Antiresorptive Effects Research Articles

Anti-inflammatory and anti-resorptive efficacy of adrenergic blockers on late replanted rat incisors.

In addition to their anti-inflammatory and anti-osteoclastogenesis properties, adrenergic blockers may also have promising anti-resorptive effects that can prevent root resorption when teeth are replanted because of avulsion. The aim of this study was to investigate the effects of phentolamine (Ph) and propranolol (Pr) in gels on the repair process of late replanted rat incisors. A further aim was to evaluate the biocompatibility of both drugs to human periodontal ligament fibroblasts (HPDLFs). Forty-eight maxillary right incisors were extracted from male Wistar rats, stored in paper napkins for 60minutes, and randomly allocated to one of eight groups (n=6). The root canal, root surface, and alveolus were treated with 0.75µg/mL Ph gel (Ph0.75), 10µg/mL Ph gel (Ph10), 100µg/mL Ph gel (Ph100), 2.5µg/mL Pr gel (Pr2.5), 10µg/mL Pr gel (Pr10), 100µg/mL Pr gel (Pr100), or sodium carboxymethylcellulose gel (CMC) before replantation. In the control group (CH), only the root canal was treated with calcium hydroxide paste. Thirty days following surgery, the animals were euthanized, and the right hemimaxilla was removed to perform micro-CT and histomorphometric analysis to determine osteoclastic activity. Ethanolic solutions of Ph10 and Pr10 were selected based on the in vivo study, and the viability of HPDLFs stimulated with lipopolysaccharide was determined by MTT assays. The micro-CT and histomorphometric analysis revealed no significant differences among the treatments (P>.05). The presence of active osteoclasts was significantly decreased in the Ph10 and Pr10 groups (P<.05). Ph10 and Pr10 produced statistically similar cell survival rates compared to the control group (P>.05). Ph10 and Pr10 significantly decreased osteoclastogenesis in delayed replanted rat teeth and were not cytotoxic toward HPDLFs.

Chronic administration of Cl-amidine, a pan-peptidylarginine deiminase inhibitor, does not reverse bone loss in two different murine models of osteoporosis.

Recent in vitro studies have shown a role for the peptidyl-arginine deiminases (PADs) in bone resorption. However, it is unknown whether these enzymes are involved in bone loss in vivo. Thus, we evaluated the antiresorptive effect of a pan-PAD inhibitor in two murine models of osteoporosis: (a) primary osteoporosis induced by ovariectomy (OVX); and (b) secondary osteoporosis associated to Type-1 diabetes induced by streptozotocin (STZ, 50 mg/kg, i.p., five daily administrations). Five weeks after OVX and 15 weeks after injections of STZ, mice received daily administrations of Cl-amidine (3 or 10 mg/kg, i.p.) or vehicle for 30 consecutive days. At the end of the treatment, femur and vertebra were harvested for microCT analysis. Blood samples were collected for determination of antibodies against cyclic citrullinated peptides (anti-CCP) by enzyme-linked immunosorbent assay. Serum levels of anti-CCP antibodies from diabetic mice were not significantly different compared to control mice. However, a significant loss of both trabecular bone at the femoral neck and cortical bone at the femoral diaphysis was found in diabetic mice, and Cl-amidine did not reverse the diabetes-induced bone loss. Mice with OVX had significantly lower serum levels of anti-CCP compared to mice with sham surgery. OVX resulted in significant loss of both trabecular bone at the L5 vertebra and distal femoral metaphysis. Cl-amidine did not block the OVX-induced bone loss. Our results suggest that chronic treatment with Cl-amidine at the doses and period of time administered is not long enough to inhibit bone loss in two different murine models of osteoporosis.

A Review of Potential Beneficial Effects of Honey on Bone Health.

