Mechanical induction of osteoanabolic Wnt1 promotes osteoblast differentiation via Plat.

Physical activity-induced mechanical stimuli play a crucial role in preserving bone mass and structure by promoting bone formation. While the Wnt pathway is pivotal for mediating the osteoblast response to loading, the exact mechanisms are not fully understood. Here, we found that mechanical stimulation induces osteoblastic Wnt1 expression, resulting in an upregulation of key osteogenic marker genes, including Runx2 and Sp7, while Wnt1 knockdown using siRNA prevented these effects. RNAseq analysis identified Plat as a major target through which Wnt1 exerts its osteogenic influence. This was corroborated by Plat depletion using siRNA, confirming its positive role in osteogenic differentiation. Moreover, we demonstrated that mechanical stimulation enhances Plat expression, which, in turn leads to increased expression of osteogenic markers like Runx2 and Sp7. Notably, Plat depletion by siRNA prevented this effect. We have established that Wnt1 regulates Plat expression by activating ß-Catenin. Silencing Wnt1 impairs mechanically induced ß-Catenin activation, subsequently reducing Plat expression. Furthermore, our findings showed that Wnt1 is essential for osteoblasts to respond to mechanical stimulation and induce Runx2 and Sp7 expression, in part through the Wnt1/ß-Catenin/Plat signaling pathway. Additionally, we observed significantly reduced Wnt1 and Plat expression in bones from ovariectomy (OVX)-induced and age-related osteoporotic mouse models compared with non-OVX and young mice, respectively. Overall, our data suggested that Wnt1 and Plat play significant roles in mechanically induced osteogenesis. Their decreased expression in bones from OVX and aged mice highlights their potential involvement in post-menopausal and age-related osteoporosis, respectively.

Association of neutrophil to lymphocyte ratio with bone mineral density in post-menopausal women: a systematic review and meta-analysis.

BACKGROUND: We conducted a systematic review and meta-analysis to compare the neutrophil lymphocyte ratio (NLR) levels between women with post-menopausal osteopenia or osteoporosis to those with normal bone mineral density (BMD). METHODS: We used Web of Science, PubMed, and Scopus to conduct a systematic search for relevant publications published before June 19, 2022, only in English language. We reported standardized mean difference (SMD) with a 95% confidence interval (CI). Because a significant level of heterogeneity was found, we used the random-effects model to calculate pooled effects. We used the Newcastle-Ottawa scale for quality assessment. RESULTS: Overall, eight articles were included in the analysis. Post-menopausal women with osteoporosis had elevated levels of NLR compared to those without osteoporosis (SMD = 1.03, 95% CI = 0.18 to 1.88, p = 0.017, I2 = 98%). In addition, there was no difference between post-menopausal women with osteopenia and those without osteopenia in neutrophil lymphocyte ratio (NLR) levels (SMD = 0.58, 95% CI=-0.08 to 1.25, p = 0.085, I2 = 96.8%). However, there was no difference between post-menopausal women with osteoporosis and those with osteopenia in NLR levels (SMD = 0.75, 95% CI=-0.01 to 1.51, p = 0.05, I2 = 97.5%, random-effect model). CONCLUSION: The results of this study point to NLR as a potential biomarker that may be easily introduced into clinical settings to help predict and prevent post-menopausal osteoporosis.

Role of Mast-Cell-Derived RANKL in Ovariectomy-Induced Bone Loss in Mice.

Mast cells may contribute to osteoporosis development, because patients with age-related or post-menopausal osteoporosis exhibit more mast cells in the bone marrow, and mastocytosis patients frequently suffer from osteopenia. We previously showed that mast cells crucially regulated osteoclastogenesis and bone loss in ovariectomized, estrogen-depleted mice in a preclinical model for post-menopausal osteoporosis and found that granular mast cell mediators were responsible for these estrogen-dependent effects. However, the role of the key regulator of osteoclastogenesis, namely, receptor activator of NFκB ligand (RANKL), which is secreted by mast cells, in osteoporosis development has, to date, not been defined. Here, we investigated whether mast-cell-derived RANKL participates in ovariectomy (OVX)-induced bone loss by using female mice with a conditional Rankl deletion. We found that this deletion in mast cells did not influence physiological bone turnover and failed to protect against OVX-induced bone resorption in vivo, although we demonstrated that RANKL secretion was significantly reduced in estrogen-treated mast cell cultures. Furthermore, Rankl deletion in mast cells did not influence the immune phenotype in non-ovariectomized or ovariectomized mice. Therefore, other osteoclastogenic factors released by mast cells might be responsible for the onset of OVX-induced bone loss.

