Inhibition Of Resorption Research Articles

Efficacy, Mechanism, and Structure-Activity Relationship of 6-Methoxy Benzofuran Derivatives as a Useful Tool for Senile Osteoporosis.

Most patients with senile osteoporosis (SOP) are severely deficient in bone mass, and treatments using bone resorption inhibitors, such as bisphosphonates, have shown limited efficacy. Small-molecule osteogenesis-promoting drugs are required to improve the treatment for this disease. Previously, we demonstrated that a compound with a benzofuran-like structure promoted bone formation by upregulating BMP-2, and it exhibited a therapeutic effect in SAMP-6 mice, glucocorticoid-induced osteoporosis rats, and ovariectomized rats. In this study, aged C57 and SAMP-6 mice models were used to investigate the therapeutic and preventive effects of compound 125 on SOP. scRNA-seq analysis showed that BMP-2 upregulation is the mechanism through which 125 accelerates bone turnover and increases the proportion of osteoblasts. We evaluated the structure-activity relationship of the candidate drugs and found that the derivative I-9 showed significantly higher efficacy than 125 and teriparatide in the zebrafish osteoporosis model. This study provides a foundation for the development of SOP drugs.

Rare localization of avascular necrosis during treatment of COVID-19 with glucocorticosteroids

The development of bony avascular necrosis induced by glucocorticoid treatment of COVID-19 is a common adverse effect, with femoral head being the most commonly affected. Timely detection of avascular necrosis is important in the prevention of osteoarthrosis and other complications.
 We present a clinical case of a 54-year-old patient hospitalized for novel coronavirus infection with complaints of severe pain in both knees 2 weeks after the disease onset. Magnetic resonance imaging revealed pronounced changes in both knees, corresponding to avascular necrosis. The results of conservative therapy, including non-steroidal anti-inflammatory drugs and bisphosphonate bone resorption inhibitors, produced a pronounced positive result. At follow-up examination 3 months later, there was no pain, but the knee joints still had slight restrictions of movement. Magnetic resonance imaging showed a significant decrease in the previously detected changes.
 The side effects of glucocorticoids (impaired glucose tolerance, increased blood pressure, tachycardia, gastrointestinal erosive ulcers, sleep disorders, etc.) are widely known, but knee osteonecrosis caused by steroid intake rarely comes to the attention of clinicians. This clinical case emphasizes the complex nature of osteonecrosis pathogenesis and demonstrates a wide range of complications in corticosteroid therapy.

A nested case-control study of factors contributing to the development of medication-related osteonecrosis of the jaw in patients using bone resorption inhibitors in Mishima City.

Medication-related osteonecrosis of the jaw (MRONJ) is characterized by necrosis of the jawbone with intraoral bacterial infection and has a significant negative impact on oral health-related quality of life. Risk factors for the onset are unknown, and definitive therapeutic approaches have not yet been defined. A case-control study at a single institution in Mishima City was conducted. The purpose of this study was to examine in detail the factors that contribute to the development of MRONJ. Medical records of MRONJ patients who visited Mishima Dental Center, Nihon University School of Dentistry, during the period 2015-2021 were extracted. Counter-matched sampling design was used to select participants matched for sex, age, and smoking for this nested case-control study. The incidence factors were statistically examined by logistic regression analysis. Twelve MRONJ patients were used as cases and 32 controls were matched. After adjustment for potential confounders, injectable bisphosphonates (aOR = 24.5; 95% CI = 1.05, 575.0; P < 0.05) were significantly associated with the development of MRONJ. High-dose bisphosphonates may be a risk factor for the development of MRONJ. Patients who use these products require careful prophylactic dental treatment against inflammatory diseases, and dentists and physicians should maintain close communication.

