Bone Protective Effects Research Articles

Fracture risk associated with common medications used in treating type 2 diabetes mellitus.

Published data on the risk of bone fractures associated with medications used for the treatment of type 2 diabetes mellitus are summarized. A systematic literature search identified 108 publications on controlled trials and 6 meta-analyses addressing the potential for fractures with the use of 7 commonly used antidiabetic classes: thiazolidinediones (TZDs), sodium-glucose cotransporter 2 (SGLT2) inhibitors, glucagon-like peptide-1 (GLP-1) agonists, dipeptidyl peptidase-4 (DPP-4) inhibitors, biguanides, insulin, and sulfonylureas. Among all the classes of agents evaluated, only TZDs have been clearly linked to significantly increased fracture risk (number needed to harm [NNH], 99 in one meta-analysis and 172 in another meta-analysis) and only in female patients. Interim data from an ongoing large placebo-controlled trial suggest that use of the SGLT2 inhibitor canagliflozin may be associated with an elevated rate of fractures (absolute risk increase, 1.4%; NNH, 71) and decreased total-hip bone mineral density. Published data regarding the other evaluated classes of agents generally show no effect on fracture risk; some evidence suggests a small bone-protective effect with the use of DPP-4 inhibitors. In patients with type 2 diabetes mellitus, evidence is strongest that, among antidiabetic drugs, TZDs increase the risk of bone fractures; thus, TZDs should be used with caution in women. Canagliflozin is the only SGLT2 inhibitor linked to an increased fracture rate. Metformin, sulfonylureas, insulin, DPP-4 inhibitors, and GLP-1 agonists appear to have overall neutral effects on bone fractures.

Pirfenidone reduces subchondral bone loss and fibrosis after murine knee cartilage injury.

Pirfenidone is an anti-inflammatory and anti-fibrotic drug that has shown efficacy in lung and kidney fibrosis. Because inflammation and fibrosis have been linked to the progression of osteoarthritis, we investigated the effects of oral Pirfenidone in a mouse model of cartilage injury, which results in chronic inflammation and joint-wide fibrosis in mice that lack hyaluronan synthase 1 (Has1-/- ) in comparison to wild-type. Femoral cartilage was surgically injured in wild-type and Has1-/- mice, and Pirfenidone was administered in food starting after 3 days. At 4 weeks, Pirfenidone reduced the appearance, on micro-computed tomography, of pitting in subchondral bone at, and cortical bone surrounding, the site of cartilage injury. This corresponded with a reduction in fibrotic tissue deposits as observed with gross joint surface photography. Pirfenidone resulted in significant recovery of trabecular bone parameters affected by joint injury in Has1-/- mice, although the effect in wild-type was less pronounced. Pirfenidone also increased Safranin-O staining of growth plate cartilage after cartilage injury and sham operation in both genotypes. Taken together with the expression of selected extracellular matrix, inflammation, and fibrosis genes, these results indicate that Pirfenidone may confer chondrogenic and bone-protective effects, although the well-known anti-fibrotic effects of Pirfenidone may occur earlier in the wound-healing response than the time point examined in this study. Further investigations to identify the specific cell populations in the joint and signaling pathways that are responsive to Pirfenidone are warranted, as Pirfenidone and other anti-fibrotic drugs may encourage tissue repair and prevent progression of post-traumatic osteoarthritis. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:365-376, 2018.

Picroside II Inhibits RANKL-Mediated Osteoclastogenesis by Attenuating the NF-κB and MAPKs Signaling Pathway In Vitro and Prevents Bone Loss in Lipopolysaccharide Treatment Mice.