Improvement in viability and mineralization of osteoporotic bone marrow mesenchymal stem cell through combined application of photobiomodulation therapy and oxytocin.

The probable positive effects of photobiomodulation therapy (PBMT) and oxytocin (OT) treatments together or alone were evaluated on cell viability along with the changes in the gene expression of Osteocalcin (OC), Osteoprotegerin (OPG), and Runt-related transcription factor 2 (Runx2) levels of sham (healthy)-Bone marrow mesenchymal stem cell(BMMSC) and ovariectomy-induced osteoporosis (OVX)-BMMSC. BMMSC was harvested from healthy and OVX rats and was cultured in osteogenic induction medium (OIM). There were five groups of BMMSCs: (1) sham -BMMSCs; (2) control -OVX-BMMSCs; (3) OT-treated-OVX-BMMSCs; (4) PBMT-treated-OVX-BMMSCs, and (5) OT + PBMT-OVX-BMMSCs. In all 5 groups, BMMSC viability and proliferation as well as gene expression of OC, OPG, and RUNX2 were evaluated. PBMT and PBMT + OT treatments showed a promising effect on the increased viability of OVX-BMMSC (ANOVA test; LSD test, p = 0.01, p = 0.002). The results of gene expression analysis revealed that the sham- BMMSCs responded optimally to OT treatment. It was also found that OVX-BMMSCs responded optimally to PBMT + OT and PBMT treatments at early and middle stages of osteogenic induction process. Nevertheless, they responded optimally to PBMT + OT and OT especially at the late stage of osteogenic induction process. PBMT and PBMT + OT treatments significantly increased viability of OVX-BMMSC in OIM in vitro. Both PBMT and PBMT + OT treatments could promote mineralization of OVX-BMMSC in the culture medium at early and middle stages of osteogenic induction process. Both OT and PBMT + OT treatments could promote mineralization of OVX-BMMSC in vitro at late stages of osteogenic induction process.

Understanding Patients' Perspectives and Educational Needs by Type of Osteoporosis in Men and Women and People with Glucocorticosteroid-Induced Osteoporosis: A Qualitative Study to Improve Disease Management.

The aim of the study was to investigate similarities and differences in health beliefs, experiences and educational needs by type of osteoporosis (OP), particularly in people with glucocorticoid-induced OP (GIOP) and men. A qualitative study was conducted via focus groups involving post-menopausal women with or without osteoporotic fractures, osteoporotic men and people with GIOP. Fifty-three participants were included in eight groups. A wide range of health beliefs was found for all types of OP. Osteoporosis was considered a natural consequence of ageing except in men or conversely a serious disease associated with risk of new fractures and disability. GIOP patients had heterogeneous knowledge of OP and reported fewer prevention behaviours, and their quality of life was affected by the causal illness. Men had difficulties coping with the loss of their functional abilities and felt that OP was a "women's" disease. Beliefs about treatments ranged from confidence to fear of adverse effects or doubt about efficacy in all types of OP. Participants were interested in physical activity, fall prevention and diet, and preferred group sessions. GIOP patients and men had an interest in face-to-face education. Men were also interested in brief information including via the Internet. Patients' beliefs about OP differed by type of OP. Specific populations such as men or people with GIOP need particular care owing to experiences and needs. Offering group sessions in educational interventions is of interest to allow for sharing experiences and also face-to-face education for men and GIOP patients or the Internet for men.

Oxidative stress as a possible pathogenic cofactor of post-menopausal osteoporosis: Existing evidence in support of the axis oestrogen deficiency-redox imbalance-bone loss.