Alendronate functionalized PLGA based nanoparticles for the effective treatment of osteoporosis-Formulation to in-vitro release kinetic studies

Osteoporosis is a bone disease caused due to the reducing bone mineral density. Porous and more fragile bones increase the risk of fractures. Hip, spine, shoulder, and wrist bones are commonly affected by osteoporosis. Low bone density is a leading cause of osteoporosis. The most efficient prescribed drugs for the treatment of osteoporosis are bisphosphonates drugs. Alendronate was the first FDA approved bisphosphonate drug for the treatment of osteoporosis. Osteoclast cells are the primary targeting site for alendronate, responsible for bone resorption. A biopharmaceutical classification system class III bisphosphonate acts as a potent, efficient, and bone resorption inhibitor drug. In the present study, alendronate functionalized PLGA based nanoparticles were developed by a solvent diffusion method and optimized for different process variables. The formulated nanoparticles were characterized for surface morphology, particle size distribution, surface charge and drug-polymer compatibility. The scanning electron microscopy and transmission electron microscopy results showed nanoparticle size in the range below 200 nm. The average particle size and zeta potential of the formulated nanoparticles were found to be 175.3 nm and -13.98 mV, respectively. The highest encapsulation efficiency was 65.23%. The release profile was dissolution medium dependent and followed by the Higuchi model of release kinetics.

Denosumab Can Prevent Collapse in Patients with Early-Stage Steroid-Induced Osteonecrosis of the Femoral Head by Inhibiting Osteoclasts and Autophagy.

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. 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. 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). 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.

PSAT188 Keeping An Eye On Bisphosphonates: Drug Induced Uveitis

Abstract Introduction Bisphosphonates are considered the treatment of choice for osteoporosis. They have strong anti-osteoclastic activity and are potent inhibitors of bone resorption. Ocular inflammation, including conjunctivitis, uveitis, episcleritis and scleritis, is a rare side effect of bisphosphonates. A few cases in the literature have reported ocular inflammation secondary to bisphosphonate use. But largely, it has been an underrecognized cause of uveitis. We report a case of unilateral uveitis secondary to bisphosphonate therapy that was completely resolved after discontinuation of the medication. Case report A 68-year-old female with a history of osteoporosis diagnosed in 2019 on routine bone density scan presented for treatment evaluation. She had a history of multiple fractures after falling from standing height but no history of kidney stones, hypercalcemia, or GERD. She was started on alendronate 70mg once a week in 2019 with stabilization in bone density on repeat scan in 2020. After several weeks of treatment, she developed left eye uveitis and was treated with phenylephrine 2.5% and prednisolone acetate 1% ophthalmic solution. Because of these symptoms, the patient had diagnostic studies done which revealed positive ANA. She then had an extensive rheumatology workup, including serum SM antibody, ANCA screen, RNP antibody, Sjogren's antibodies, DNA (DS) antibody, and HLA-B27 DNA typing, which were all negative. Due to some case reports citing an association of bisphosphonate use with eye inflammation, the bisphosphonate was stopped with gradual improvement in her eye symptoms. An attempt to restart alendronate resulted in worsening eye symptoms, so the therapy was ultimately switched to denosumab. Discussion The incidence of ocular inflammation after bisphosphonate initiation is 0.08%. Symptoms usually develop 24 hours to a few weeks after starting treatment. The potential pathogenesis of bisphosphonate-induced ocular inflammation is thought to be secondary to bloodstream absorption and secretion of the medication into tears from the lacrimal gland causing irritation to the eyes’ mucous membranes. Originally it was thought that ocular inflammation only occurred with nitrogen-containing bisphosphonates, due to the nitrogen group possibly playing a role in activating gamma delta T cells leading to the release of acute phase reactants, such as cytokines. More recently, both nitrogen and non-nitrogen containing bisphosphonates have been associated with reported cases of ocular inflammation. Presentation can be either unilateral or bilateral, but the majority of reported cases were unilateral. All patients receiving bisphosphonates who develop signs and symptoms of ocular inflammation should be referred promptly to an ophthalmologist. The drug should be discontinued once the diagnosis is made to prevent further progression. In conclusion, clinicians should be aware of the potential for ocular inflammation upon bisphosphonate initiation. Patients may benefit from switching to a different class of medication, such as denosumab, if they experience symptoms of ocular inflammation with bisphosphonates. Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m.

Age-Related Changes in Calcitonin-Producing Thyroid C-Cells of Male Wistar Rats.