Picroside II, one of the major components isolated from the seed of natural plant picrorhiza, is widely used in traditional Chinese medicine. The present study was performed to define effects of picroside II on nuclear factor-kappaB ligand (RANKL)-stimulated osteoclast differentiation in vitro and on lipopolysaccharide (LPS)-induced bone loss in vivo. The bone marrow cells (BMMs) were harvested and induced with RANKL followed by treatment with picroside II at several doses, and the differentiation of osteoclasts from these cells was evaluated by tartrate-resistant acid phosphatase (TRAP) staining and resorption pit formation assay. The effects of picroside II on osteoclastogenesis were studied by examining RANKL-induced osteoclast F-actin ring formation and osteoclast bone resorption. Moreover, we explored the mechanisms of these downregulation effects by performed Western blotting and quantitative RT-PCR examination. Results demonstrated picroside II strongly inhibited RANKL-induced osteoclast formation when added during the early stage of BMMs cultures, suggesting that it acts on osteoclast precursors to inhibit RANKL/RANK signaling. Moreover, picroside II markedly decreased the phosphorylation of p38, ERK, JNK, p65, and I-κB degradation, and significantly suppressed c-Fos and nuclear factor of activated T-cells cytoplasmic 1 (NFATc1), both the key transcription factors during osteoclastogenesis. Furthermore, in vivo studies verified the bone protection effects of picroside II. These results collectively suggested that picroside II acted as an anti-resorption agent by blocking osteoclast activation. J. Cell. Biochem. 118: 4479-4486, 2017. © 2017 Wiley Periodicals, Inc.

(−)-Epiafzelechin Protects against Ovariectomy-induced Bone Loss in Adult Mice and Modulate Osteoblastic and Osteoclastic Functions In Vitro

The present study was designed to characterize the bone protective effects of (−)-epiafzelechin (EAF), a flavan-3-ol, in mature ovariectomized mice model and its ability to stimulate osteoblastic activity and inhibit osteoclastic activity. Mature C57BL/6 mice (three to four months old) were either ovariectomised (OVX) or sham-operated and subjected to treatment (vehicle, 17β-oestradiol (E2, 200 μg/kg/day) or EAF (500 μg/kg/day) orally for six weeks. EAF and E2 significantly reduced urinary calcium (Ca) excretion, serum osteocalcin (OCN), and urinary deoxy-pyridinoline (DPD); increased bone mineral density (BMD); and improved micro-architectural properties in OVX mice. EAF significantly increased cell viability, alkaline phosphatise (ALP) activity, and collagen content, as well as runt-related transcriptional factor 2 (Runx2) mRNA expression in murine osteoblastic MC3T3-E1 cells. In addition, EAF significantly reduced the viability of osteoclast precursor murine leukemia monocyte RAW 264.7 cells and tartrate-resistant acid phosphatase (TRAP) activities in mature osteoclastic RAW 264.7 cells. EAF is a bioactive flavan-3-ol that protects estrogen deficiency-induced bone loss in OVX mice and exerts direct modulating effects in bone cells in vitro.

Effects of a tissue-selective estrogen complex on B lymphopoiesis and B cell function

Background/objective17β-estradiol (E2) has major effects on the immune system. It induces thymic atrophy, inhibits both T and B lymphopoiesis and stimulates antibody production treatment with E2 has protective effects on the skeleton but is associated with negative side effects in reproductive organs. A tissue-selective estrogen complex (TSEC) comprise of estrogens combined with a selective estrogen receptor modulator (SERM). TSEC therapy displays the bone-protective effects of estrogen, while the negative side effects on reproductive organs are blocked by the SERM. In a recent publication we showed that treatment with the TSEC E2+bazedoxifene (bza) potently inhibits experimental arthritis and associated osteoporosis. In order to elucidate immunological mechanisms involved in those effects, the aim of this study was to investigate how E2+bza treatment affects the healthy immune system. MethodsOvariectomized C57BL/6N mice were treated with vehicle, E2, bza or E2+bza. Weights of uterus and thymus were determined and fluorescence-activated cell sorting was used to analyze B cell populations in bone marrow and spleen. Immunoglobulin production from B cells in bone marrow and spleen were determined using ELISPOT. ResultsAddition of bza to E2-treatment totally antagonized the E2-mediated proliferative effect on uterus. On the contrary, addition of bza to E2-treatment did not block the E2-induced thymic atrophy or inhibition of B lymphopoiesis, and did not block the E2-induced increase in immunoglobulin secretion from bone marrow B cells. ConclusionsAddition of bza to E2-treatment blocks E2-induced uteroproliferation but does not alter E2-mediated effects on thymus, B lymphopoiesis or B cell function.

Bone-Protective Effects of Dried Plum in Postmenopausal Women: Efficacy and Possible Mechanisms.