Post-menopausal osteoporosis (PO) is one of the major health issues associated with menopause-related oestrogen withdrawal. Despite the intense research and the relevant progress achieved in the last two decades, the pathogenic mechanism underlying PO is still poorly understood. As a consequence of this gap in the knowledge, such disorder and the related complications are still difficult to be effectively prevented. A wealth of experimental and epidemiological/clinical evidence suggests that the endocrine change associated to menopausal transition might lead to a derangement of redox homeostasis, that is, the prelude to the health-threaten condition of oxidative stress (OxS). In turn, this (bio)chemical stress has been widely hypothesized to contribute, most likely in synergy with inflammation, to the development of menopause-related diseases, including PO. The main aim of this review is to discuss the current literature evidence on the association between post-menopausal oestrogen withdrawal, OxS and PO. It is also aimed to provide a critical overview of the most significant epidemiological studies on the effects of dietary antioxidants on bone health and to devise a strategy to overcome the limitations emerged and controversial results.

Pharmacological activation of aldehyde dehydrogenase 2 promotes osteoblast differentiation via bone morphogenetic protein-2 and induces bone anabolic effect.

Aldehyde dehydrogenases (ALDHs) are a family of enzymes involved in detoxifying aldehydes. Previously, we reported that an ALDH inhibitor, disulfiram caused bone loss in rats and among ALDHs, osteoblast expressed only ALDH2. Loss-of-function mutation in ALDH2 gene is reported to cause bone loss in humans which suggested its importance in skeletal homeostasis. We thus studied whether activating ALDH2 by N-(1, 3-benzodioxol-5-ylmethyl)-2, 6-dichlorobenzamide (alda-1) had osteogenic effect. We found that alda-1 increased and acetaldehyde decreased the differentiation of rat primary osteoblasts and expressions of ALDH2 and bone morphogenetic protein-2 (BMP-2). Silencing ALDH2 in osteoblasts abolished the alda-1 effects. Further, alda-1 attenuated the acetaldehyde-induced lipid-peroxidation and oxidative stress. BMP-2 is essential for bone regeneration and alda-1 increased its expression in osteoblasts. We then showed that alda-1 (40mg/kg dose) augmented bone regeneration at the fracture site with concomitant increase in BMP-2 protein compared with control. The osteogenic dose (40mg/kg) of alda-1 attained a bone marrow concentration that was stimulatory for osteoblast differentiation, suggesting that the tissue concentration of alda-1 matched its pharmacologic effect. In addition, alda-1 promoted modeling-directed bone growth and peak bone mass achievement, and increased bone mass in adult rats which reiterated its osteogenic effect. In osteopenic ovariectomized (OVX) rats, alda-1 reversed trabecular osteopenia with attendant increase in serum osteogenic marker (procollagen type I N-terminal peptide) and decrease in oxidative stress. Alda-1 has no effect on liver and kidney function. We conclude that activating ALDH2 by alda-1 had an osteoanabolic effect involving increased osteoblastic BMP-2 production and decreased OVX-induced oxidative stress.

Design and synthesis of dalbergin analogues and evaluation of anti-osteoporotic activity.

The chemical modifications of the hydroxyl group of dalbergin have been described via the introduction of cyclic amine, ester and amide groups. Among the twenty-three prepared novel analogues of dalbergin, compound 4d (EC50 2.3µM) showed significantly increased proliferation as assessed by alkaline phosphatase activity and mineralization in calvarial osteoblast cells in vitro. Compound 4d, at a dose of 1.0mg/kg body weight exhibited the significant osteoprotective effect. It showed a significant increase in osteogenic gene expression RunX2 (∼4fold), ALP (∼5fold), OCN (∼4fold) and COL1 (∼4fold) as compared to control group at the same dose in vivo assay.

Randomized trial comparing efficacies of zoledronate and alendronate for improving bone mineral density and inhibiting bone remodelling in women with post-menopausal osteoporosis.