Bone remodelling is a complex and tightly regulated process. Disruption of bone remodelling skewing towards resorption will cause osteoporosis and increase the risk of fragility fracture. Honey is a natural product containing various bioactive ingredients with health benefits, especially polyphenols. Therefore, honey may be a novel dietary supplement to prevent osteoporosis. This review aims to summarize the current evidence on the effects of honey on bone health. The evidence reported so far indicates a skeletal-beneficial effect of honey in animal models of osteoporosis. However, the number of studies on humans is limited. Honey can protect the bone via its antioxidant and anti-inflammatory properties, primarily through its polyphenol content that acts upon several signalling pathways, leading to bone anabolic and antiresorptive effects. In conclusion, honey is a potential functional food for bone health, but the dose and the bioactive contents of honey need to be verified prior to its application in humans.

FORMULATION DEVELOPMENT AND IN VITRO EVALUATION OF ALENDRONATE BUCCAL TABLETS

The aim of this work was to develop a mucoadhesive buccal tablet for the buccal delivery of the alendronate via buccal mucosa. Buccal tablets of alendronate are designed to release drug at mucosal site for extended period of time without wash out of drug by saliva. Alendronate sodium is a bisphosphonates which has antiresorptive effect which is implicated in the prophylaxis and treatment of osteoporosis. Sodium alginate, ethyl cellulose and carbopol were selected as mucoadhesive polymers on the basis of their matrix forming properties. The objective of the study is to improve the bioavailability of alendronate buccal tablets. Extensive literature survey was done for the collection of theoretical and technical data. The methodology part includes the explanation of implemented methods in the present study. In present study, an attempt was made to design mucoadhesive buccal tablets containing alendronate, sodium alginate, ethyl cellulose and carbopol using as polymers. The tablets were prepared by direct compression method. The formulations were evaluated for hardness, thickness, friability, weight variation, drug content estimation, surface pH determination, swelling index, in vitro drug release. In vitro bioadhesive strength &amp; in vitro release studies showed that formulation F11 showed optimum bioadhesive &amp; exhibited optimum drug release 97.6% in 7hr. Kinetics results reveals that the F11 formulation follows zero order kinetics as correlation coefficient (r2) values are higher than that of first- order release kinetics.Optimized formula F11 show drug is released by non-Fickian diffusion mechanism. The stability studies of formulation F11 prepared mucoadhesive buccal tablets of alendronate were stable. Overall evaluations of the mucoadhesive of tablets show good mucoadhesive properties.

A nutraceutical composition containing diosmin and hesperidin has osteogenic and anti-resorptive effects and expands the anabolic window of teriparatide

A combination of diosmin and hesperidin (9:1 ratio) is marketed as a dietary supplement/nutraceutical for cardiovascular health. We studied the skeletal effect of this combination (90% diosmin and 10% hesperidin, henceforth named as DH). We showed that a) in rats with femur osteotomy, DH stimulated callus bone regeneration, b) in growing rats, DH promoted peak bone mass achievement and c) in OVX rats rendered osteopenic, DH completely restored femur trabecular bones and strength along with the increases in surface referent bone formation and serum osteogenic marker. Furthermore, DH suppressed bone resorption in OVX rats as well as in OVX rats treated with teriparatide (human parathyroid hormone 1–34) but did not affect the osteoanabolic effect of teriparatide. These data suggested that DH could prolong the anabolic window of teriparatide. To understand the mechanism of DH action, we performed pharmacokinetic studies and observed that upon its oral administration the only circulating metabolites was diosmetin (the aglycone form of diosmin) while none of the two input flavanones were detectable. Accordingly, subsequent experiments with diosmetin revealed that it was a selective estrogen receptor-β agonist that stimulated osteoblast differentiation and suppressed sclerostin the anti-osteoblastogenic Wnt antagonist. Taken together, our study defined a positive skeletal effect of DH.

Bisphosphonates and Cancer: A Relationship Beyond the Antiresorptive Effects

Bisphosphonates (BPs) are stable analogues of the Inorganic Pyrophosphate (PPi), an endogenous regulator of bone mineralization, which can resist the hydrolysis in the gastrointestinal tract. Their conformation allows targeting the bone as a result of their three-dimensional structure, which makes them primary agents against osteoclast-mediated bone loss. They are used in many bone pathological conditions, like bone metastasis, because of its ability to modulate bone metabolism into a less favorable place to cancer cell growth, through the inhibition of osteoclastogenesis and bone resorption. This review is focused on the mechanisms of action through which BPs affect the cellular activity and survival, mainly on their antitumoral effects. In conclusion, BPs are considered the primary therapy for skeletal disorders due to its high affinity for bone, but now they are also considered as potential antitumor agents due to its ability to induce tumor cell apoptosis, inhibition of cell adhesion, invasion and proliferation, modulation of the immune system to target and eliminate cancer cells as well as affect the angiogenic mechanisms. Like any other drug, they also have some adverse effects, but the most common, the acute phase reaction, can be minimized with the intake of calcium and vitamin D.