Thyroid C-cells secrete the hormone calcitonin (CT) which acts as an inhibitor of bone resorption. Our aim was to examine the age-related changes in the structure and function of CT-producing C-cells, using histomorphometric, ultrastructural, and biochemical analyses. We used young adult (3-months-old), middle-aged (16-months-old), and old (24-months-old) male rats. The peroxidase-antiperoxidase method was applied for localization of CT. Stereological analysis was performed using the newCAST stereological software package. Serum samples were analyzed for the determination of CT, testosterone (T), calcium (Ca2+), and phosphorus (P). We found a significant increase in the volume density (Vv) of C-cells in both older groups (p < 0.05). The percentage of smaller volume range C-cells increased (p < 0.0001), while the proportion of greater volume range C-cells decreased (p < 0.05) with ageing. Ultrastructural analysis revealed a larger number of secretory granules in older rats. Serum CT increased (p < 0.001), while serum T and P were reduced (p < 0.01) in older rats. Serum Ca2+ was lower (p < 0.0001) in middle-aged rats compared to young adults. We revealed a 20% incidence of C-cell hyperplasia in older rats and one case of medullary thyroid carcinoma in an old rat. Our findings indicate that the ageing process causes significant histomorphometric changes at the thyroid C-cell level.

BNTA alleviates inflammatory osteolysis by the SOD mediated anti-oxidation and anti-inflammation effect on inhibiting osteoclastogenesis.

Abnormal activation and overproliferation of osteoclast in inflammatory bone diseases lead to osteolysis and bone mass loss. Although current pharmacological treatments have made extensive advances, limitations still exist. N-[2-bromo-4-(phenylsulfonyl)-3-thienyl]-2-chlorobenzamide (BNTA) is an artificially synthesized molecule compound that has antioxidant and anti-inflammatory properties. In this study, we presented that BNTA can suppress intracellular ROS levels through increasing ROS scavenging enzymes SOD1 and SOD2, subsequently attenuating the MARK signaling pathway and the transcription of NFATc1, leading to the inhibition of osteoclast formation and osteolytic resorption. Moreover, the results also showed an obvious restrained effect of BNTA on RANKL-stimulated proinflammatory cytokines, which indirectly mediated osteoclastogenesis. In line with the in vitro results, BNTA protected LPS-induced severe bone loss in vivo by enhancing scavenging enzymes, reducing proinflammatory cytokines, and decreasing osteoclast formation. Taken together, all of the results demonstrate that BNTA effectively represses oxidation, regulates inflammatory activity, and inhibits osteolytic bone resorption, and it may be a potential and exploitable drug to prevent inflammatory osteolytic bone diseases.

Hypercholesterolemia diagnosis, treatment patterns and target achievement in patients with acute coronary syndromes in Germany.

Patients who experience an acute coronary syndrome (ACS) are at high risk of further cardiovascular events. Long-term treatment of cardiovascular risk factors, such as hyperlipidemia, is critical to prevent progression of coronary heart disease. However, many patients do not reach recommended target levels for low-density lipoprotein (LDL) cholesterol, despite receiving lipid-lowering therapy. To obtain an insight into the current treatment situation for very high-risk patients after an initial ACS in Germany. The multicenter HYDRA-ACS registry study was initiated to document the clinical characteristics of very high-risk patients with ACS and hyperlipidemia in clinical practice. In addition, lipid profiles, lipid-lowering therapy, and lipid target achievement during treatment were documented over 1 year. 353 patients who were documented had a mean age of 57.3years, mean body mass index was 28.6kg/m2, and 73.4% were male; 52.4% had a family history of myocardial infarction (MI) and 32.6% a family history of coronary heart disease (CHD). Patients' medical histories commonly included CHD (32.9%), percutaneous coronary intervention (PCI; 25.5%), and previous ACS (23.0%). Common comorbidities included hypertension (68.6%), diabetes (17.3%), heart failure (16.7%), and stable angina pectoris (15.9%). The proportion of patients receiving lipid-lowering therapy increased from 65.7% at baseline to 100% at the 12-month follow-up (p < 0.0001). Substantial increases in use were seen for statins (85.0% vs. 36.5%, p = 0.0002) and cholesterol resorption inhibitors (32.9% vs. 8.6%, p = 0.0003). Use of combination therapy increased. The proportion of patients undertaking physical exercise increased (p < 0.0001), as did consumption of fruit and vegetables (p = 0.0222) and fish (p = 0.0162), while alcohol consumption decreased (p = 0.0019). Median LDL cholesterol level decreased significantly from baseline (87 vs. 166mg/dL, p < 0.0001), and the proportion of patients with a level < 70mg/dL increased (50.0% vs. 5.7%, p < 0.0001). Median HDL cholesterol increased (47 vs. 45mg/dL, p = 0.0235) and median triglyceride level decreased (119 vs. 148mg/dL, p = 0.0080). The proportion of patients receiving antihypertensive drugs and platelet aggregation inhibitors increased. The most frequent cardiovascular events during the 12-month follow-up were PCI (25.9%) and cardiac catheterization without PCI (12.9%); MI occurred in 2.4% of patients; no deaths were reported. This study provides a contemporary picture of the treatment of hyperlipidemia after ACS in patients in Germany. Despite treatment with lipid-lowering therapy, many patients did not achieve recommended lipid targets by 12months after an ACS event.