WHAT IS KNOWN AND OBJECTIVE: Bisphosphonates are the first-line medications for treating osteoporosis. The aim of our prospective study was to compare the efficacy of zoledronate with that of alendronate in women with post-menopausal osteoporosis based on the evaluations of bone mineral density (BMD) and serum levels of biochemical markers of bone remodelling. METHODS: Chinese women with post-menopausal osteoporosis were randomly assigned to the zoledronate (n = 52) or alendronate (n = 53) group, and were treated with 5 mg zoledronate intravenously once per year and 70 mg alendronate orally once per week, respectively. During a 3-year follow-up period, the lumbar spine, femoral neck and total hip were examined using dual-energy x-ray absorptiometry every 12 months to assess BMD, and the serum levels of amino-terminal propeptide of type I procollagen (P1NP) and carboxy-terminal cross-linked telopeptides of type 1 collagen (CTX) were measured to evaluate bone formation and resorption, respectively. RESULTS AND DISCUSSION: Greater increases in BMD occurred in the zoledronate group over the 3-year follow-up period, with increases in BMD of 41·3%, 13·5% and 20·0% at the lumbar spine, femoral neck and total hip, respectively, compared with 16·9%, 5·88% and 8·93% in the alendronate group, respectively (P < 0·05 for all). At the 3-year follow-up, P1NP and ß-CTX levels were reduced by 42·1% and 50·5% in the zoledronate group, respectively, whereas the levels of each were reduced by 19·5% and 19·4% in the alendronate group, respectively (P < 0·05 for all). WHAT IS NEW AND CONCLUSIONS: Once yearly zoledronate administered intravenously was more efficacious for improving BMD and reducing the serum levels of P1NP and ß-CTX in Chinese women with post-menopausal osteoporosis than alendronate administered orally once per week. The incidence of adverse events after the second and third zoledronate treatments was substantially lower than that in the alendronate group, suggesting a substantially lower risk of adverse events with long-term use of zoledronate in Chinese women, compared with that of alendronate use.

Effectiveness of romosozumab in primary biliary cholangitis at half the recommended dose in an underweight patient.

Romosozumab (RSB) is a monoclonal antibody to sclerostin that is approved for post-menopausal osteoporosis at high fracture risk. It is administered as a monthly 210 mg subcutaneous injection for 12 months. We report the response to half the standard dose of RSB in an underweight patient with severe osteoporosis and primary biliary cholangitis (PBC). Using half dose RSB (approximately 3 mg/kg RSB), she demonstrated significant improvement in lumbar spine BMD, paralleling the results of phase III trials. This case highlights the effectiveness of RSB in a patient with concomitant PBC, in addition to its effectiveness at half the recommended dose in an underweight patient.

Anti-osteoporotic effect of Terminalia arjuna (Roxb.) Wight & Arn. in bilateral ovariectomized induced post-menopausal osteoporosis in experimental rats.

OBJECTIVES: In ancient times Terminalia arjuna (Roxb.) Wight & Arn. (TA) was used for fast healing of fracture and to strengthen the bone. However, no scientific study has been done to validate its usefulness in the alleviation of osteoporosis. To investigate the efficacy of stem bark TA against post-menopausal osteoporosis using bilateral ovariectomized rat model. METHODS: Aqueous (TAA) and methanolic (TAM) extracts of TA was evaluated for its anti-osteoporotic activity. Sham control rats were allotted as Group I (Normal control); Group II animals acted as OVX control (Disease control); Group III OVX rats were treated with estrogen (Standard group - 2 mg/kg) Group IV and V OVX rats give treatment to TAA (250 and 500 mg/kg, p.o.), respectively. This treatment is continue for the four weeks and at the end, serum biochemical parameters such as serum calcium and alkaline phosphate were evaluated. Femoral bone parameters (Compression of vertebrae, femoral neck load testing, Three point bending of tibia, Femur length and weight), histology, body weight, and fifth lumbar vertebra breaking strength were also assessed after the sacrificing the animal. RESULTS: In OVX rats, atrophy of uterus and descent of BMD were suppressed by treatment with TAA and TAM. In addition, TAM 500 completely corrected the decreased serum concentration of Calcium, Phosphorus, ALP and TRAP observed in OVX rats. TAA and TAM both increased biomechanical strength significantly in comparison to the sham group. Histological results also revealed its protective action through elevation of bone formation. TAM significantly increase the uterine and femoral bone weight The TAM showed maximum anti-osteoporotic activity in in vivo study as compare to TAA. CONCLUSIONS: The results, evaluated on the basis of biochemical, bone mineral density, biomechanical, and histopathological parameters, presented that TAA and TAM has a definite antiosteoporotic effect, like to estrogen, especially effective for inhibition bone fracture induced by estrogen deficiency.

A standardized extract of Coleus forskohlii root protects rats from ovariectomy-induced loss of bone mass and strength, and impaired bone material by osteogenic and anti-resorptive mechanisms.