Osteoporosis is an age-related chronic disease characterized by a loss of bone mass and quality, and is associated with an increased risk of fragility fractures. Postmenopausal women are at the greatest risk of developing osteoporosis due to the cessation in ovarian hormone production, which causes accelerated bone loss. As the demographic shifts to a more aged population, a growing number of postmenopausal women will be afflicted with osteoporosis. Certain lifestyle factors, including nutrition and exercise, are known to reduce the risk of developing osteoporosis and therefore play an important role in bone health. In terms of nutrition, accumulating evidence suggests that dried plum (Prunus domestica L.) is potentially an efficacious intervention for preventing and reversing bone mass and structural loss in an ovariectomized rat model of osteoporosis, as well as in osteopenic postmenopausal women. Here, we provide evidence supporting the efficacy of dried plum in preventing and reversing bone loss associated with ovarian hormone deficiency in rodent models and in humans. We end with the results of a recent follow-up study demonstrating that postmenopausal women who previously consumed 100 g dried plum per day during our one-year clinical trial conducted five years earlier retained bone mineral density to a greater extent than those receiving a comparative control. Additionally, we highlight the possible mechanisms of action by which bioactive compounds in dried plum exert bone-protective effects. Overall, the findings of our studies and others strongly suggest that dried plum in its whole form is a promising and efficacious functional food therapy for preventing bone loss in postmenopausal women, with the potential for long-lasting bone-protective effects.

Dried Plum's Unique Ability to Prevent and Reverse Bone Loss in Ovarian Hormone Deficiency: Efficacy and Possible Mechanisms

Osteoporosis is a chronic disorder associated with aging that is characterized by a loss of bone mass and quality leading to an increased risk of fragility fractures. Postmenopausal women are at the greatest risk of developing osteoporosis due to a cessation in ovarian hormone production, thus leading to accelerated bone loss. As the demographic shifts to a more aged population, a growing number of postmenopausal women will be afflicted with osteoporosis. A search for promising non‐pharmacological alternative therapies for osteoporosis is of prime importance as medications used for the prevention and treatment of osteoporosis can be associated with side effects and low compliance. Certain lifestyle factors, including nutrition, are known to reduce the risk of developing osteoporosis and therefore play an important role in bone health. In terms of nutrition, dried plum (prune) has been shown to be one of the most efficacious interventions for preventing and reversing bone loss in an ovariectomized rat model of osteoporosis as well as in postmenopausal women. The purpose of this presentation is to provide an overview of the efficacy of dried plum for preventing and reversing bone loss associated with ovarian hormone deficiency and to highlight possible mechanisms of action. We end with the results of a follow‐up study demonstrating that postmenopausal women taking dried plums during our one year clinical trial conducted five years earlier retained bone mineral density compared to the control. Overall, these findings suggest that dried plum is a promising functional food therapy for postmenopausal bone loss with the potential for a long‐lasting bone‐protective effect.Support or Funding InformationUSDA, California Dried Plum, Abbott Laboratories

Psoralidin, a prenylated coumestan, as a novel anti-osteoporosis candidate to enhance bone formation of osteoblasts and decrease bone resorption of osteoclasts

Traditional Chinese medicines (TCM) have been proven to prevent osteoporosis, but their clinical applications are not widely recognized due to their complicated ingredients. Psoralidin, a prenylated coumestan, has been reported to prevent bone loss of ovariectomized rats, but detailed mechanisms are still not clear. In current study, we found that both psoralidin and coumestrol promoted osteoblast proliferation and differentiation, as evidenced by improvements in cell proliferation and alkaline phosphatase activity; increased formation of ALP colonies and calcified nodules; enhanced secretion of collagen-I, BMP-2, osteocalcin and osteopontin; and stimulation of the expression of IGF-1, β-catenin, Runx-2, Osterix, and OPG, as well as the mRNA ratio of OPG/RANKL, while significantly decreasing the expression of RANKL. In addition, both psoralidin and coumestrol inhibited osteoclast formation and osteoclastic bone resorption, as demonstrated by the lower tartrate-resistant acid phosphatase activity and smaller area, with fewer resorption pits formed. Interestingly, psoralidin showed much stronger effects than coumestrol at enhancing osteoblast proliferation/differentiation or inhibiting osteoclast differentiation and bone resorption. Moreover, we found that both psoralidin and coumestrol suppressed COX-2 and ROS production in rat osteoblastic calvarias cells, and psoralidin showed stronger effects than coumestrol. Furthermore, we detected that by blocking estrogen receptors with ICI 182.780 (an estrogen receptor antagonist), the osteoprotective effects of psoralidin and coumestrol were also blocked. Our findings demonstrated that psoralidin and coumestrol exert their bone-protective effects by enhancing bone formation of osteoblasts and inhibiting bone resorption of osteoclasts. These roles might be mediated by their antioxidant activity and transduced through estrogen receptor signaling.