Annals for Educators - 2 July 2019.

Annals for Educators - 2 July 2019.

Abstract 3002: Bone-protective curcumin circulates as a pro-drug conjugate that is activated in bone by β-glucuronidase

Abstract Curcumin (CURC), a turmeric-derived dietary polyphenol, prevents osteoclast formation and bone resorption in murine models of arthritis, post-menopausal osteoporosis, and bone metastatic breast cancer despite being rapidly conjugated upon ingestion in both rodents and humans to form curcumin-glucuronide (G-CURC). However, recent studies from our laboratory demonstrate that aglycone CURC is enriched in bone relative to the circulation. Studies were therefore undertaken to compare the anti-resorptive effects of aglycone CURC vs G-CURC and to elucidate mechanisms responsible for enrichment of aglycone CURC in bone, including clinically relevant influences of age, sex, and reproductive status. CURC dose-dependently inhibited RANKL-stimulated osteoclast formation in RAW264.7 cell cultures, while G-CURC was without effect. Likewise, CURC dose-dependently inhibited TGFβ-stimulated PTHrP secretion from MDA-MB-231 breast cancer cells, which readily form PTHrP-driven osteolytic bone metastases in vivo. In wild type (WT) C57BL/6J mice, heparanase (HPSE) and β-glucuronidase (GUSB) were the only enzymes with reported deglucuronidation activity expressed in bone (Western). However, only GUSB was able to recognize G-CURC as a substrate, deconjugating G-CURC to form CURC (LC/MS). Consistent with these findings, tissue-specific levels of CURC were highest in bone (vs. heart, muscle, or kidney) and proportional to tissue specific GUSB enzyme activity. To verify the role of GUSB in CURC bone enrichment, CURC metabolism and GUSB enzyme expression and activity were compared among mice with normal levels of GUSB (C57BL/6J) vs. partial (C3H/HeJ) or complete (mucopolysaccharidosis VII (mps/mps]) deficiencies in GUSB expression. As expected, partial (55% of WT) or complete deficiencies in GUSB expression significantly reduced CURC enrichment in bone. While GUSB can be positively regulated by pharmacologic doses of androgens, neither male sex nor ovariectomy (OVX) altered GUSB activity (per protein) in bone relative to intact females, although a small but statistically significant increase in free curcumin was demonstrated in males (17%) and OVX females (10%). Age did not significantly change the enrichment of CURC in bone of 4 vs 28-week mice. These findings suggest bio-inactive G-CURC acts as pro-drug that is converted to active CURC within bone, independent of sex, age or reproductive status, where it can inhibit the formation of bone resorbing osteoclasts or secretion of osteolytic PTHrP from breast cancer bone metastases. Citation Format: Andrew Kunihiro, Julia A. Brickey, jennifer B. Frye, Paula B. Luis, Claus Schneider, Janet L. Funk. Bone-protective curcumin circulates as a pro-drug conjugate that is activated in bone by β-glucuronidase [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3002.

Bone-Forming and Antiresorptive Effects of Romosozumab in Postmenopausal Women With Osteoporosis: Bone Histomorphometry and Microcomputed Tomography Analysis After 2 and 12 Months of Treatment.