Introduction: In obese humans, Coleus forskohlii root extract (CF) protects against weight gain owing to the presence of forskolin, an adenylate cyclase (AC) activator. As AC increases intracellular cyclic adenosine monophosphate (cAMP) levels in osteoblasts that has an osteogenic effect, we thus tested the skeletal effects of a standardized CF (CFE) in rats. Methods: Concentrations of forskolin and isoforskolin were measured in CFE by HPLC. CFE and forskolin (the most abundant compound present in CFE) were studied for their osteogenic efficacy in vitro by alkaline phosphatase (ALP), cAMP and cyclic guanosine monophosphate (cGMP) assays. Femur osteotomy model was used to determine the osteogenic dose of CFE. In growing rats, CFE was tested for its osteogenic effect in intact bone. In adult ovariectomized (OVX) rats, we assessed the effect of CFE on bone mass, strength and material. The effect of forskolin was assessed in vivo by measuring the expression of osteogenic genes in the calvarium of rat pups. Results: Forskolin content in CFE was 20.969%. CFE increased osteoblast differentiation and intracellular cAMP and cGMP levels in rat calvarial osteoblasts. At 25 mg/kg (half of human equivalent dose), CFE significantly enhanced calcein deposition at the osteotomy site. In growing rats, CFE promoted modeling-directed bone formation. In OVX rats, CFE maintained bone mass and microarchitecture to the level of sham-operated rats. Moreover, surface-referent bone formation in CFE treated rats was significantly increased over the OVX group and was comparable with the sham group. CFE also increased the pro-collagen type-I N-terminal propeptide: cross-linked C-telopeptide of type-I collagen (PINP : CTX-1) ratio over the OVX rats, and maintained it to the sham level. CFE treatment decreased the OVX-induced increases in the carbonate-to-phosphate, and carbonate-to-amide-I ratios. CFE also prevented the OVX-mediated decrease in mineral crystallinity. Nanoindentation parameters, including modulus and hardness, were decreased by OVX but CFE maintained these to the sham levels. Forskolin stimulated ALP, cAMP and cGMP in vitro and upregulated osteogenic genes in vivo. Conclusion: CFE, likely due to the presence of forskolin displayed a bone-conserving effect via osteogenic and anti-resorptive mechanisms resulting in the maintenance of bone mass, microarchitecture, material, and strength.

Disturbed bone marrow adiposity in patients with Cushing's syndrome and glucocorticoid- and postmenopausal- induced osteoporosis.

Background: Skeletal stem/progenitor cells (SSPCs) in the bone marrow can differentiate into osteoblasts or adipocytes in response to microenvironmental signalling input, including hormonal signalling. Glucocorticoids (GC) are corticosteroid hormones that promote adipogenic differentiation and are endogenously increased in patients with Cushing´s syndrome (CS). Here, we investigate bone marrow adiposity changes in response to endogenous or exogenous GC increases. For that, we characterize bone biopsies from patients with CS and post-menopausal women with glucocorticoid-induced osteoporosis (GC-O), compared to age-matched controls, including postmenopausal osteoporotic patients (PM-O). Methods: Transiliac crest bone biopsies from CS patients and healthy controls, and from postmenopausal women with GC-O and matched controls were analysed; an additional cohort included biopsies from women with PM-O. Plastic-embedded biopsies were sectioned for histomorphometric characterization and quantification of adipocytes. The fraction of adipocyte area per tissue (Ad.Ar/T.Ar) and marrow area (Ad.Ar/Ma.Ar), mean adipocyte profile area (Ad.Pf.Ar) and adipocyte profile density (N.Ad.Pf/Ma.Ar) were determined and correlated to steroid levels. Furthermore, the spatial distribution of adipocytes in relation to trabecular bone was characterized and correlations between bone marrow adiposity and bone remodeling parameters investigated. Results: Biopsies from patients with CS and GC-O presented increased Ad.Ar/Ma.Ar, along with adipocyte hypertrophy and hyperplasia. In patients with CS, both Ad.Ar/Ma.Ar and Ad.Pf.Ar significantly correlated with serum cortisol levels. Spatial distribution analyses revealed that, in CS, the increase in Ad.Ar/Ma.Ar near to trabecular bone (<100 µm) was mediated by both adipocyte hypertrophy and hyperplasia, while N.Ad.Pf/Ma.Ar further into the marrow (>100 µm) remained unchanged. In contrast, patients with GC-O only presented increased Ad.Ar/Ma.Ar and mean Ad.Pf.Ar>100 µm from trabecular bone surface, highlighting the differential effect of increased endogenous steroid accumulation. Finally, the Ad.Ar/Ma.Ar and Ad.Ar/T.Ar correlated with the canopy coverage above remodeling events. Conclusion: Increased cortisol production in patients with CS induces increased bone marrow adiposity, primarily mediated by adipocyte hypertrophy. This adiposity is particularly evident near trabecular bone surfaces, where hyperplasia also occurs. The differential pattern of adiposity in patients with CS and GC-O highlights that bone marrow adipocytes and their progenitors may respond differently in these two GC-mediated bone diseases.