The Novel Pan-PIM Kinase Inhibitor, PIM447, Displays Dual Antimyeloma and Bone-Protective Effects, and Potently Synergizes with Current Standards of Care.

PIM kinases are a family of serine/threonine kinases recently proposed as therapeutic targets in oncology. In the present work, we have investigated the effects of the novel pan-PIM kinase inhibitor, PIM447, on myeloma cells and myeloma-associated bone disease using different preclinical models. In vitro/ex vivo cytotoxicity of PIM447 was evaluated on myeloma cell lines and patient samples. Synergistic combinations with standard treatments were analyzed with Calcusyn Software. PIM447 effects on bone cells were assessed on osteogenic and osteoclastogenic cultures. The mechanisms of PIM447 were explored by immunoblotting, qPCR, and immunofluorescence. A murine model of disseminated multiple myeloma was employed for in vivo studies. PIM447 is cytotoxic for myeloma cells due to cell-cycle disruption and induction of apoptosis mediated by a decrease in phospho-Bad (Ser112) and c-Myc levels and the inhibition of mTORC1 pathway. Importantly, PIM447 demonstrates a very strong synergy with different standard treatments such as bortezomib + dexamethasone (combination index, CI = 0.002), lenalidomide + dexamethasone (CI = 0.065), and pomalidomide + dexamethasone (CI = 0.077). PIM447 also inhibits in vitro osteoclast formation and resorption, downregulates key molecules involved in these processes, and partially disrupts the F-actin ring, while increasing osteoblast activity and mineralization. Finally, PIM447 significantly reduced the tumor burden and prevented tumor-associated bone loss in a disseminated murine model of human myeloma. Our results demonstrate dual antitumoral and bone-protective effects of PIM447. This fact, together with the very strong synergy exhibited with standard-of-care treatments, supports the future clinical development of this drug in multiple myeloma. Clin Cancer Res; 23(1); 225-38. ©2016 AACR.

Milk Basic Protein Facilitates Increased Bone Mass in Growing Mice.

Milk basic protein (MBP) comprises a group of basic whey proteins and is effective in preventing bone loss by promoting bone deposition (bone formation) and suppressing withdrawn (bone resorption). We previously revealed the bone protective effects of MBP during life phases involving excessive bone resorption, such as in adults and postmenopausal women, and in animal models (ovariectomized rats and mice). However, it was unclear whether MBP increases bone mass during the growth stage, when there is more bone formation than resorption. We therefore investigated the effect of MBP supplementation on bone mass in 6-wk-old mice provided water supplemented with MBP [0.01%, 0.1%, 1.0% (w/w)] or deionized water (control) ad libitum for 10 wk. Analysis by micro-computerized tomography showed that MBP significantly increased tibia cortical bone mineral density and femur trabecular bone volume to tissue volume compared with mice provided deionized water. Next, the function of MBP in bone remodeling (bone formation and resorption) was evaluated using an in vitro system and the results demonstrated that MBP directly promoted osteoblast proliferation and inhibited osteoclastogenesis. Moreover, the plasma level of insulin-like growth factor-1 was increased by MBP supplementation, suggesting that MBP indirectly promoted osteoblast proliferation/differentiation. These effects enhance bone formation and/or inhibit bone resorption, resulting in increased bone mass in growing mice.

Discovery of a New Class of Cathepsin K Inhibitors in Rhizoma Drynariae as Potential Candidates for the Treatment of Osteoporosis.

