and bone destruction in vivo. On the whole, our findings imply that AOAA may potentially have therapeutic effects on prostate cancer and prostate cancer-induced osteolysis.

Blue Light-Emitting Diode Irradiation Without a Photosensitizer Alters Oral Microbiome Composition of Ligature-Induced Periodontitis in Mice.

Objective: This study investigated the suppressive effects of blue light-emitting diode (LED) irradiation on bone resorption and changes in the oral microbiome of mice with ligature-induced periodontitis. Background: Wavelength of blue light has antimicrobial effects; however, whether blue LED irradiation alone inhibits the progression of periodontitis remains unclear. Methods: Nine-week-old male mice ligated ligature around the right maxillary second molar was divided into ligation alone (Li) and ligation with blue LED irradiation (LiBL) groups. The LiBL group underwent blue LED (wavelength, 455 nm) irradiation four times in a week at 150 mW/cm2 without a photosensitizer on the gingival tissue around the ligated tooth at a distance of 5 mm for 5 min. The total energy density per day was 45 J/cm2. Bone resorption was evaluated using micro-computed tomography at 8 days. Differences in the oral microbiome composition of the collected ligatures between the Li and LiBL groups were analyzed using next-generation sequencing based on the 16S rRNA gene from the ligatures. Results: Blue LED irradiation did not suppress bone resorption caused by ligature-induced periodontitis. However, in the LiBL group, the α-diversity, number of observed features, and Chao1 were significantly decreased. The relative abundances in phylum Myxococcota and Bacteroidota were underrepresented, and the genera Staphylococcus, Lactococcus, and Lactobacillus were significantly overrepresented by blue LED exposure. Metagenomic function prediction indicated an increase in the downregulated pathways related to microbial energy metabolism after irradiation. The co-occurrence network was altered to a simpler structure in the LiBL group, and the number of core genera decreased. Conclusions: Blue LED irradiation altered the composition and network of the oral microbiome of ligature-induced periodontitis in mice.

Osteogenic Effects of KY-054, a Novel Coumarin Derivative on Femur Cortical Bone in Ovariectomized Female Rats.

Osteoporosis is treated with oral and parenteral bone resorption inhibitors such as bisphosphonates, and parenteral osteogenic drugs including parathyroid hormone (PTH) analogues and anti-sclerostin antibodies. In the present study, we synthesized KY-054, a 4,6-substituted coumarin derivative, and found that it potently promoted osteoblast differentiation with an increase in alkaline phosphatase (ALP) activity at 0.01-1 µM in mouse-derived mesenchymal stem cells (ST2 cells) and rat bone marrow-derived mesenchymal stem cells (BMSCs). In the ovariectomized (OVX) rats, KY-054 (10 mg/kg/d, 8 weeks) increased plasma bone-type ALP activity, suggesting in vivo promoting effects on osteoblast differentiation and/or activation. In dual-energy X-ray absorption (DEXA) scanning, KY-054 significantly increased the distal and diaphyseal femurs areal bone mineral density (aBMD) that was decreased by ovariectomy, indicating its beneficial effects on bone mineral contents (BMC) and/or bone volume (BV). In micro-computed tomography (micro-CT) scanning, KY-054 had no effect on metaphysis trabecular bone loss and microarchitecture parameters weakened by ovariectomy, but instead increased metaphysis and diaphysis cortical bone volume (Ct.BV) and cortical BMC (Ct.BMC) without reducing medullary volume (Med.V), resulting in increased bone strength parameters. It is concluded that KY-054 preferentially promotes metaphysis and diaphysis cortical bone osteogenesis with little effect on metaphysis trabecular bone resorption, and is a potential orally active osteogenic anti-osteoporosis drug candidate.

Insights into the antiosteoporotic mechanism of the soy-derived isoflavone genistein: Modulation of the Wnt/beta-catenin signaling.

