Antiresorptive Properties Research Articles

Immune regulatory and anti-resorptive activities of tanshinone IIA sulfonate attenuates rheumatoid arthritis in mice.

Rheumatoid arthritis (RA) is an autoimmune disease characterized by chronic inflammation and painful joint destruction. Current treatments are helpful in RA remission, but strong immunosuppressive activity and patient resistance are clinical issues. This study explores a dual-action inhibitor, possessing both anti-inflammatory and anti-resorptive properties, as a novel treatment for RA. Therapeutic efficacy and mechanisms of ectosteric (tanshinone IIA sulfonate [T06]) and active site-directed (odanacatib [ODN]) inhibitors of cathepsin K (CatK) were evaluated in RA mouse models. Pathology was assessed through biochemical analyses and histopathological examination. Flow cytometry analysis was performed to characterize immune cells. Anti-inflammatory effects of T06 on nuclear factor kappa beta (NF-κB) pathway were studied in macrophages. T06 effectively lowered the number of joint-resident immune cells, accompanied by significantly reduced production of inflammatory cytokines and collagenolytic proteases. This also included the suppression of Th17 cells and IL-17, resulting in the reduction of osteoclasts in arthritic joints and amplification of the overall anti-resorptive effect of T06, which has been attributed to its selective inhibition of the collagenolytic activity of CatK by preventing its oligomerization. The anti-inflammatory mechanism of T06 was based on blocking the phosphorylation of IκBα in the NF-κB pathway, resulting in reduced activation and expression of inflammatory cytokines. In contrast, ODN had no effect on inflammation and disease progression and was limited to the inhibition of CatK. The combined anti-resorptive and anti-inflammatory activities characterize T06 as a novel therapeutic agent for RA.

Farnesyl pyrophosphate synthase inhibitors with antiosteoporosis efficacy in ovariectomized rats: A mixed binding approach beyond bisphosphonates

The primary focus of bisphosphonate medications is on targeting human farnesyl pyrophosphate synthase (hFPPS), an essential regulator of mammalian isoprenoids. Yet, these drugs encounter limitations due to their restricted "druglike" properties and their effectiveness primarily in treating skeletal disorders. In this study, we synthesized novel non-bisphosphonate compounds, using 4,4'-(ethane-1,2-diylbis(oxy))bis(3-methoxybenzaldehyde) (1) as a starting compound, with the aim of targeting hFPPS through a mixed binding approach. Among the various compounds tested, compounds 4a and 4b exhibited significant inhibition of hFPPS activity, with IC50 values of 1.108 and 1.24 μM, respectively. Docking studies further revealed that both compounds bound within the allylic binding site and near the isopentenyl diphosphate (IPP) site within the hFPPS pocket. Molecular dynamic simulations were performed on the best docking pose of the most potent compound 4a to confirm the formation of a stable complex with hFPPS. In an in vivo study conducted on ovariectomized rats, various biochemical markers including osteocalcin, estradiol, osteoprotegerin, bone mineral content, and density were negatively impacted, while levels of bone specific alkaline phosphatase, receptor activator of nuclear factor kappa-Β ligand, serum/urinary calcium, and phosphate increased. Notably, compound 4a exhibited antiresorptive properties similar to zoledronate, effectively restoring most of the perturbed biochemical estimations. These findings suggest the potential of compound 4a, a non-bisphosphonate compound, as alternative therapeutic agents for combating osteoporosis.

3D-Bioprinted Gelatin Methacryloyl-Strontium-Doped Hydroxyapatite Composite Hydrogels Scaffolds for Bone Tissue Regeneration.

New gelatin methacryloyl (GelMA)-strontium-doped nanosize hydroxyapatite (SrHA) composite hydrogel scaffolds were developed using UV photo-crosslinking and 3D printing for bone tissue regeneration, with the controlled delivery capacity of strontium (Sr). While Sr is an effective anti-osteoporotic agent with both anti-resorptive and anabolic properties, it has several important side effects when systemic administration is applied. Multi-layer composite scaffolds for bone tissue regeneration were developed based on the digital light processing (DLP) 3D printing technique through the photopolymerization of GelMA. The chemical, morphological, and biocompatibility properties of these scaffolds were investigated. The composite gels were shown to be suitable for 3D printing. In vitro cell culture showed that osteoblasts can adhere and proliferate on the surface of the hydrogel, indicating that the GelMA-SrHA hydrogel has good cell viability and biocompatibility. The GelMA-SrHA composites are promising 3D-printed scaffolds for bone repair.