Rhizoma Drynariae (RD), as one of the most common clinically used folk medicines, has been reported to exert potent anti-osteoporotic activity. The bioactive ingredients and mechanisms that account for its bone protective effects are under active investigation. Here we adopt a novel in silico target fishing method to reveal the target profile of RD. Cathepsin K (Ctsk) is one of the cysteine proteases that is over-expressed in osteoclasts and accounts for the increase in bone resorption in metabolic bone disorders such as postmenopausal osteoporosis. It has been the focus of target based drug discovery in recent years. We have identified two components in RD, Kushennol F and Sophoraflavanone G, that can potentially interact with Ctsk. Biological studies were performed to verify the effects of these compounds on Ctsk and its related bone resorption process, which include the use of in vitro fluorescence-based Ctsk enzyme assay, bone resorption pit formation assay, as well as Receptor Activator of Nuclear factor κB (NF-κB) ligand (RANKL)-induced osteoclastogenesis using murine RAW264.7 cells. Finally, the binding mode and stability of these two compounds that interact with Ctsk were determined by molecular docking and dynamics methods. The results showed that the in silico target fishing method could successfully identify two components from RD that show inhibitory effects on the bone resorption process related to protease Ctsk.

Safety and efficacy of tocotrienol supplementation for bone health in postmenopausal women: protocol for a dose–response double-blinded placebo-controlled randomised trial

IntroductionOsteoporosis is a major health concern in postmenopausal women, and oxidative stress contributes to the development of bone loss. Cellular studies and ovariectomised rat model mimicking bone loss in postmenopausal...

EURYCOMA LONGIFOLIA, A MALAYSIAN MEDICINAL HERB, SIGNIFICANTLY UPREGULATES PROLIFERATION AND DIFFERENTIATION IN PRE-OSTEOBLASTS (MC3T3-E1): AN IN VITRO MODEL

Objective: Eurycoma longifolia (EL), a well-recognized Malaysian medicinal herb, has gained widespread popularity due to its ability to protect against bone calcium loss in androgen-deficient osteoporosis. Nevertheless numerous animal studies have proved the bone protective effect of EL; however, the exact mechanism is not well-explained yet. Thus, the present study was aimed to explore the in vitro basis of bone protective effects of EL by using mouse pre-osteoblast cell line (MC3T3-E1).Methods: The cytotoxicity and proliferative potential of EL were evaluated by lactate dehydrogenase (LDH) and cell counting methods. Despite cell growth, the ability of EL to promote osteogenic differentiation of bone-forming cells was assessed by quantifying collagen (early differentiation marker) and calcium (late differentiation marker) in EL-treated bone forming cells.Results: Resulting data obtained from dose optimization study revealed that EL at 5 to 50 µg/ml concentration showed marked effects in significantly promoting cell growth in MC3T3-E1 cells. As such, resulting data also demonstrated the superior potential of EL in up regulating collagen synthesis and mineralization (calcium deposition) in MC3T3-E1 cells at 25 µg/ml, in comparison to untreated (negative control) and dihydrotestosterone (5α-DHT)-treated cells (positive control).Conclusion: These pronounced effects of EL on osteoblasts provide an in vitro basis for the bone protective potential of EL and thus can be considered as an alternative regimen for the treatment of androgen-deficient male osteoporosis.

Effects of salvianolate on bone metabolism in glucocorticoid-treated lupus-prone B6.MRL-Fas (lpr) /J mice.

AimTo investigate the bone-protective effects of salvianolate (Sal), a total polyphenol from Radix Salviae miltiorrhizae, on bone tissue in the spontaneous lupus-prone mouse model, B6.MRL-Faslpr/J, undergoing glucocorticoid (GC) treatment.MethodsFifteen-week-old female B6.MRL-Faslpr/J mice were administered either a daily dose of saline (lupus group), prednisone 6 mg/kg (GC group), Sal 60 mg/kg (Sal group); or GC plus Sal (GC + Sal group) for a duration of 12 weeks. Age-matched female C57BL/6J wild-type (WT) mice were used for control. Micro-computed tomography assessments, bone histomorphometry analysis, bone biomechanical test, immunohistochemistry and immunoblotting analysis for bone markers, and renal histology analysis were performed to support our research endeavor.ResultsLupus mice developed a marked bone loss and deterioration of mechanical properties of bone due to an increase in bone resorption rather than suppression of bone formation. GC treatment strongly inhibited bone formation in lupus mice. Sal treatment significantly attenuated osteogenic inhibition, and also suppressed hyperactive bone resorption, which recovered the bone mass and mechanical properties of bone in both the untreated and GC-treated lupus mice.ConclusionThe data support further preclinical investigation of Sal as a potential therapeutic strategy for the treatment of systemic lupus erythematosus-related bone loss.