Mechanism and efficacy of parathyroid hormone in osteoporosis

Background: Parathyroid hormone (PTH) and teriparatide, which is a PTH analog, are special options of osteoanabolic therapies for osteoporosis treatment. Their efficacy in improving the bone mineral density (BMD) and reducing fracture risk is considered to have a long-awaited justification.Current Concepts: PTH is an 84-amino acid polypeptide that plays a key role in the calcium homeostasis of the human body. It yields anabolic effects on the bone by intermittent injections. During the first 6 months of PTH treatment, bone formation increases rapidly and bone resorption rises gradually. PTH is believed to be maximally anabolic during the anabolic window. In the phase III trial of teriparatide, significant reductions in vertebral and non-vertebral fractures were identified. Teriparatide has been studied in drug-induced osteoporosis, postmenopausal women with osteoporosis, and men with osteoporosis. The data derived from clinical trials with teriparatide showed an increase of the BMD in the treatment group compared to that of the placebo. Selective advantages on fracture healing have been shown in some studies; however, consensus on the relationship between teriparatide and bone healing is unclear.Discussion and Conclusion: Teriparatide has been approved for osteoporosis treatment in various situations, including postmenopausal women, men with osteoporosis, and cases with glucocorticoid-induced osteoporosis. Additionally, it can be useful in high risk for fracture groups, if fractures persist despite bone resorption inhibitor therapy, and if bone resorption inhibitor administration is difficult and contraindicated.

Medication-related osteonecrosis of the jaw after tooth extraction in patients receiving pharmaceutical treatment for osteoporosis: A retrospective cohort study

Background/purposeBone resorption inhibitors, such as bisphosphonates (BPs) and anti-receptor activator of nuclear factor kappa B ligand antibodies (denosumab; Dmab), are used to treat osteoporosis and effectively reduce the risk of fracture. However, medication-related osteonecrosis of the jaw (MRONJ) has been reported as a rare adverse effect. Invasive tooth extraction procedures are reportedly a factor in the development of MRONJ. In this study, we aimed to retrospectively observe and clinically examine the effect of medication status on MRONJ development after tooth extraction in patients receiving drug treatment for osteoporosis. Materials and methodsThis study was conducted among patients who visited our hospital between December 2015 and December 2021. We collected and analyzed the medical information of patients who underwent dental extractions while using osteoporosis medications, including oral and injectable BPs and Dmab. ResultsAmong antiresorptive medication users, 40 patients (70 teeth) underwent extraction. The mean duration of BP/Dmab use was 40.4 months, and the mean duration of drug holiday was 6.9 months. MRONJ after tooth extraction was not seen in BP users, but we observed two cases in Dmab users. A significant difference in MRONJ development was confirmed with the use of injectable compared with oral medication administration (odds ratio＝5.01). ConclusionThe use of injectable bone resorption inhibitors was associated with a higher risk of developing MRONJ. The route of administration, duration of medication, and withdrawal period should be carefully considered to prevent MRONJ after tooth extraction.