Hip structural analysis, trabecular bone score, and bone mineral density in post-menopausal women with type-2 diabetes mellitus: a multi-center cross-sectional study in the south of Iran.

This study aimed to evaluate bone mineral density (BMD), trabecular microarchitecture, and proximal hip geometry in diabetic postmenopausal women, where BMD alone cannot reflect bone strength adequately. We found significantly lower trabecular bone score and BMD at the distal radius and total forearm in diabetic subjects compared to controls. PURPOSE: The limitations resulting from the exclusive assessment of bone mineral density (BMD) in people with diabetes can lead to underestimation of microarchitectural and geometric changes, both of which play an essential role in the fracture risk. Therefore, we aimed to evaluate BMD, trabecular bone score (TBS), and hip structural analysis (HSA) in diabetic type-2 post-menopausal women and compare them with healthy postmenopausal subjects. METHODS: BMD was assessed at the lumbar spine, femoral sites, distal radius, and total forearm using dual-energy X-ray absorptiometry (DXA); TBS was measured based on DXA images using the software at the same region of interest as the BMD measurements; geometric assessment at the proximal femur was performed by the HSA program. RESULTS: A total of 348 ambulatory type-2 diabetic postmenopausal women and 539 healthy postmenopausal women were enrolled. TBS and BMD at the distal radius and total forearm were significantly (P value < 0.05) lower in cases compared to controls after age and body mass index (BMI) adjustment. In addition, degraded bone microarchitecture was significantly (P value < 0.05) more prevalent in diabetic subjects than in non-diabetic controls after adjusting for age and BMI. A number of geometric indices of the proximal hip were significantly lower in the controls than in those with diabetes (P-value < 0.05). CONCLUSION: This study may highlight the utility of the TBS and BMD at the distal radius and total forearm in subjects with type-2 diabetes mellitus, where the BMD at central sites may not adequately predict fracture risk.

The additive effect of vitamin K supplementation and bisphosphonate on fracture risk in post-menopausal osteoporosis: a randomised placebo controlled trial.

This study assessed whether vitamin K, given with oral bisphosphonate, calcium and/or vitamin D has an additive effect on fracture risk in post-menopausal women with osteoporosis. No difference in bone density or bone turnover was observed although vitamin K1 supplementation led to a modest effect on parameters of hip geometry. PURPOSE: Some clinical studies have suggested that vitamin K prevents bone loss and may improve fracture risk. The aim was to assess whether vitamin K supplementation has an additive effect on bone mineral density (BMD), hip geometry and bone turnover markers (BTMs) in post-menopausal women with osteoporosis (PMO) and sub-optimum vitamin K status receiving bisphosphonate, calcium and/or vitamin D treatment. METHODS: We conducted a trial in 105 women aged 68.7[12.3] years with PMO and serum vitamin K1 ≤ 0.4 µg/L. They were randomised to 3 treatment arms; vitamin K1 (1 mg/day) arm, vitamin K2 arm (MK-4; 45 mg/day) or placebo for 18 months. They were on oral bisphosphonate and calcium and/or vitamin D. We measured BMD by DXA, hip geometry parameters using hip structural analysis (HSA) software and BTMs. Vitamin K1 or MK-4 supplementation was each compared to placebo. Intention to treat (ITT) and per protocol (PP) analyses were performed. RESULTS: Changes in BMD at the total hip, femoral neck and lumbar spine and BTMs; CTX and P1NP did not differ significantly following either K1 or MK-4 supplementation compared to placebo. Following PP analysis and correction for covariates, there were significant differences in some of the HSA parameters at the intertrochanter (IT) and femoral shaft (FS): IT endocortical diameter (ED) (% change placebo:1.5 [4.1], K1 arm: -1.02 [5.07], p = 0.04), FS subperiosteal/outer diameter (OD) (placebo: 1.78 [5.3], K1 arm: 0.46 [2.23] p = 0.04), FS cross sectional area (CSA) (placebo:1.47 [4.09],K1 arm: -1.02[5.07], p = 0.03). CONCLUSION: The addition of vitamin K1 to oral bisphosphonate with calcium and/or vitamin D treatment in PMO has a modest effect on parameters of hip geometry. Further confirmatory studies are needed. TRIAL REGISTRATION: The study was registered at Clinicaltrial.gov:NCT01232647.