Functional morphology of pituitary -thyroid and -adrenocortical axes in middle-aged male rats treated with Vitex agnus castus essential oil

We previously reported that Vitex agnus-castus L. essential oil (VACEO), when administered to middle-aged males, exerts a bone-protective effect, induces silencing of locomotor activities and decreases pituitary prolactin immunopositivity. To further assess the putative endocrine effects of VACEO, we examined the pituitary-thyroid and -adrenocortical axes in our model. Sixteen-month-old Wistar rats were subcutaneously administered 60mg/kg of VACEO dissolved in sterile olive oil, while the control group received the same amount of vehicle alone for three weeks. Pituitaries, thyroids and adrenals were analyzed by qualitative and quantitative histological approaches. Concentration of thyroid stimulating hormone (TSH), total thyroxine and triiodothyronine (TH), adrenocorticotrophic hormone (ACTH), corticosterone in serum and in adrenal tissue were measured. In VACEO-treated rats, the relative volume density of pituitary thyrotrophs increased (p<0.001), while intensity of cytoplasmic TSHβ immunostaining decreased (p<0.001), consistent with elevated TSH in serum (p<0.01). The thyroid tissue was characterized by a micro-follicular structure, increased relative volume of follicular epithelium (p<0.05), decreased volume of luminal colloid (p<0.001) and increased basolateral expression of sodium-iodide symporter-immunopositivity (p<0.05). Serum TH also increased (p<0.01). The relative volume density of pituitary corticotrophs decreased (p<0.05), compatible with decline in circulating ACTH (p<0.05). Neither tissue nor serum corticosterone levels were affected by VACEO treatment. In conclusion, the observed changes in TSH and ACTH strongly indicate central endocrine effects of prolonged VACEO treatment. In this respect, production of ACTH decreased without impact on corticosterone production. Increase in serum concentration of both TH and TSH are not compatible with a negative feedback loop and suggest a major change in set-point regulation of the hypothalamic-pituitary-thyroid axis.

Olives and Bone: A Green Osteoporosis Prevention Option.

Skeletal degeneration due to aging, also known as osteoporosis, is a major health problem worldwide. Certain dietary components confer protection to our skeletal system against osteoporosis. Consumption of olives, olive oil and olive polyphenols has been shown to improve bone health. This review aims to summarize the current evidence from cellular, animal and human studies on the skeletal protective effects of olives, olive oil and olive polyphenols. Animal studies showed that supplementation of olives, olive oil or olive polyphenols could improve skeletal health assessed via bone mineral density, bone biomechanical strength and bone turnover markers in ovariectomized rats, especially those with inflammation. The beneficial effects of olive oil and olive polyphenols could be attributed to their ability to reduce oxidative stress and inflammation. However, variations in the bone protective, antioxidant and anti-inflammatory effects between studies were noted. Cellular studies demonstrated that olive polyphenols enhanced proliferation of pre-osteoblasts, differentiation of osteoblasts and decreased the formation of osteoclast-like cells. However, the exact molecular pathways for its bone health promoting effects are yet to be clearly elucidated. Human studies revealed that daily consumption of olive oil could prevent the decline in bone mineral density and improve bone turnover markers. As a conclusion, olives, olive oil and its polyphenols are potential dietary interventions to prevent osteoporosis among the elderly.

Kanamycin inhibits daidzein metabolism and abilities of the metabolites to prevent bone loss in ovariectomized mice.