Bone remodeling is a process that involves osteoblasts, osteoclasts, and osteocytes, and different intracellular signaling, such as the canonical Wnt/β-catenin pathway. Dysregulations of this pathway may also occur during secondary osteoporosis, as in the case of glucocorticoid-induced osteoporosis (GIO), which accelerates osteoblast and osteocyte apoptosis by reducing bone formation, osteoblast differentiation and function, accelerates in turn osteoblast, and osteocyte apoptosis. Genistein is a soy-derived nutrient belonging to the class of isoflavones that reduces bone loss in osteopenic menopausal women, inhibiting bone resorption; however, genistein may also favor bone formation. The aim of this study was to investigate whether estrogen receptor stimulation by genistein might promote osteoblast and osteocyte function during glucocorticoid challenge. Primary osteoblasts, collected from C57BL6/J mice, and MLO-A5 osteocyte cell line were used to reproduce an in vitro model of GIO by adding dexamethasone (1 μM) for 24 h. Cells were then treated with genistein for 24 h and quantitative Polymerase Chain Reaction (qPCR) and western blot were performed to study whether genistein activated the Wnt/β-catenin pathway. Dexamethasone challenge reduced bone formation in primary osteoblasts and bone mineralization in osteocytes; moreover, canonical Wnt/β-catenin pathway was reduced following incubation with dexamethasone in both osteoblasts and osteocytes. Genistein reverted these changes and this effect was mediated by both estrogen receptors α and β. These data suggest that genistein could induce bone remodeling through Wnt/β-catenin pathway activation.

Local Application of Melatonin on Dental Implant Osseointegration: Analysis of Removal Torque. Experimental Study on Rabbits

Melatonin may interfere with the function of osteoclasts and inhibit bone resorption mainly due to its antioxidant properties and ability to detoxify free radicals. This inhibition can be enhanced by the reaction of indolamine in osseoclastogenesis and may have benefits in implantology. Aims: To evaluate the mechanical and biological behavior of osseointegration using melatonin. To compare the stability coefficient of implants at the time of placement (initial or mechanical ISQ) and after 60 days (final or biological ISQ). To measure the disinsertion torque in both groups of rabbits, with and without melatonin application. Materials and Methods: A total of 16 implants of the same brand and size were placed, with 9 of them receiving 3mg of melatonin powder prior to installation and 7 control implants without melatonin. Resonance frequency analysis (Osstell®) was used to measure initial and biological anchorage, as well as removal torque. Results: The mean removal torque for melatonin-treated implants was 99.8 Ncm, and for control implants, the mean was 87.2 Ncm. The differences between the two groups were not statistically significant. However, there were significant differences in biological ISQ values. Conclusions: The use of melatonin improved the response to osseointegration, particularly in the measurement of final or biological ISQ values.

Anti-Siglec-15 Antibody Prevents Marked Bone Loss after Acute Spinal Cord Injury-Induced Immobilization in Rats.

Rapid and extensive sublesional bone loss after spinal cord injury (SCI) is a difficult medical problem that has been refractory to available interventions except the antiresorptive agent denosumab (DMAB). While DMAB has shown some efficacy in inhibiting bone loss, its concurrent inhibition of bone formation limits its use. Sialic acid-binding immunoglobulin-like lectin (Siglec)-15 is expressed on the cell surface of mature osteoclasts. Anti-Siglec-15 antibody (Ab) has been shown to inhibit osteoclast maturation and bone resorption while maintaining osteoblast activity, which is distinct from current antiresorptive agents that inhibit the activity of both osteoclasts and osteoblasts. The goal of the present study is to test a Siglec-15 Ab (NP159) as a new treatment option to prevent bone loss in an acute SCI model. To this end, 4-month-old male Wistar rats underwent complete spinal cord transection and were treated with either vehicle or NP159 at 20 mg/kg once every 2 weeks for 8 weeks. SCI results in significant decreases in bone mineral density (BMD, -18.7%), trabecular bone volume (-43.1%), trabecular connectivity (-59.7%), and bone stiffness (-76.3%) at the distal femur. Treatment with NP159 almost completely prevents the aforementioned deterioration of bone after SCI. Blood and histomorphometric analyses revealed that NP159 is able to greatly inhibit bone resorption while maintaining bone formation after acute SCI. In ex vivo cultures of bone marrow cells, NP159 reduces osteoclastogenesis while increasing osteoblastogenesis. In summary, treatment with NP159 almost fully prevents sublesional loss of BMD and metaphysis trabecular bone volume and preserves bone strength in a rat model of acute SCI. Because of its unique ability to reduce osteoclastogenesis and bone resorption while promoting osteoblastogenesis to maintain bone formation, Siglec-15 Ab may hold greater promise as a therapeutic agent, compared with the exclusively antiresorptive or anabolic agents that are currently used, in mitigating the striking bone loss that occurs after SCI or other conditions associated with severe immobilization. © 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.