Inhibitory action of methylene bisphosphonic acid on metabolic activity and viability of J774A.1 cells

Bisphosphonates (BPs) are primary agents in the current pharmacological arsenal against osteoclast-related bone loss due to osteoporosis, Paget’s disease and bone tumors. Due to the lack of complete understanding of the molecular mechanism of their action in bone tissue and the overlap of key properties between BPs of different generations, integral studies of BPs inhibitory and antiresorptive properties are relevant today. The present work was carried out to establish a comprehensive study of the inhibitory effects of methylene bisphosphonic acid (MBPA) on the mevalonate pathway, metabolic activity and cell death in vitro compared to zoledronic acid (Zol). Farnesyl pyrophosphate synthase activity of MBPA-treated J774A.1 cells was inhibited by 80%, compared with a 79% reduction in Zol-treated samples. The ability of MBPA to decrease the percentage of viable cells in culture is slightly lower compared with Zol. After 24 h of incubation with lowest concentration, the percentage of inhibition of metabolic activity was 10.6 and 25%, respectively. After 48 h, these values were 34.8 and 55.6%, respectively. The inhibitory effects of MBPA and Zol on the intensity of incorporation of radioactively labeled precursor [14C]-acetate to the cholesterol fraction were 76.2 and 59.1%, respectively. In the case of isoprenoid fraction, the inhibitory effects were 40.9% and 51.2%, respectively. MBPA and Zol differently induced apoptosis in the J774A.1 cells culture, increased count of apoptotic cells in 2.4 and 6.3 times, and also increased the number of propidium iodide-positive cells in 7.4 and 19 times, respectively. MBPA and Zol also increased the number of TUNEL-positive cells in macrophage culture in 2.6 and 5 times, respectively. Zoledronate significantly reduced carbonic anhydrase 2 and nuclear factor of activated T-cells 1 gene expression levels compared to the MBPA action. Thus, the use of MBPA in future research and therapy of both cancer and osteoporosis looks promising due to lower cytotoxicity, high efficiency of mevalonate pathway inhibition and the possibility of dosage variation. Keywords: cell death, cell viability, FPPS enzymatic activity, gene expression, J774A.1 macrophages, methylene bisphosphonic acid, radioisotopes., zoledronic acid

Chenopodium Ambrosioides Linn Mitigates Bone Loss in Rats with Periodontitis.

Periodontitis is an inflammatory disease that causes bone loss. Some patients do not respond well to the classic treatment and need therapies that minimize bone loss, the main sequel of the disease. Chenopodium ambrosioides L. has stood out due to its anti-inflammatory and anti-oxidative activities. However, no study has yet investigated its effect on periodontitis. This study aimed to evaluate the bone protective effect of Chenopodium ambrosioides L. (CAL) extract on ligature-induced periodontitis model in rats. For this, a pre-clinical assay was performed, using male Wistar rats divided into 3 groups: Naive (N) (n=6), not submitted to any procedure; Saline (SAL) (n=6), submitted to ligature-induced periodontitis and receiving 2 ml/kg of 0.9% saline solution; and CAL extract, which was subdivided into 3 subgroups (n=6/subgroup) receiving the CAL at 3 (CAL3), 10 (CAL10) or 30 mg/kg (CAL30). All agents were given, by oral gavage, 30 min before periodontitis induction and daily until euthanasia (11th day). By then, maxillae were removed for macroscopic, histological, and histometric analyses. Kidneys, liver, and stomach were collected to evaluate the safety of CAL extract. High-performance liquid chromatography (HPLC) assay was used to investigate the flavonoid content in the extract. Chenopodium ambrosioides L. extract at 30mg/kg showed a reduction by 58% in bone loss marked by an increase (+35%) in the number of osteoblasts and a reduction (-51%) on the number of osteoclasts (p< 0.05). No significant alteration in the liver, kidney, or stomach was seen. Rutin was the main flavonoid found. In summary, it was observed that Chenopodium ambrosioides L. extract has shown important anti-inflammatory and bone anabolic and anti-resorptive properties without causing toxicity in the main organs. Rutin, as the main flavonoid of the extract, seems to be responsible for the beneficial effect of this agent.