A novel extraction method enhanced the osteogenic and anti-osteoporosis effect of tea extract without any hepatotoxicity in ovariectomized rats.

Tea (Camellia sinensis) has several reported health benefits, including that on bone health attributed to catechins of which the most abundant is epigallocatechin-3-gallate (EGCG). However, several preclinical and clinical studies raise safety concerns about EGCG in tea extract causing acute liver failure. Tea also contains kaempferol, albeit scanty, and it has hepatoprotective and osteogenic effects. Here, we utilized a novel extraction procedure of acid hydrolysis to enhance the osteogenic effect of tea extract while reducing its hepatotoxicity. The resultant extract (USKECSE) has a ~40-fold increase in kaempferol and a 2.5-fold reduction in EGCG content compared with the hydroethanolic extract (USCSE). In a female Sprague Dawley (SD) rat femur osteotomy model, USKECSE (100 mg/kg) but not USCSE promoted bone regeneration. In a rat postmenopausal osteoporosis model induced by bilateral ovariectomy (OVX), USKECSE through an osteogenic mechanism maintained bone mass, strength, and microarchitecture to the levels of ovary-intact rats with no hepatotoxic effect. After a single oral dose (100 mg/kg) of USKECSE to adult rats, kaempferol was detectable for 48 hours, suggesting its significant absorption and distribution in plasma. Peak kaempferol concentration in plasma (Cmax) was 483 ng/ml (2 µM), and at this concentration, kaempferol induces osteoblast differentiation. USKECSE had no genotoxicity, and its safety index assessed by preclinical toxicity studies, including safety pharmacology, was >20-fold. Taken together, we report a novel extraction process that enhanced the osteogenicity and concomitantly reduced hepatotoxicity of tea extract with significant kaempferol bioavailability and a favorable systemic safety profile. Based on these data, we propose assessing the USKECSE effect for postmenopausal osteoporosis treatment.

Osteoporosis risk group: Screening for osteoporosis in dental clinics using panoramic radiographs.

Osteoporosis is a specific condition which is characterized by low bone mineral density (BMD) and deterioration of bone structure resulting in an increased susceptibility to fractures. It contributes to a great deal of morbidity and mortality, and is a large burden to the healthcare system, especially in the case of the elderly population. In the last four decades, a plethora of studies have reported characteristic oral radiographic findings in the early stages of osteoporosis, suggesting the possible use of oral radiographic signs for the early detection of the condition. Digital orthopantomographs (OPGs) are usually taken for the screening of dental patients during routine dental evaluations. These radiographs and the characteristic changes seen on them may have a significant role in the screening for initial osteoporotic changes. A number of precise radiomorphometric indices of the mandible have also been developed to allow quantification of the mandibular bone mass for identification of the initial signs of osteoporosis. The present review focuses on the possible role of panoramic radiographs in the initial screening for osteoporosis in dental clinics in high-risk groups.

Elevated lncRNA MIAT in peripheral blood mononuclear cells contributes to post-menopausal osteoporosis.