BackgroundDaidzein is an isoflavone derived from soybeans that exerts preventive effects on bone loss in ovariectomized (OVX) animals. These effects have been correlated with increasing serum equol levels. In the present study, we investigated the effects of antibiotic intake on equol metabolism from daidzein, and the corresponding levels of bone loss in OVX mice.MethodsEight-week-old female ddY mice (n = 42) were either ovariectomized (OVX) or subjected to a sham operation (sham). OVX mice were then divided into six dietary subgroups: control diet (control), 0.3 % kanamycin diet (KN), 0.1 % daidzein diet (Dz), 0.1 % daidzein and 0.0375 % kanamycin diet (Dz+KN3.75), 0.1 % daidzein and 0.075 % kanamycin diet (Dz+KN7.5), and 0.1 % daidzein and 0.3 % kanamycin diet (Dz+KN30). The mice were fed their respective diets for 4 weeks.ResultsUterine weight and femoral bone mineral density (BMD) were significantly lower in the OVX mice compared in the sham mice. No significant differences in uterine weight were observed among all OVX dietary subgroups. The Dz subgroup was found to exhibit higher plasma equol and O-desmethylangolensin (O-DMA) concentrations, as well as greater femoral BMD, compared to all other OVX subgroups. Furthermore, when compared to the Dz group, kanamycin intake decreased plasma equol and O-DMA concentrations, as well as femoral BMD in the OVX mice.ConclusionsThese results suggest that kanamycin intake inhibited the conversion of daidzein to equol and O-DMA, blocking the preventive effects of daidzein on bone loss in OVX mice. Therefore, the bone-protective effects of daidzein intake may be predominantly associated with increased plasma concentrations of either equol or O-DMA.

Effects of ospemifene on bone parameters including clinical biomarkers in postmenopausal women.

Ospemifene is an estrogen-receptor agonist/antagonist (also known as a selective estrogen-receptor modulator) that is FDA approved for the treatment of moderate-to-severe dyspareunia, a symptom of vulvovaginal atrophy, due to menopause. Preclinical and clinical data suggest that ospemifene may also have an effect on bone health in postmenopausal women. Relevant articles, including cellular and preclinical studies and clinical trials written in English pertaining to ospemifene and bone health, were identified from a database search of PubMed (from its inception to June 2015) and summarized in this comprehensive review. In vitro data suggest that ospemifene may mediate a positive effect on bone through osteoblasts. Ospemifene effectively reduced bone loss and resorption in ovariectomized rats, with activity comparable to estradiol and raloxifene. Clinical data from three phase 1 or 2 clinical trials (2 placebo- and 1 raloxifene-controlled) found ospemifene 60 mg/d to have a positive effect on the biochemical markers for bone turnover in healthy, postmenopausal women with significant improvements relative to placebo and comparable to raloxifene. Ospemifene 60 mg/d may have a protective effect on the bone health of women being treated for dyspareunia. The initial clinical data for ospemifene follows a trend similar to raloxifene and bazedoxifene, suggesting that ospemifene may have bone-protective effects in postmenopausal women. However, additional rigorous clinical trials are necessary to confirm any positive effects ospemifene may have on vertebral fractures and bone mineral density in healthy and osteoporotic women.

Inhibition of mTOR signaling by everolimus has concurrent anti-tumor and bone-protective effects in murine osteolytic cancer models

Searchable abstracts of presentations at key conferences on calcified tissues ISSN 2052-1219 (online)

Icariin attenuates titanium-particle inhibition of bone formation by activating the Wnt/β-catenin signaling pathway in vivo and in vitro.

Wear-debris-induced periprosthetic osteolysis (PIO) is a common clinical condition following total joint arthroplasty, which can cause implant instability and failure. The host response to wear debris promotes bone resorption and impairs bone formation. We previously demonstrated that icariin suppressed wear-debris-induced osteoclastogenesis and attenuated particle-induced osteolysis in vivo. Whether icariin promotes bone formation in a wear-debris-induced osteolytic site remains unclear. Here, we demonstrated that icariin significantly attenuated titanium-particle inhibition of osteogenic differentiation of mesenchymal stem cells (MSCs). Additionally, icariin increased bone mass and decreased bone loss in titanium-particle-induced osteolytic sites. Mechanistically, icariin inhibited decreased β-catenin stability induced by titanium particles in vivo and in vitro. To confirm icariin mediated its bone-protective effects via the Wnt/β-catenin signaling pathway, we demonstrated that ICG-001, a selective Wnt/β-catenin inhibitor, attenuated the effects of icariin on MSC mineralization in vitro and bone formation in vivo. Therefore, icariin could induce osteogenic differentiation of MSCs and promote new bone formation at a titanium-particle-induced osteolytic site via activation of the Wnt/β-catenin signaling pathway. These results further support the protective effects of icariin on particle-induced bone loss and provide novel mechanistic insights into the recognized bone-anabolic effects of icariin and an evidence-based rationale for its use in PIO treatment.