Long non-coding RNA LncTUG1 regulates favourable compression force-induced cementocytes mineralization via PU.1/TLR4/SphK1 signalling.

Orthodontic tooth movement (OTM) is a highly coordinated biomechanical response to orthodontic forces with active remodelling of alveolar bone but minor root resorption. Such antiresorptive properties of root relate to cementocyte mineralization, the mechanisms of which remain largely unknown. This study used the microarray analysis to explore long non-coding ribonucleic acids involved in stress-induced cementocyte mineralization. Gain- and loss-of-function experiments, including Alkaline phosphatase (ALP) activity and Alizarin Red S staining, quantitative real-time polymerase chain reaction (qRT-PCR), Western blot, and immunofluorescence analyses of mineralization-associated factors, were conducted to verify long non-coding ribonucleic acids taurine-upregulated gene 1 (LncTUG1) regulation in stress-induced cementocyte mineralization, via targeting the Toll-like receptor 4 (TLR4)/SphK1 axis. The luciferase reporter assays, chromatin immunoprecipitation assays, RNA pull-down, RNA immunoprecipitation, and co-localization assays were performed to elucidate the interactions between LncTUG1, PU.1, and TLR4. Our findings indicated that LncTUG1 overexpression attenuated stress-induced cementocyte mineralization, while blocking the TLR4/SphK1 axis reversed the inhibitory effect of LncTUG1 on stress-induced cementocyte mineralization. The in vivo findings also confirmed the involvement of TLR4/SphK1 signalling in cementocyte mineralization during OTM. Mechanistically, LncTUG1 bound with PU.1 subsequently enhanced TLR4 promotor activity and thus transcriptionally elevated the expression of TLR4. In conclusion, our data revealed a critical role of LncTUG1 in regulating stress-induced cementocyte mineralization via PU.1/TLR4/SphK1 signalling, which might provide further insights for developing novel therapeutic strategies that could protect roots from resorption during OTM.

О роли инозитолов и их синергистов при перименопаузальном остеопорозе и синдроме поликистозных яичников

The hormonal restructuring of a woman’s body is essential in the development of perimenopausal osteoporosis. Perimenopause is characterized by a decreased osteoprotective action of estrogens, increased severity of insulin resistance, chronic inflammation, and the negative impact of these factors on bone structure (suppression of osteoblast function, activation of osteoclasts). This article presents the results of a systematic literature review on the effects of B8 vitamers (myoinositol, D-chiroinositol) and their synergists (manganese, folate) on bone tissue. Phospho-derivatives of inositols may influence bone repair process through (1) activity of inositol-dependent proteins (Inpp4b, IP6K1, SHIP1), NFATc1 protein, and the RANKL/NF-kB cascade, (2) participation in the signaling cascade of calcium-sensing receptor (CASR) and in the mechanisms of realization of antiresorptive properties of strontium, (3) participation in the realization of biological effects of parathyroid hormone (PTH), (4) estrogen-dependent regulation of osteoblast apoptosis. The supplemental administration of myoinositol, D-chiroinositol, manganese, and folate in the perimenopausal period may have a positive effect on bone metabolism in women. Key words: osteopenia, hypoestrogenism, polycystic ovary syndrome, Dikirogen, myoinositol, D-chiroinositol, manganese pyroglutamate, folic acid, nutrient deficiencies

Anti-RANKL Therapy Prevents Glucocorticoid-Induced Bone Loss and Promotes Muscle Function in a Mouse Model of Duchenne Muscular Dystrophy

