Anti-osteoporosis Drugs Research Articles

Management of Osteoporosis in Women with Breast Cancer

The screening, prevention and treatment of osteoporosis are similar in women with or without breast cancer. Breast cancer treatments, such as aromatase inhibitors, chemotherapy-induced ovarian failure and gonadotropin-releasing hormone antagonists all decrease estrogen levels, which in turn causes net bone resorption and bone loss. Bone loss over time will be of sufficient magnitude to cause some women to experience fractures. Thus, osteoporosis is an equation; the peak bone mass achieved by age 30 years minus the age-related and menopausal bone loss. Women should have their bone density measured by dual x-ray absorptiometry scans every 2 years. As clinically indicated, women should receive anti-osteoporosis drugs such as zoledronic acid, denosumab or oral bisphosphonates.

Ganoderma lucidum Immune Modulator Protein rLZ-8 Could Prevent and Reverse Bone Loss in Glucocorticoids-Induced Osteoporosis Rat Model.

Immune modulation has been recognized as an effective anti-osteoporosis strategy since the pivotal role of the RANK/RANKL/OPG signaling in bone metabolism and remodeling was discovered. To investigate the potential preventive and/or therapeutic effects of immune modulator protein Ling Zhi-8 (LZ-8) on osteoporosis, the osteoporosis animal model was established in Wistar rats by intramuscular injection of dexamethasone (DEX), namely glucocorticoids-induced osteoporosis (GIOP) rat model. To investigate the potential preventive effect of rLZ-8 on GIOP, we co-treated the rats with DEX and rLZ-8 intraperitoneally during the GIOP modeling stage and analyze the bone mass measured by bone mineral content (BMC) and bone mineral density (BMD), as well as levels of phosphorus (Pi), calcium (Ca2+) and hydroxyproline (HOP) in femur of GIOP rats. Consistently, all results suggested that rLZ-8 could prevent bone loss in the femurs of GIOP rats. Through analyzing the trabeculae morphology and the trabeculae amount by H&E staining, we found rLZ-8 could also improve the structural deterioration in femurs of GIOP rats. In order to further verify the results and its mechanism obtained from bone analysis, multiple biomarkers, including minerals metabolism (Pi and Ca2+), bone formation markers (osteocalcin, ALP and IGF-1), bone resorption markers (TRACP5b, CTX-1 and HOP), cytokines (IL-1β, IL-6 and TNF-α), oxidative stress indicators (GSH-px, SOD and MDA) and hormone molecules (testosterone, estradiol, calcitonin and parathyroid hormone) have been detected in serum or urine of rats. Results of these biomarkers in serum or urine confirmed rLZ-8’s protective effect in GIOP. Through analyzing the relative expression level of OPG and RANKL in femurs via western blot, we foundrLZ-8 could increase OPG/RANKL ratio which could impede osteoclastogenesis process. To test the potential therapeutic effect of rLZ-8 on successfully generated GIOP rats, we administrated rLZ-8 to rats for three weeks starting from the ending day of 7 weeks treatment of DEX. We found rLZ-8 could also reverse the bone loss in GIOP rats. Through the BWs and organ coefficient analysis, we found rLZ-8 has little toxicity to the rats. Our results suggested that rLZ-8 may be developed into promising anti-osteoporosis drug with both preventive and therapeutic properties.