Raman Spectroscopic Investigation of Osteoclastic Activity under the Influence of Bisphosphonate

The bone resorption inhibitor bisphosphonate (BP) is used to prevent fractures in patients with osteoporosis and bone metastases caused by cancer. However, BP induces apoptosis of osteoclasts and excessively suppresses bone turnover, so that side effects such as jawbone necrosis have become a problem. In the super-aging society that Japan is facing, it is expected that jawbone necrosis (Medication-related osteonecrosis of the jaw: MRONJ) will increase as the number of osteoporosis patients increases. There are many unclear points about the pathophysiology of jawbone necrosis, and there have been attempts to clarify it. Most of the research on osteoclasts so far has comprised destructive and invasive analyses, such as TRAP staining and PCR by culturing osteoclasts on a plastic plate, which is the original physiological function of osteoclasts. “Bone resorption” cannot be analyzed in real time. In this study, Raman spectroscopy is used to show the state of bone resorption of osteoclasts cultured on ivory sections or octacalcium phosphate plates noninvasively and without the need for colorimetric assays. This makes it possible to clarify the effect of BP on osteoclast metabolism in an environment closer to that of a living body. If this method is established, then we aim to elucidate the pathophysiology of bone pathologies and medical treatments that directly affect osteoclasts, such as medication-related osteonecrosis, and establish a diagnostic method.

Investigation on the bisphosphonate and osseointegrated implants: a concise systematic review

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 has this disorder, it occurs twice as often in women than in men. It is estimated that 1.3 million fractures and 133,000 all hip fractures occur every year as a result of osteoporosis. The aim of this study was to discuss aspects of the pharmacological action of Bisphosphonates (BP) and their influence on the bone tissue when associated with treatment with dental implants. There are several types of treatments that prevent or prevent the progression of osteoporosis. So, BP, such as alendronate, are inhibitors 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.

Inhibiting Endothelin Receptors with Macitentan Strengthens the Bone Protective Action of RANKL Inhibition and Reduces Metastatic Dissemination in Osteosarcoma.

Simple SummaryThe efficacy of current osteosarcoma therapy is diminished by two adverse events, namely resistance to chemotherapy and metastatic dissemination. In recent decades, research has been devoted to reducing these adverse events. Inhibiting bone resorption has shown promising effects on metastatic dissemination and tumor growth, with, however, the formation of significant tumoral mineralized tissue. Endothelin signaling is implicated in activating the cell that forms the mineralized tissues, consequently the impact of inhibiting it alone and in combination with the inhibition of bone resorption was evaluated using osteosarcoma models. The results obtained showed that inhibiting endothelin signaling significantly reduced the formation of mineralized tumor tissue concomitantly to metastatic dissemination without affecting sensitivity to chemotherapy. This inhibition appears to be a promising new therapeutic tool in the fight against osteosarcoma.Current treatments for osteosarcoma, combining conventional polychemotherapy and surgery, make it possible to attain a five-year survival rate of 70% in affected individuals. The presence of chemoresistance and metastases significantly shorten the patient’s lifespan, making identification of new therapeutic tools essential. Inhibiting bone resorption has been shown to be an efficient adjuvant strategy impacting the metastatic dissemination of osteosarcoma, tumor growth, and associated bone destruction. Unfortunately, over-apposition of mineralized matrix by normal and tumoral osteoblasts was associated with this inhibition. Endothelin signaling is implicated in the functional differentiation of osteoblasts, raising the question of the potential value of inhibiting it alone, or in combination with bone resorption repression. Using mouse models of osteosarcoma, the impact of macitentan, an endothelin receptor inhibitor, was evaluated regarding tumor growth, metastatic dissemination, matrix over-apposition secondary to RANKL blockade, and safety when combined with chemotherapy. The results showed that macitentan has no impact on tumor growth or sensitivity to ifosfamide, but significantly reduces tumoral osteoid tissue formation and the metastatic capacity of the osteosarcoma. To conclude, macitentan appears to be a promising therapeutic adjuvant for osteosarcoma alone or associated with bone resorption inhibitors.