ABSTRACTSclerostin, a protein produced by osteocytes, inhibits bone formation. Administration of sclerostin antibody results in increased bone formation in multiple animal models. Romosozumab, a humanized sclerostin antibody, has a dual effect on bone, transiently increasing serum biochemical markers of bone formation and decreasing serum markers of bone resorption, leading to increased BMD and reduction in fracture risk in humans. We aimed to evaluate the effects of romosozumab on bone tissue. In a subset of 107 postmenopausal women with osteoporosis in the multicenter, international, randomized, double‐blind, placebo‐controlled Fracture Study in Postmenopausal Women with Osteoporosis (FRAME), transiliac bone biopsies were performed either after 2 (n = 34) or 12 (n = 73) months of treatment with 210 mg once monthly of romosozumab or placebo to evaluate histomorphometry and microcomputed tomography‐based microarchitectural endpoints. After 2 months, compared with either baseline values assessed after a quadruple fluorochrome labeling or placebo, significant increases (P < 0.05 to P < 0.001) in dynamic parameters of formation (median MS/BS: romosozumab 1.51% and 5.64%; placebo 1.60% and 2.31% at baseline and month 2, respectively) were associated with a significant decrease compared with placebo in parameters of resorption in cancellous (median ES/BS: placebo 3.4%, romosozumab 1.8%; P = 0.022) and endocortical (median ES/BS: placebo 6.3%, romosozumab 1.6%; P = 0.003) bone. At 12 months, cancellous bone formation was significantly lower (P < 0.05 to P < 0.001) in romosozumab versus placebo and the lower values for resorption endpoints seen at month 2 persisted (P < 0.001), signaling a decrease in bone turnover (P = 0.006). No significant change was observed in periosteal and endocortical bone. This resulted in an increase in bone mass and trabecular thickness with improved trabecular connectivity, without significant modification of cortical porosity at month 12. In conclusion, romosozumab produced an early and transient increase in bone formation, but a persistent decrease in bone resorption. Antiresorptive action eventually resulted in decreased bone turnover. This effect resulted in significant increases in bone mass and improved microarchitecture.© 2019 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research (ASBMR).

A dual amylin and calcitonin receptor agonist inhibits pain behavior and reduces cartilage pathology in an osteoarthritis rat model

Pain and disability are the main clinical manifestations of osteoarthritis, for which only symptomatic therapies are available. Hence, there is a need for therapies that can simultaneously alter disease progression and provide pain relief. KBP is a dual amylin- and calcitonin-receptor agonist with antiresorptive and chondroprotective properties. In this study we investigated the effect of KBP in a rat model of osteoarthritis. Medial meniscectomy (MNX) was performed in 39 rats, while 10 underwent sham surgery. Rats were treated with KBP and/or naproxen. Nociception was assessed by mechanical and cold allodynia, weight bearing asymmetry, and burrowing behavior. Blood samples were collected for biomarker measurements, and knees for histology. Cartilage histopathology was evaluated according to the advanced Osteoarthritis Research International (OARSI) score and KBPs invitro antiresorptive effects were assessed using human osteoclasts cultured on bone. The MNX animals displayed an increased nociceptive behavior. Treatment with KBP attenuated the MNX-induced osteoarthritis-associated joint pain. The cartilage histopathology was significantly lower in rats treated with KBP than in MNX animals. Bone and cartilage degradation, assessed by CTX-I and CTX-II plasma levels, were decreased in all KBP-treated groups and KBP potently inhibited bone resorption invitro. Our study demonstrates the effectiveness of KBP in ameliorating osteoarthritis-associated joint pain and in protecting the articular cartilage, suggesting KBP as a potential drug candidate for osteoarthritis.

Anti-inflammatory and antiresorptive functions of melatonin on experimentally induced periapical lesions.