Primary Osteoporosis Management by the Marche Region Health Care System

Osteoporosis is an illness that affects the skeleton and is characterized by progressive loss of bone mass as well asby micro architectural deterioration of bone tissue of the same. This condition exposes the person to fracture risk, aparticularly feared event not only in terms of individual health but even in terms of economic burden. The fractures,in fact, are accompanied by autonomy loss, institutionalization risk, comorbidity and mortality. On an economic level,the reduction of the same absorbs many more resources than anti-osteoporosis drug therapies even in the event thatall patients are reached with ascertained osteoporosis and with 100% adherence to medication. In the elderly, in addition to incurring in loss of bone density risk there is an increase of fall risk. Both of these factors add up causing anincrease of fracture risk. Due to the demographic increase and life expectancy, osteoporosis and fracturing events willtend to increase, causing an increase in costs. Today, the data collected in Italy regarding osteoporosis prevalenceand fragility fractures incidences are not entirely exhaustive. Concerning fractures, data is reliably collected usingthe “Diagnosis Related Group Classification” and refers to those of the femur.Detect and describe the pathway that the patient with primary osteoporosis follows in the Marche Region.Through the regional Single Booking Center (CUP) and the websites of the Italian League of Osteoporosis (LIOS)and the Italian Society of Osteoporosis, Mineral Metabolism and Skeleton Diseases (SIOMMMS), eleven serviceshave been identified, belonging to the four health care companies of the Marche Region (Asur, Inrca-Irccs, AO Ospedali Riuniti Marche Nord, AOU Ospedali Riuniti Ancona), which can be contacted for an osteoporosis checkup. Aquestionnaire was therefore prepared based on the recommendations contained in the SIOMMMS (2012), SIMFERand SIGN (2015) guidelines and sent to the above-mentioned services. The questionnaires are seven, duly completedand used for processing data.In the Marche Region, the medical specialties that deal with osteoporosis are various, demonstrating the fact that thisis a “border illness”. Concerning the interception of the patient, his sending to a specialized service, the diagnosticapproach and the use of risk-scoring tools, there is a substantial homogeneity throughout the regional territory. Thepatient is sent to the specialized center by the general practitioner (GP) or other specialist, based on the presence ofrisk factors for osteoporosis alone or on the basis of their presence in association with BMD measurement (body massdensity measurement) already known. For the purposes of diagnosis, the investigations required are the dual-energyx-ray absorptiometry (DXA) and the blood test while the use of risk-scoring tools are mainly dictated by the need todefine the threshold of pharmacological intervention and give the patient perception of its own fracture risk. The mostused algorithm is DeFRA. During the evaluation of the patient, all services detect pain and fall risk.The approach to osteoporosis and fall risk is purely pharmacological. From a non-pharmacological point of view,attention is paid in informing the patient about the modifiable risk factors for osteoporosis and falls. Only some services carry out interventions aimed at promoting adherence to treatment, resorting to different actions. In conclusion,the main critical issues relating to taking care of a fracture risk patient are: accessibility to information, early andexhaustive interception of the population at risk, detection of the fracture risk in relation to bone demineralizationand fall risk, adherence to therapy

Primary Osteoporosis Management by the Marche Region Health Care System

Osteoporosis is an illness that affects the skeleton and is characterized by progressive loss of bone mass as well as by micro architectural deterioration of bone tissue of the same. This condition exposes the person to fracture risk, a particularly feared event not only in terms of individual health but even in terms of economic burden. The fractures, in fact, are accompanied by autonomy loss, institutionalization risk, comorbidity and mortality. On an economic level, the reduction of the same absorbs many more resources than anti-osteoporosis drug therapies even in the event that all patients are reached with ascertained osteoporosis and with 100% adherence to medication. In the elderly, in addition to incurring in loss of bone density risk there is an increase of fall risk. Both of these factors add up causing an increase of fracture risk. Due to the demographic increase and life expectancy, osteoporosis and fracturing events will tend to increase, causing an increase in costs. Today, the data collected in Italy regarding osteoporosis prevalence and fragility fractures incidences are not entirely exhaustive. Concerning fractures, data is reliably collected using the "Diagnosis Related Group Classification" and refers to those of the femur. Detect and describe the pathway that the patient with primary osteoporosis follows in the Marche Region. Through the regional Single Booking Center (CUP) and the websites of the Italian League of Osteoporosis (LIOS) and the Italian Society of Osteoporosis, Mineral Metabolism and Skeleton Diseases (SIOMMMS), eleven services have been identified, belonging to the four health care companies of the Marche Region (Asur, Inrca-Irccs, AO Ospedali Riuniti Marche Nord, AOU Ospedali Riuniti Ancona), which can be contacted for an osteoporosis checkup. A questionnaire was therefore prepared based on the recommendations contained in the SIOMMMS (2012), SIMFER and SIGN (2015) guidelines and sent to the above-mentioned services. The questionnaires are seven, duly completed and used for processing data. In the Marche Region, the medical specialties that deal with osteoporosis are various, demonstrating the fact that this is a "border illness". Concerning the interception of the patient, his sending to a specialized service, the diagnostic approach and the use of risk-scoring tools, there is a substantial homogeneity throughout the regional territory. The patient is sent to the specialized center by the general practitioner (GP) or other specialist, based on the presence of risk factors for osteoporosis alone or on the basis of their presence in association with BMD measurement (body mass density measurement) already known. For the purposes of diagnosis, the investigations required are the dual-energy x-ray absorptiometry (DXA) and the blood test while the use of risk-scoring tools are mainly dictated by the need to define the threshold of pharmacological intervention and give the patient perception of its own fracture risk. The most used algorithm is DeFRA. During the evaluation of the patient, all services detect pain and fall risk. The approach to osteoporosis and fall risk is purely pharmacological. From a non-pharmacological point of view, attention is paid in informing the patient about the modifiable risk factors for osteoporosis and falls. Only some services carry out interventions aimed at promoting adherence to treatment, resorting to different actions. In conclusion, the main critical issues relating to taking care of a fracture risk patient are: accessibility to information, early and exhaustive interception of the population at risk, detection of the fracture risk in relation to bone demineralization and fall risk, adherence to therapy.