Bisphosphonates prevent bone loss in glucocorticoid (GC)-treated boys with Duchenne muscular dystrophy (DMD) and are recommended as standard of care. Targeting receptor activator of nuclear factor kappa-B ligand (RANKL) may have advantages in DMD by ameliorating dystrophic skeletal muscle function in addition to their bone anti-resorptive properties. However, the potential effects of anti-RANKL treatment upon discontinuation in GC-induced animal models of DMD are unknown and need further investigation prior to exploration in the clinical research setting. In the first study, the effects of anti-RANKL and deflazacort (DFZ) on dystrophic skeletal muscle function and bone microstructure were assessed in mdx mice treated with DFZ or anti-RANKL, or both for 8 weeks. Anti-RANKL and DFZ improved grip force performance of mdx mice but an additive effect was not noted. However, anti-RANKL but not DFZ improved ex vivo contractile properties of dystrophic muscles. This functional improvement was associated with a reduction in muscle damage and fibrosis, and inflammatory cell number. Anti-RANKL treatment, with or without DFZ, also improved trabecular bone structure of mdx mice. In a second study, intravenous zoledronate (Zol) administration (1 or 2 doses) following 2 months of discontinuation of anti-RANKL treatment was mostly required to record an improvement in bone microarchitecture and biomechanical properties in DFZ-treated mdx mice. In conclusion, the ability of anti-RANKL therapy to restore muscle function has profound implications for DMD patients as it offers the possibility of improving skeletal muscle function without the steroid-related skeletal side effects.

Mechanisms underlying the long-term and withdrawal effects of denosumab therapy on bone.

Denosumab, a human monoclonal antibody against receptor activator of nuclear factor-κB ligand (RANKL), is a potent inhibitor of osteoclast differentiation and activity. As the first biologic drug used to treat osteoporosis, denosumab has shown potent anti-resorptive properties and anti-fracture efficacy. The effects of this drug are also unique compared with the effects of bisphosphonates: namely, long-term treatment with this drug results in a continuous gain of bone mineral density, whereas withdrawal of the drug results in a transient overshoot in bone turnover and rapid bone loss. Although the mechanisms for these specific effects remain incompletely understood, emerging experimental and clinical data have started to highlight potential biological and pharmacological mechanisms by which denosumab might affect osteoclasts, as well as osteoblasts, and cause both sustained bone gain and bone loss upon treatment cessation. This Perspective discusses those potential mechanisms and the future studies and clinical implications that might ensue from these findings.

Npp1 prevents external tooth root resorption by regulation of cervical cementum integrity

Tooth roots embedded in the alveolar bone do not typically undergo resorption while the bone continues remodeling in its physiological state. In this study, we analyzed genetically modified mice with the functional inactivation of nucleotide pyrophosphatase 1 (Npp1), encoded by ectonucleotide pyrophosphatase/phosphodiesterase 1 (Enpp1). This mutation leads to the formation of ectopic cervical cementum vulnerable to external tooth root resorption. Cementoblasts with the inactivation of Enpp1 extensively expressed non-collagenous matrix proteins enriched with bone sialoprotein (Bsp), dentin matrix protein 1 (Dmp1), and osteopontin (Opn), which have roles in mineralization through nucleation and in cell adhesion through the Arg-Gly-Asp (RGD) motif. In cementoblasts with the inactivation of Enpp1, β-catenin was significantly activated and induced the expression of these non-collagenous matrix proteins. In addition, adenosine triphosphate (ATP), which is the most preferred substrate of Npp1, accumulated extracellularly and autocrinally induced the expression of the receptor activator of nuclear factor κB ligand (Rankl) in cementoblasts with inactivated Npp1. Consequently, these results strongly suggest that functional Npp1 preserves cervical cementum integrity and supports the anti-resorptive properties of tooth roots through ATP homeostasis in the physiological state of cervical cementum.