To investigate the effects of systemically administered melatonin on inflammation and alveolar bone resorption in rats with experimentally induced periapical lesions. Thirty adult Sprague Dawley rats were divided equally into negative, positive control and melatonin groups. The pulp chambers of their mandibular first molars were exposed to the oral environment to induce experimental periapical lesions in the positive control and melatonin groups. The melatonin group received daily intraperitoneal injections of melatonin at a dose of 10mgkg-1 . After 21days, the animals were euthanized; the hemi-mandible parts were prepared for radiological, histopathological, immunohistochemical (IL-1β, RANK, RANKL, OPG and tartrate-resistant acid phosphatase (TRAP) and Brown-Brenn (bacteria) evaluations. Data were analysed by Kruskal-Wallis (for non-parametric data) and one-way anova tests (for parametric data) (P<0.05). The area of radiographic periapical bone loss was significantly smaller in rats that were given daily intraperitoneal injections of melatonin (P<0.01). The histopathological scores of the melatonin group were significantly lower than those of positive control group (P<0.01). Histomorphometrically, the area of periapical bone loss in the melatonin group was significantly smaller than the positive control group (P<0.01). The expression of IL1-β, RANK and RANKL was significantly higher in the positive control group, whereas OPG was significantly higher in the melatonin group (P<0.01). The number of osteoclasts was significantly greater in the positive control group by TRAP staining analyses (P<0.01). The scores for bacteria localization using Brown-Brenn staining in the melatonin group was significantly lower than that of the positive control group (P<0.01). Melatonin demonstrated antiresorptive effects on bone associated with experimentally induced periapical lesions in rats via its anti-inflammatory activity. Further studies are necessary to evaluate its possible effects on the healing of periapical lesions.

Electroacupuncture increases immunoexpression of CB1 and CB2 receptors in experimental model of inflammatory bone loss.

This study evaluated the participation of CB1 and CB2 receptors in the antiresorptive effect of electroacupuncture (EA) on an experimental model of inflammatory bone loss in rats. 30 rats were divided into five groups: C (control); EP (experimental periodontitis); EA (C+ EA); EP-EA (EP+ EA in the acupoints LI4, LG11, ST36, ST44); EP - EA-sham (EP+ EA in sham acupoints). For the EP groups, a ligature was placed around the right mandibular first molars at day 1. Sessions of EA or EA-sham were assigned every other day. Animals were euthanized at day 11. Histometric analysis was performed to evaluate the percentage of bone area in the furcation area. Immunolabeling patterns in the periodontal tissues and immunofluorescent staining in the trigeminal ganglia and in the trigeminal spinal tract for CB1 and CB2 receptors were performed. It was observed increased bone loss in the furcation in the EP and EP-EA-sham groups, in comparison to the other groups (p < 0.05). Enhanced CB2 immunolabeling was observed in the periodontal tissues in the EP-EA group, when compared to the EP and EP-EA-sham groups (p < 0.05). Increased CB1 immunofluorescent staining was observed in the neural tissues in the EA treated group in comparison with the other groups (p < 0.05), while no expression of CB2 was observed in those regions. Our study showed that in the presence of inflammatory bone disease, EA treatment reduced bone erosion and increased the immunoexpression of CB1 in the neural tissues and CB2 in the periodontal tissues.

GLP-2 and GIP exert separate effects on bone turnover: A randomized, placebo-controlled, crossover study in healthy young men

Glucagon-like peptide-2 (GLP-2) and glucose-dependent insulinotropic polypeptide (GIP) both inhibit bone resorption in humans but the underlying mechanisms are poorly understood. In vitro, GLP-2 activates the GIP-receptor (GIPR). Based on in vitro studies, we hypothesized that the antiresorptive effect of GLP-2 was mediated through the GIPR. This was tested using the selective GIPR-antagonist GIP(3-30)NH2. The study was a randomized, single-blinded, placebo-controlled, crossover study conducted at Hvidovre University Hospital, Denmark. Eight healthy young men were included and studied on four study days: GIP (200 μg), GLP-2 (800 μg), GIP(3-30)NH2 (800 pmol/kg/min) + GLP-2 (800 μg), and placebo. The main outcomes were bone resorption measured as collagen type 1 C-terminal telopeptide (CTX) and bone formation measured as procollagen type 1 N-terminal propeptide (P1NP). CTX (mean ± SEM) significantly decreased after both GIP (to 55.3 ± 6.3% of baseline at t = 90 min) and GLP-2 (to 60.5 ± 5.0% of baseline at t = 180 min). The maximal reduction in CTX after GIP(3-30)NH2 + GLP-2 (to 63.2 ± 3.1% of baseline) did not differ from GLP-2 alone (p = 0.95) nor did net AUC0-240 (-6801 ± 879%*min vs -6027 ± 648%*min, p = 0.56). At t = 30 min, GIP significantly (p < 0.0001) increased P1NP to 115.1 ± 2.2% of baseline compared with 103.1 ± 1.5% after placebo. Both GLP-2 and GIP(3-30)NH2 + GLP-2 significantly (p < 0.0001) decreased P1NP to 91.3 ± 1.1% and 88.1 ± 3.0% of baseline, respectively (at t = 45 min) compared with placebo. GIPR antagonism did not inhibit the GLP-2-induced reduction in bone resorption (CTX) in healthy young men. In contrast to GLP-2, GIP increased P1NP despite decreasing CTX indicating an uncoupling of bone resorption from formation. Thus, GLP-2 and GIP seem to exert separate effects on bone turnover in humans. ClinicalTrials.gov (NCT03159741).