Inflammatory cytokines contribute to the development of osteoporosis with sophisticated mechanisms. Globally alteration of long-chain non-coding RNA was screened in osteoporosis, while we still know little about their functional role in the inflammatory cytokine secretion. In this study, we collected the peripheral blood mononuclear cells (PBMCs) from post-menopausal osteoporosis patients to measure lncRNA MIAT (lncMIAT) expression levels, and explored the molecular mechanism of lncMIAT induced inflammatory cytokine secretion. We identified increased lncMIAT expression in the PBMCs of post-menopausal osteoporosis patients, which was an important predictive biomarker for the diagnosis. LncMIAT expression in PBMCs was positively correlated with the inflammatory cytokine secretion. Mechanism study indicated that lncMIAT increased the expression levels of p38MAPK by crosstalk with miR-216a in PBMCs. The lncMIAT/miR-216a/p38MAPK signaling contributed predominantly to the increased inflammatory cytokine secretion in the PBMCs from postmenopausal osteoporosis. In conclusion, we identified that increased lncMIAT in PBMCs induced inflammatory cytokine secretion, which contributed to the development of post-menopausal osteoporosis. lncMIAT/miR-216a axis was critical for the regulation of AMPK/p38MAPK signaling, which may be a promising therapeutic target for osteoporosis treatment by inflammatory cytokine inhibition.

Exploring the bone sparing effects of postbiotics in the post-menopausal rat model.

BACKGROUND: Post-menopausal osteoporosis is a concern of health organizations, and current treatments do not seem enough. Postbiotics as bioactive compounds produced by probiotics may be an attractive alternative for bone health. In this study, we prepared, formulated, and compared the effects of cell lysate and supernatant of five native probiotic strains (Lactobacillus acidophilus, Lactobacillus reuteri, Lactobacillus casei, Bifidobacterium longum, and Bacillus coagulans) in ovariectomized (OVX) rats. METHODS: The probiotic strains were isolated, and their cell-free supernatants and biomasses as postbiotics were extracted and formulated using standard microbial processes. The Sprague-Dawley rats were fed by 1 × 109 CFU/ml/day postbiotic preparations for 4 weeks immediately after ovariectomy. Dual-energy X-ray absorptiometry (DEXA) scans were accomplished to evaluate femur, spine, and tibia BMD. The serum biochemical markers [calcium, phosphorus, and alkaline phosphatase] were assessed. RESULTS: Postbiotics could considerably improve the global and femur area in OVX rats. In the case of global bone mineral density (BMD), Lactobacillus casei lysate and supernatant, Bacillus coagulans lysate and supernatant, lysate of Bifidobacterium longum and Lactobacillus acidophilus, and Lactobacillus reuteri supernatant significantly increased BMD. We found Bacillus coagulans supernatant meaningfully enriched tibia BMD. CONCLUSION: Postbiotic could ameliorate bone loss resulting from estrogen deficiency. Also, the effects of postbiotics on different bone sites are strain-dependent. More clinical studies need to explore the optimal administrative dose and duration of the specific postbiotics in protecting bone loss.

Agastache rugosa ethanol extract suppresses bone loss via induction of osteoblast differentiation with alteration of gut microbiota.

PURPOSE: Osteoporosis is a metabolic skeletal disease characterized by bone loss and an increased risk of fractures. This study aimed to investigate the therapeutic effect of Agastache rugosa on postmenopausal osteoporosis and elucidate its mechanisms in modulating the bone status. METHODS AND RESULTS: In the osteoblast differentiation process with MC3T3-E1 pre-osteoblasts, ethanol extract of Agastache rugosa (EEAR) and its compounds increased the expression of the proteins and genes of the osteoblast differentiation-related markers such as Runt-related transcription factor 2 (RUNX2) and ß-catenin along with the elevation of calcium deposits. An ovariectomized mouse model was utilized to determine the impact of EEAR extract on postmenopausal osteoporosis. Twelve weeks of AR treatment suppressed the loss of bone strength, which was observed through micro-computed tomography. AR elevated osteogenic markers in the bone marrow cells, and collagen type 1 alpha 1 in the distal femoral bone. The results of the 16S rRNA gene sequencing analysis of cecal gut microbiomes demonstrated that AR reversed the ovariectomy-induced changes in the gut microbiomes. CONCLUSION: Ethanol extract of Agastache rugosa has a therapeutic effect on postmenopausal osteoporosis via bone morphogenic protein, transforming growth factor ß, and Wnt signaling pathway. It also increases the diversity of gut microbiota. Therefore, these data suggest that EEAR could be a potential candidate to treat postmenopausal osteoporosis.