Effect of flavonoids from Rhizoma Drynariae on osteoporosis rats and osteocytes

In this experimental study, we evaluated the protective effects and the safety of main flavanones derived from Rhizoma Drynariae (Gusuibu) in vitro and in vivo. The MTT assay showed that compared with vehicle treatment, treatment with such flavanones as neoeriocitrin, naringin, and naringenin significantly promoted the viability of osteocyte-like cells. Quantitative real-time PCR showed that neoeriocitrin and naringin significantly attenuated mRNA expressions of RANKL and SOST in osteocyte-like cells. In rats with retinoic acid-induced osteoporosis, total flavonoid of Rhizoma Drynariae (TFRD), naringin, and naringenin significantly increased the number of trabeculae and improved trabecular bone structure compared with no treatment, without affecting liver and renal function. In addition, naringenin and naringin administration significantly increased bone mineral density of femur neck and femur shaft compared with the osteoporotic model rats. Western blot analysis showed that naringenin and naringin significantly attenuated protein expressions of bone resorption-related factors (TRAP, RANKL and RANK), and inhibited sclerostin expression compared with the osteoporotic model rats. On the other hand, naringin markedly increased protein expressions of ALP and PTH1R, and TFRD and naringenin also promoted PTH1R expression compared with the model rats. In conclusion, such flavanones as naringenin and naringin exhibited antiresorptive properties, and naringin particularly showed potential benefits for osteoporosis treatment.

Overview of the clinical efficacy and safety of eldecalcitol for the treatment of osteoporosis

SummaryEldecalcitol (ELD) is a new oral analog of the active form of vitamin D with anti-resorptive properties. We conducted a meta-analysis to investigate the efficacy and safety of ELD in osteoporosis. Compared with alfacalcidol, ELD significantly lowered vertebral facture risk, increased bone mineral density, but also had a higher risk of hypercalciuria.PurposeThis study aimed to investigate the efficacy and safety of eldecalcitol (ELD) in osteoporosis by examining fracture rates, bone mineral density (BMD), bone turnover markers, and adverse events as outcomes.MethodsPubMed, EMBASE, and Cochrane Library were searched up to July 20, 2020, to identify eligible randomized controlled trials. The odds ratio (OR) or weighted mean difference (WMD) with 95% confidence interval was calculated by the random-effects model.ResultsELD significantly increased lumbar BMD (WMD: 2.80; 95% CI: 1.60, 4.00; P < 0.001, 2 studies involved), total hip BMD (WMD: 2.11; 95% CI: 0.68, 3.55; P = 0.004, 2 studies involved), and femoral neck BMD (WMD: 1.78; 95% CI: 0.76, 2.79; P = 0.001, 1 study involved) compared with alfacalcidol. Moreover, ELD caused a significantly lower rate of vertebral fracture (OR: 0.52; 95% CI: 0.29–0.95; P = 0.034, 2 studies involved) than alfacalcidol, but did not lower the rate of non-vertebral facture (OR: 0.44; 95% CI: 0.06–3.05; P = 0.405, 2 studies involved) compared with alfacalcidol. ELD significantly reduced the percentage change in bone-specific alkaline phosphatase (WMD: − 15.40; 95% CI: − 20.30, − 10.60; P < 0.001, 1 study involved) and serum type I collagen C-telopeptide (WMD: − 38.50; 95% CI: − 50.00, − 27.10; P < 0.001, 1 study involved) as compared with alfacalcidol. ELD was also associated with higher risk of hypercalciuria compared with alfacalcidol (OR: 1.64; 95% CI: 1.22, 2.20; P = 0.001, 2 studies involved).ConclusionsThis systematic review indicated that ELD was superior than alfacalcidol for improving vertebral fracture risk and BMD. Further large-scale trials should be conducted to verify the long-term effects and safety of ELD in osteoporosis.Prospero registration numberCRD42020147518.

Pharmacological Therapies for the Management of Inflammatory Bone Resorption in Periodontal Disease: A Review of Preclinical Studies.

Periodontitis, a highly prevalent multicausal chronic inflammatory and destructive disease, develops as a result of complex host-parasite interactions. Dysbiotic bacterial biofilm in contact with the gingival tissues initiates a cascade of inflammatory events, mediated and modulated by the host's immune response, which is characterized by increased expression of several inflammatory mediators such as cytokines and chemokines in the connective tissue. If periodontal disease (PD) is left untreated, it results in the destruction of the supporting tissues around the teeth, including periodontal ligament, cementum, and alveolar bone, which lead to a wide range of disabilities and poor quality of life, thus imposing significant burdens. This process depends on the differentiation and activity of osteoclasts, the cells responsible for reabsorbing the bone tissue. Therefore, the inhibition of differentiation or activity of these cells is a promising strategy for controlling bone resorption. Several pharmacological drugs that target osteoclasts and inflammatory cells with immunomodulatory and anti-inflammatory effects, such as bisphosphonates, anti-RANK-L antibody, strontium ranelate, cathepsin inhibitors, curcumin, flavonoids, specialized proresolving mediators, and probiotics, were already described to manage inflammatory bone resorption during experimental PD progression in preclinical studies. Meantime, a growing number of studies have described the beneficial effects of herbal products in inhibiting bone resorption in experimental PD. Therefore, this review summarizes the role of several pharmacological drugs used for PD prevention and treatment and highlights the targeted action of all those drugs with antiresorptive properties. In addition, our review provides a timely and critical appraisal for the scientific rationale use of the antiresorptive and immunomodulatory medications in preclinical studies, which will help to understand the basis for its clinical application.