Anacardic acid inhibits RANKL-induced osteoclastogenesis in vitro and prevents ovariectomy-induced bone loss in vivo.

Postmenopausal osteoporosis is the most common form of primary osteoporosis, and the incidence of the condition is rapidly increasing. In consideration of the limitations of current therapeutic options for the treatment of postmenopausal osteoporosis, there is an urgent need to develop safer alternatives. Anacardic acid, a natural phenolic acid compound extracted from cashew nut shell, possesses potent antitumor and anti-inflammatory effects and inhibits NF-κB signaling. However, its effect on osteoclasts remains unknown. This study reports the first evidence for the antiosteoclastogenic and antiresorptive effects of anacardic acid on bone marrow-derived macrophage-derived osteoclasts. Mechanistically, anacardic acid disrupts the phosphorylation of TGF-β activated kinase 1 and subsequently suppresses multiple receptor activator of NF-κB ligand-induced signaling cascades, ultimately inhibiting the induction and activation of the crucial osteoclast transcriptional factor nuclear factor of activated T-cell cytoplasmic 1. Consistent with cellular results in vitro, anacardic acid treatment improves bone density in the murine model of ovariectomy-induced bone loss. Taken together, our study provides promising evidence for the therapeutic application of anacardic acid as a new potential pharmacological treatment for osteoporosis.-Zhao, K., Jia, Y., Peng, J., Pang, C., Zhang, T., Han, W., Jiang, J., Lu, X., Zhu, J., Qian, Y. Anacardic acid inhibits RANKL-induced osteoclastogenesis in vitro and prevents ovariectomy-induced bone loss in vivo.

Anti-resorptive effects of cementocytes during orthodontic tooth movement

Purpose: To investigate the mechanism involved in the anti-resorptive effect of cementocytes during orthodontic tooth movement in mice and human specimens.Methods: The morphology, molecular structure and biological expression of cellular cementum in mice and human samples were examined using hematoxylin and eosin staining, immuno-histochemical staining, scanning electron microscopy, and Raman spectroscopy. The expressions of osteoprotegerin (OPG), receptor activator of nuclear κB ligand (RANKL) and sclerostin (SOST) encoding genes in cementocytes and alveolar bone osteocytes were evaluated by quantitative real-time polymerase chain reaction (qRT-PCR).Results: Results demonstrated that cementocyte lacunae were larger and more irregular in shape than the regular ellipsoid osteocyte lacunae. The ratio of phosphate to amino acid was significantly lower in cellular cementum than that in alveolar bone and dentin. In mice, OPG/RANKL ratio was significantly higher in cementocytes (4.8 ± 0.37) than in alveolar bone osteocytes (0.17 ± 0.42) in natural state. In humans, OPG/RANKL ratio was 1.41 ± 0.07 in cementocytes and 0.71 ± 0.04 in alveolar bone osteocytes under natural conditions, and 37.69 ± 0.15 in cementocytes and 1.95 ± 0.83 in alveolar bone osteocytes applying fluid flow shear stress. Moreover, SOST was extremely low expressed under force application in cementocytes.Conclusion: Under fluid flow sheer stress, cementocytes stimulate the differentiation of osteoblasts and inhibit the activation of osteoclasts, showing greater potential for bone protection than alveolar bone osteocytes. Cementocytes might play an important role in preventing root resorption in the process of orthodontic tooth movement.Keywords: Cementocytes, Bone protection, Microfluidic chip, Orthodontic tooth movement

Effects of Intravenous Zoledronate on Bone Turnover and Bone Density Persist for at Least 11 Years in HIV-Infected Men.