Aged bone matrix-derived extracellular vesicles as a messenger for calcification paradox

Adipocyte differentiation of bone marrow mesenchymal stem/stromal cells (BMSCs) instead of osteoblast formation contributes to age- and menopause-related marrow adiposity and osteoporosis. Vascular calcification often occurs with osteoporosis, a contradictory association called “calcification paradox”. Here we show that extracellular vesicles derived from aged bone matrix (AB-EVs) during bone resorption favor BMSC adipogenesis rather than osteogenesis and augment calcification of vascular smooth muscle cells. Intravenous or intramedullary injection of AB-EVs promotes bone-fat imbalance and exacerbates Vitamin D3 (VD3)-induced vascular calcification in young or old mice. Alendronate (ALE), a bone resorption inhibitor, down-regulates AB-EVs release and attenuates aging- and ovariectomy-induced bone-fat imbalance. In the VD3-treated aged mice, ALE suppresses the ovariectomy-induced aggravation of vascular calcification. MiR-483-5p and miR-2861 are enriched in AB-EVs and essential for the AB-EVs-induced bone-fat imbalance and exacerbation of vascular calcification. Our study uncovers the role of AB-EVs as a messenger for calcification paradox by transferring miR-483-5p and miR-2861.

Effects of Exposure to Trade Antifouling Paints and Biocides on Larval Settlement and Metamorphosis of the Compound Ascidian Botryllus schlosseri

To evaluate the effects of antifouling paints and biocides on larval settlement and metamorphosis, newly hatched swimming larvae of the compound ascidian Botryllus schlosseri, a dominant species of soft-fouling in coastal communities, were exposed to (i) substrata coated with seven antifouling paints on the market containing different biocidal mixtures and types of matrices and (ii) sea water containing various concentrations of eight biocidal constituents. All antifouling paints showed high performance, causing 100% mortality and metamorphic inhibition, with ≥75% not-settled dead larvae. All antifouling biocides prevented the settlement of larvae. The most severe larval malformations, i.e., (i) the formation of a bubble encasing the cephalenteron and (ii) the inhibition of tail resorption, were observed after exposure to metal and organometal compounds, including tributyltin (TBT) at 1 μM (325.5 µg L−1), zinc pyrithione (ZnP) at 1 μM (317.7 µg L−1), and CuCl at 0.1 μM (98.99 µg L−1), and to antimicrobials and fungicides, including Sea-Nine 211 at 1 μM (282.2 µg L−1) and Chlorothalonil at 1 μM (265.9 µg L−1). The herbicides seemed to be less active. Irgarol 1051 was not lethal at any of the concentrations tested. Diuron at 250 μM (58.2 mg L−1) and 2,3,5,6-tetrachloro-4-(methylsulphonyl)pyridine (TCMS pyridine) at 50 μM (14.8 mg L−1) completely inhibited larval metamorphosis. These results may have important implications for the practical use of different antifouling components, highlighting the importance of their testing for negative impacts on native benthic species.

Effects of Sparganii Rhizoma on Osteoclast Formation and Osteoblast Differentiation and on an OVX-Induced Bone Loss Model.

Postmenopausal osteoporosis is caused by an imbalance between osteoclasts and osteoblasts and causes severe bone loss. Osteoporotic medicines are classified into bone resorption inhibitors and bone formation promoters according to the mechanism of action. Long-term use of bisphosphonate and selective estrogen receptor modulators (SERMs) can cause severe side effects in postmenopausal osteoporosis patients. Therefore, it is important to find alternative natural products that reduce osteoclast activity and increase osteoblast formation. Sparganii Rhizoma (SR) is the dried tuberous rhizome of Sparganium stoloniferum Buchanan-Hamilton and is called “samreung” in Korea. However, to date, the effect of SR on osteoclast differentiation and the ovariectomized (OVX)-induced bone loss model has not been reported. In vitro, tartrate-resistant acid phosphatase (TRAP) staining, western blots, RT-PCR and other methods were used to examine the effect of SR on osteoclast differentiation and osteoblasts. In vivo, we confirmed the effect of SR in a model of OVX-induced postmenopausal osteoporosis. SR inhibited osteoclast differentiation and decreased the expression of TNF receptor-associated factor 6 (TRAF6), nuclear factor of activated T cells 1 (NFATc1) and c-Fos pathway. In addition, SR stimulates osteoblast differentiation and increased protein expression of the bone morphogenetic protein 2 (BMP-2)/SMAD signaling pathway. Moreover, SR protected against bone loss in OVX-induced rats. Our results appear to advance our knowledge of SR and successfully demonstrate its potential role as a osteoclastogenesis-inhibiting and osteogenesis-promoting herbal medicine for the treatment of postmenopausal osteoporosis.