LOW RISK OF SPONTANEOUS MEDICATION-RELATED OSTEONECROSIS OF THE JAW IN FIBROUS DYSPLASIA PATIENTS AFTER ANTIRESORPTIVE THERAPIES: A SYSTEMATIC REVIEW

<h3>Objectives</h3> The objective of this systematic review was to evaluate the risk for spontaneous occurrence of medicated-related osteonecrosis of the jaw (MRONJ) in patients with fibrous dysplasia (FD) and McCune-Albright syndrome (MAS). FD is a rare genetic disorder caused by somatic activating mutations of the GNAS locus encoding the Gsα signaling protein, resulting in reduction of GTPase activity and prolonged activation of Gsα, leading to excessive production of Cyclic adenosine monophosphate (cAMP), which disrupts the ability of bone mesenchymal stem cells to differentiate to mature osteogenic cells. With the increased use of bisphosphonates for the antiresorptive properties, the role of antiresorptives in controlling activity within FD lesions and improvement of bone quality is still inconclusive. <h3>Study Design</h3> A systematic review of the literature was performed by searching PubMed and EMBASE databases using controlled search vocabulary, namely, fibrous dysplasia, McCune-Albright syndrome, jaw, osteonecrosis, antiresorptives, antiresorptive therapy, bisphosphonate, denosumab, teriparatide, estrogen, estrogen therapy, hormone therapy, raloxifene, bazedoxifene, calcitonin, and cathepsin K inhibitor. Articles were limited to human studies, in the English language, in which patients were on antiresorptives for at least 2 years. PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) statement guidelines were used to eliminate nonrelevant studies. The patient, intervention, comparison, outcome, and time (PICOT) question asked was, "Do antiresorptives cause spontaneous occurrence of MRONJ in patients with FD/MAS monitored for at least 2 years of therapy?" <h3>Results</h3> Among the 65 records screened, only 3 articles were eligible for qualitative synthesis based on PRISMA screening criteria. There were no reported cases of spontaneous MRONJ among the patients with FD/MAS across these studies. This is a significant finding among this cohort of patients. <h3>Conclusion</h3> Patients with FD demonstrated low susceptibility to spontaneous occurrence of MRONJ, but more confirmatory studies are still needed. This systematic review was limited by the low number of FD/MAS eligible studies. This could be because of the rare genetic nature of FD/MAS, with low patient recruitment in clinical studies among factors. These pose significant challenges to implementing well-designed randomized placebo-controlled clinical trials that focus on antiresorptive-induced osteonecrosis of the jaw in FD/MAS. As more clinical studies become available, a future follow-up systematic review may provide additional insights into MRONJ complications in patients with FD/MAS treated with antiresorptives.

Added effect of 1% topical alendronate in intra-bony and inter-radicular defects as part of step II periodontal therapy: a systematic review with meta-analysis and trial sequential analysis

BackgroundThis systematic review and meta-analysis aimed to investigate the role of alendronate combined with step 2 of periodontal therapy in reducing probing pocket depth, improving clinical attachment level, and reducing bone defect depth in intra-bony and inter-radicular defects.MethodsRCTs with more than 6 months follow-up were included in this study. Risk of bias assessment was performed using the Cochrane collaboration tool. In addition, meta-analysis and trial sequential analysis were used to aggregate the available evidence.ResultsSeven studies met the inclusion criteria and were included in the systematic review. Topical application of alendronate during second step of periodontal therapy significantly improved PD and CAL.ConclusionLocal application of alendronate may confer a beneficial effect when applied during step II of periodontal therapy even if long term studies are needed to confirm these results.Clinical relevanceConsidering the emerging role of host-inflammatory response in treatment of periodontitis and the antiresorptive and osteostimulative properties of bisphosphonates, several studies are focusing on the role of alendronate as an addition to non-surgical periodontal therapy.