Previously we reported the results of a 4-year extension of a 2-year randomized placebo-controlled trial showing that the antiresorptive effects of two annual 4-mg doses of zoledronate in HIV-infected men persisted for at least 5 years after the second dose. We set out to determine whether the effects on BMD and bone turnover persist beyond 10 years. We invited all participants in the original trial known to be alive and living in New Zealand to attend an additional visit approximately 12 years after trial entry and 11 years after their second dose of study medication. The outcome measures were BMD at the lumbar spine, proximal femur, and total body, and markers of bone turnover. Twenty-five of the 43 men originally enrolled in the trial attended the final visit, representing 25 of 31 (81%) participants alive and residing in New Zealand at the time. The average duration of follow-up was 12.4 years. At the final visit, BMD remained higher in the zoledronate group than the placebo group (lumbar spine 3.7%, 95% CI, 0.1 to 7.3; total hip 3.7%, 95% CI, 1.2 to 6.2; femoral neck 5.0%, 95% CI, 2.1 to 7.9; total body 2.4%, 95% CI, 0.7 to 4.0), and the between-group differences in BMD remained stable between 6 and 12 years. Serum CTx remained lower in the zoledronate group than the placebo group between 6 and 12 years and, at the final visit, was 45% lower (95% CI, 25 to 64) than the placebo group. P1NP was 26% (95% CI, 4 to 48) lower in the zoledronate group than the placebo group at the final visit. In summary, two annual 4-mg doses of zoledronate have effects on bone turnover and BMD in men that persist for at least 11 years after the second dose. © 2019 American Society for Bone and Mineral Research.

Beta-Glucuronidase Catalyzes Deconjugation and Activation of Curcumin-Glucuronide in Bone.

The biological basis for documented in vivo bone-protective effects of turmeric-derived curcumin is unclear since curcumin is barely detectable in serum, being rapidly conjugated to form what is thought to be an inactive glucuronide. Studies were therefore undertaken to test the postulate that antiresorptive effects of curcumin require deconjugation within bone to form the bioactive aglycone and that β-glucuronidase (GUSB), a deconjugating enzyme expressed by hematopoietic marrow cells, facilitates this site-specific transformation. Consistent with this postulate, aglycone, but not glucuronidated, curcumin inhibited RANKL-stimulated osteoclastogenesis, a key curcumin target in bone. Aglycone curcumin, expressed relative to total curcumin, was higher in bone marrow than in serum of curcumin-treated C57BL/6J mice, while remaining a minor component. Ex vivo, under conditions preventing further metabolism of the unstable aglycone, the majority of curcumin-glucuronide delivered to marrow in vivo was hydrolyzed to the aglycone, a process that was inhibited by treatment with saccharolactone, a GUSB inhibitor, or in mice having reduced (C3H/HeJ) or absent (mps/mps) GUSB activity. These findings suggest that curcumin, despite low systemic bioavailability, may be enzymatically activated (deconjugated) within GUSB-enriched bone to exert protective effects, a metabolic process that could also contribute to bone-protective effects of other highly glucuronidated dietary polyphenols.

Osteogenesis Imperfecta: New Perspectives From Clinical and Translational Research.

ABSTRACTOsteogenesis imperfecta (OI) is a monogenic bone fragility disorder that usually is caused by mutations in one of the two genes coding for collagen type I alpha chains, COL1A1 or COL1A2. Mutations in at least 18 other genes can also lead to an OI phenotype. As genetic testing is more widely used, mutations in these genes are also more frequently discovered in individuals who have a propensity for fractures, but who do not have other typical clinical characteristics of OI. Intravenous bisphosphonate therapy is still the most widely used drug treatment approach. Preclinical studies in OI mouse models have shown encouraging effects when the antiresorptive effect of a bisphosphonate was combined with bone anabolic therapy using a sclerostin antibody. Other novel experimental treatment approaches include inhibition of transforming growth factor beta signaling with a neutralizing antibody and the inhibition of myostatin and activin A by a soluble activin receptor 2B. © 2019 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research

Zoledronate treatment duration is linked to bisphosphonate-related osteonecrosis of the jaw prevalence in rice rats with generalized periodontitis.