Risk of Medication-Related Osteonecrosis of the Jaw after Dental Extractions in Patients Receiving Bone Resorption Inhibitors – A Retrospective Study of 240 Patients

Risk of Medication-Related Osteonecrosis of the Jaw after Dental Extractions in Patients Receiving Bone Resorption Inhibitors – A Retrospective Study of 240 Patients

Incidence of Antiresorptive Agent-Related Osteonecrosis of the Jaw in Urologic Cancers

Antiresorptive agent-related osteonecrosis of the jaw (ARONJ) is a serious adverse event of bone resorption inhibitors (BRIs), such as zoledronic acid and denosumab. Based on the results of phase 3 clinical trials for BRIs, the frequency of ARONJ is 1 to 2%, but the actual frequency is presumed to be higher. We studied 143 patients with urologic cancers with bone metastases who were treated with zoledronic acid or denosumab at our hospital between April 2007 and March 2020. ARONJ occurred in 24 patients (16.8%) ; that is, 14 of the 113 patients (12.4%) who received zoledronic acid alone, 8 of the 24 patients (33.3%) who received denosumab alone, and 2 of the 6 patients (33.3%) who sequentially switched from zoledronic acid to denosumab. ARONJ was cured in 8 patients (33.3%), improved in 3 patients (12.5%), unchanged in 4 patients (16.7%), and worsened in 9 patients (37.5%). The frequency of ARONJ increased as the duration of BRI administration prolonged. Time-to-ARONJ was shorter in patients treated with denosumab than in patients treated with zoledronic acid. The occurrence of ARONJ may be underestimated; therefore, further studies are needed to investigate the actual frequency of ARONJ in Japan.

Efficacy of Alendronate Functionalized Solid Lipid Nanoparticles for Osteoporosis Treatment- Development and Release Kinetics Study

Osteoporosis means "Porous bone” is a disease characterized by progressive bone thinning. The deterioration of bone tissue can lead to bone fragility and fracture, especially of the hip, spine, shoulder and wrist. Osteoporosis is caused generally due the decreasing bone mineral density (BMD). Osteoporosis affects 30-40% women after menopause all around the world. Bisphosphonates are the most commonly prescribed drugs for the treatment of osteoporosis in the US and many other countries including India. Alendronate- sodium (AS) is a widely used anti-osteoporosis drug, exhibits strong inhibitory effect on bone resorption performed by osteoclast cells and acts as a potent, specific inhibitor of osteoclast-mediated bone resorption. AS was the first FDA approved bisphosphonate for treatment of osteoporosis in the US in 1995. The objective of the present study was to develop, optimize, and evaluate Solid Lipid Nanoparticles (SLN) of Alendronate-sodium drug which improve the solubility, dissolution rate and enhance the bioavailability of the drug. AS loaded Solid Lipid Nanoparticles have been developed using Glyceral Monosterate (GMS) as lipid and poloxamer 407 as the emulsifier by Emulsion -Solvent evaporation method. Different process variables i.e. concentration of surfactant, homogenization speed and time have been optimized. Formulated SLNs with GMS showed low particle size and high entrapement efficiency. The SLNs were characterized using Zeta sizer, transmission electron microscopy (TEM) and scanning electron microscopy (SEM). In-vitro drug release study was performed by dialysis bag diffusion method and different mathematical models were applied for the release study.