Extract and fraction of Musa paradisiaca flower have osteogenic effect and prevent ovariectomy induced osteopenia

BackgroundOsteoporosis is an asymptomatic bone disorder leading to altered bone microarchitecture, mineralization and strength. Musa paradisiaca has been reported to have antioxidant and anti-inflammatory effects in various diseases. Its impact on postmenopausal osteoporosis has not been investigated yet. PurposeThe intention of the current study was to evaluate the bone regeneration and osteoprotective potential of extract and fraction of M. paradisiaca flower in ovariectomized (Ovx) Sprague Dawley (SD) rats, a model of post-menopausal bone loss. The study also aims to identify osteogenic compounds from active fraction. MethodsEthanolic extract (MFE) and butanolic fraction (MFE-Bu) from flower of M. paradisiaca were prepared and their efficacy was tested in rat femur osteotomy model at different doses. Effective dose from both extract (250 mg/kg) and fraction (50 mg/kg) were taken for study in osteopenic bone loss model. PTH was taken as reference standard (20 µg/kg/twice a week). Bones were harvested at autopsy for dynamic and static histomorphometry. Serum was collected for ELISA. Pure compounds were isolated from butanolic fraction (MFE-Bu), and were assessed for their osteogenic effect. ResultsMFE and MFE-Bu were observed for their potential in bone healing and prevention of bone loss. Both MFE and MFE-Bu promoted new bone regeneration at injury site as assessed by microCT and calcein dye labeling studies. These also led to restoration of bone microarchitecture deteriorated as a result of osteopenia and improved bone biomechanical properties. Extract as well as the fraction exhibited dual bone anabolic and anti-resorptive properties where they elevated serum procollagen type I N-terminal propeptide (P1NP), a bone formation marker and suppressed serum C-telopeptide of type I collagen (CTX-1), a bone resorption marker. As many as four osteogenic compounds were isolated from MFE-Bu. Oleracein-E was found to be the most potent osteogenic agent based on osteoblast differentiation, mineralization assays, qPCR and protein expression studies. ConclusionOur studies demonstrates that ethanolic extract from the flower of M. paradisiaca and its butanolic fraction exhibit dual osteogenic and anti-resorptive potential, and have an advantage over PTH which though promotes bone formation but is also bone catabolic in nature.

Targeting Notch Inhibitors to the Myeloma Bone Marrow Niche Decreases Tumor Growth and Bone Destruction without Gut Toxicity.

Systemic inhibition of Notch with γ-secretase inhibitors (GSI) decreases multiple myeloma tumor growth, but the clinical use of GSI is limited due to its severe gastrointestinal toxicity. In this study, we generated a GSI Notch inhibitor specifically directed to the bone (BT-GSI). BT-GSI administration decreased Notch target gene expression in the bone marrow, but it did not alter Notch signaling in intestinal tissue or induce gut toxicity. In mice with established human or murine multiple myeloma, treatment with BT-GSI decreased tumor burden and prevented the progression of multiple myeloma-induced osteolytic disease by inhibiting bone resorption more effectively than unconjugated GSI at equimolar doses. These findings show that BT-GSI has dual anti-myeloma and anti-resorptive properties, supporting the therapeutic approach of bone-targeted Notch inhibition for the treatment of multiple myeloma and associated bone disease. SIGNIFICANCE: Development of a bone-targeted Notch inhibitor reduces multiple myeloma growth and mitigates cancer-induced bone destruction without inducing the gastrointestinal toxicity typically associated with inhibition of Notch.

Advances in Osteoporotic Bone Tissue Engineering.