ObjectivesTo determine the extent that zoledronate (ZOL) dose and duration is associated with bisphosphonate‐related osteonecrosis of the jaw (BRONJ) prevalence in rice rats with generalized periodontitis (PD), characterize structural and tissue‐level features of BRONJ‐like lesions in this model, and examine the specific anti‐resorptive role of ZOL in BRONJ.Materials and MethodsRice rats (n = 228) consumed high sucrose‐casein diet to enhance generalized PD. Groups of rats received 0, 8, 20, 50 or 125 µg/kg IV ZOL/4 weeks encompassing osteoporosis and oncology ZOL doses. Rats from each dose group (n = 9–16) were necropsied after 12, 18, 24 and 30 weeks of treatment. BRONJ‐like lesion prevalence and tissue‐level features were assessed grossly, histopathologically and by MicroCT. ZOL bone turnover effects were assessed by femoral peripheral quantitative computed tomography, serum bone turnover marker ELISAs and osteoclast immunolabelling.ResultsPrevalence of BRONJ‐like lesions was significantly associated with (a) ZOL treatment duration, but plateaued at the lowest oncologic dose, and (b) there was a similar dose‐related plateau in the systemic anti‐resorptive effect of ZOL. ZOL and BRONJ‐like lesions also altered the structural and tissue‐level features of the jaw.ConclusionThe relationship between BRONJ‐like lesion prevalence and ZOL dose and duration varies depending on the co‐ or pre‐existing oral risk factor. At clinically relevant doses of ZOL, BRONJ‐like lesions are associated with anti‐resorptive activity.

Extract and fraction of Cassia occidentalis L. (a synonym of Senna occidentalis) have osteogenic effect and prevent glucocorticoid-induced osteopenia

Ethnopharmacological relevanceCassia occidentalis L., a synonym of Senna occidentalis (belongs to Caesalpiniaceae family) is an annual plant. Pursuing a lead from a folk practice prevalent since the late nineteenth century in Andhra Pradesh, a Southern state of India, of use of Cassia occidentalis leaf and stem for treating patients with fracture and bone diseases, we have not only confirmed its fracture healing activity but also demonstrated efficacy in preventing glucocorticoid-induced osteoporosis (GIO), the commonest form of medication-induced bone loss caused chiefly due to impairment of bone formation. Aim of the studyIn the present work, the effects of extract and fraction of leaf and stem of Cassia occidentalis was investigated in fracture healing and GIO models of rat. The study also aimed to identify osteogenic compounds from this plant. Materials and methodsEthanolic extracts from leaf and stem of Cassia occidentalis were prepared and their efficacy tested in rat femur osteotomy (fracture healing) model. Subsequently, a butanolic fraction was prepared and osteogenic efficacy compared with the ethanolic extract, and upon finding the former to be more potent, its osteogenic effect was studied in details in GIO model. Chemical finger-printing and isolation of ten pure compounds were done to assess their osteogenic effect in rat primary osteoblast cultures. ResultsEthanolic extract of stem was more effective than the leaf extract in enhancing bone regeneration at the site of osteotomy. Further, butanolic fraction of the ethanolic extract of stem was more effective than the later in bone regeneration at the femur osteotomy site and in preventing bone loss in GIO model. The mechanism of skeletal preservation involved stimulation of new bone formation and inhibition of bone resorption. As many as six osteogenic compounds were isolated out of which apigenin-6C-glucopyranoside was most effective in vitro. ConclusionOur study found that a standardized extract of an ethanolic extract and its butanolic fraction from the stem of Cassia occidentalis has osteogenic as well as anti-resorptive effects, resulting in the protection against glucocorticoid-induced bone loss. Our results contribute towards validation of the traditional use of Cassia occidentalis in fracture healing and also suggest its beneficial use in GIO for which clinical trials are warranted.