The increase in osteoporotic fracture worldwide is urging bone tissue engineering research to find new, improved solutions both for the biomaterials used in designing bone scaffolds and the anti-osteoporotic agents capable of promoting bone regeneration. This review aims to report on the latest advances in biomaterials by discussing the types of biomaterials and their properties, with a special emphasis on polymer-ceramic composites. The use of hydroxyapatite in combination with natural/synthetic polymers can take advantage of each of their components properties and has a great potential in bone tissue engineering, in general. A comparison between the benefits and potential limitations of different scaffold fabrication methods lead to a raised awareness of the challenges research face in dealing with osteoporotic fracture. Advances in 3D printing techniques are providing the ways to manufacture improved, complex, and specialized 3D scaffolds, capable of delivering therapeutic factors directly at the osteoporotic skeletal defect site with predefined rate which is essential in order to optimize the osteointegration/healing rate. Among these factors, strontium has the potential to increase osseointegration, osteogenesis, and healing rate. Strontium ranelate as well as other biological active agents are known to be effective in treating osteoporosis due to both anti-resorptive and anabolic properties but has adverse effects that can be reduced/avoided by local release from biomaterials. In this manner, incorporation of these agents in polymer-ceramic composites bone scaffolds can have significant clinical applications for the recovery of fractured osteoporotic bones limiting or removing the risks associated with systemic administration.

Effect of Long-term Use of Steroidal Anti-inflammatory Drugs on the Periodontal State: A Review

Corticosteroids are chemically similar to endogenous cortisol and mostly prescribed for their antiinflammatoryand immunosuppressive properties, which are due to the inhibition of phospholipase A2activity. These drugs are extensively used in the treatment of a plethora of autoimmune disorders suchas rheumatoid arthritis, various breathing disorders and also disorders of connective tissue. In the fieldof dentistry these drugs are prescribed in most of the mucocutaneous disorders such as they are mostlyused in inflammatory diseases such as oral lichen planus, pemphigus, and oral stomatitis to alleviate postoperativediscomfort and swelling. These drugs can be administered systemically,topically or asinhalationaltherapy. Evidence concludes that short term corticosteroids possess antiresorptive properties and its localapplication shows a favourable effect on the periodontal ligament, but when administered systemically fora long period could lead to periodontal diseases as it has shown to increase attachment with alveolar boneand destruction of transseptalfibers. Oral manifestations are dependent on duration,dose and frequency ofuse. It is commonly associated withmoniliasis, dental caries,altered taste sensation, ulceration of the tongue,buccal mucosa, and gingiva due to xerostomia,gingival inflammation, periodontal inflammation,and immunesuppression. They can either cause dramatic improvement or dramatic adverse reactions which can lead toa considerable increase in the distributionof periodontal disorders. In patients on long-term corticosteroidtherapy, oral health is generally not given importance during management. Hence this review explains aboutvarious effects of different types of corticosteroids on periodontium used in dentistry.

Determination of bisphosphonates anti-resorptive properties based on three forms of ceramic materials: Sorption and release process evaluation

There is a strong need to search for more effective compounds with bone anti-resorptive properties, which will cause fewer complications than commonly used bisphosphonates. To achieve this goal, it is necessary to search for new techniques to characterize the interactions between bone and drug. By studying their interaction with hydroxyapatite (HA), this study used three forms of ceramic materials, two of which are bone-stimulating materials, to assess the suitability of new active substances with anti-resorptive properties. In this study, three methods based on HA in loose form, polycaprolactone/HA (a polymer-ceramic materials containing HA), and polymer-ceramic monolithic in-needle extraction (MINE) device (a polymer inert skeleton), respectively, were used. The affinity of risedronate (a standard compound) and sixteen aminomethylenebisphosphonates (new compounds with potential antiresorptive properties) to HA was defined according to the above-mentioned methods. Ten monolithic materials based on 2-hydroxyethyl methacrylate/ethylene dimethacrylate are prepared and studied, of which one was selected for more-detailed further research. Simulated body fluids containing bisphosphonates were passed through the MINE device. In this way, sorption–desorption of bisphosphonates was evaluated using this MINE device. The paper presents the advantages and disadvantages of each technique and its suitability for assessing new active substances. All three methods allow for the selection of several compounds with potentially higher anti-resorptive properties than risedronate, in hope that it reflects their higher bone affinity and release ability.