Osteoblastic and anti-osteoclastic activities of strontium-substituted silicocarnotite ceramics: In vitro and in vivo studies

Osteoporosis bone defect is a refractory orthopaedic disease which characterized by impaired bone quality and bone regeneration capacity. Current therapies, including antiosteoporosis drugs and artificial bone grafts, are not always satisfactory. Herein, a strontium-substituted calcium phosphate silicate bioactive ceramic (Sr-CPS) was fabricated. In the present study, the extracts of Sr-CPS were prepared for in vitro study and Sr-CPS scaffolds were used for in vivo study. The cytocompatibility, osteogenic and osteoclastogenic properties of Sr-CPS extracts were characterized in comparison to CPS. Molecular mechanisms were also evaluated by Western blot. Sr-CPS extracts were found to promote osteogenesis by upregulating Wnt/β-catenin signal pathways and inhibit osteoclastogenesis through downregulating NF-κB signal pathway. In vivo, micro-CT, histological and histomorphometric observation were conducted after 8 weeks of implantation to evaluate the bone formation using calvarial defects model in ovariectomized rats. Compared with CPS, Sr-CPS significantly promoted critical sized ovariectomy (OVX) calvarial defects healing. Among all the samples, Sr-10 showed the best performance due to a perfect match of bone formation and scaffold degradation rates. Overall, the present study demonstrated that Sr-CPS ceramic can dually modulate both bone formation and resorption, which might be a promising candidate for the reconstruction of osteoporotic bone defect.

Sodium alendronate loaded poly(l-lactide- co-glycolide) microparticles immobilized on ceramic scaffolds for local treatment of bone defects

Bone tissue regeneration in critical-size defects is possible after implantation of a 3D scaffold and can be additionally enhanced once the scaffold is enriched with drugs or other factors supporting bone remodelling and healing. Sodium alendronate (Aln), a widely used anti-osteoporosis drug, exhibits strong inhibitory effect on bone resorption performed by osteoclasts. Thus, we propose a new approach for the treatment of bone defects in craniofacial region combining biocompatible titanium dioxide scaffolds and poly(l-lactide-co-glycolide) microparticles (MPs) loaded with Aln. The MPs were effectively attached to the surface of the scaffolds’ pore walls by human recombinant collagen. Drug release from the scaffolds was characterized by initial burst (24 ± 6% of the drug released within first 24 h) followed by a sustained release phase (on average 5 µg of Aln released per day from Day 3 to Day 18). In vitro tests evidenced that Aln at concentrations of 5 and 2.5 µg/ml was not cytotoxic for MG-63 osteoblast-like cells (viability between 81 ± 6% and 98 ± 3% of control), but it prevented RANKL-induced formation of osteoclast-like cells from macrophages derived from peripheral blood mononuclear cells, as shown by reduced fusion capability and decreased tartrate-resistant acid phosphatase 5b activity (56 ± 5% reduction in comparison to control after 8 days of culture). Results show that it is feasible to design the scaffolds providing required doses of Aln inhibiting osteoclastogenesis, reducing osteoclast activity, but not affecting osteoblast functions, which may be beneficial in the treatment of critical-size bone tissue defects.

Effects of anti-osteoporosis drugs against dexamethasone-induced osteoporosis-like phenotype using a zebrafish scale-regeneration model

There are several animal models of glucocorticoid-induced osteoporosis (GIOP), but each requires a long time to evaluate drug effects. Zebrafish scales are classified as dermal bone and potentially represent a convenient animal model of GIOP because they rapidly regenerate following their removal. We clarified that dexamethasone-treated regenerating scales showed malformations, decreased size and circularity. Anti-osteoporosis drugs rescued the scale malformation phenotype eight-days following the removal of scales. Hence, the dexamethasone-induced regenerating scale malformation model may be a useful animal model for discovering drugs to treat GIOP.

Osthole-loaded N-octyl-O-sulfonyl chitosan micelles (NSC-OST) inhibits RANKL-induced osteoclastogenesis and prevents ovariectomy-induced bone loss in rats.

Osthole (OST), a derivative of Fructus Cnidii, has been proved to have potential anti‐osteoporosis effects in our recent studies. However, its pharmacological effects are limited in the human body because of poor solubility and bioavailability. Under the guidance of the classical theory of Chinese medicine, Osthole‐loaded N‐octyl‐O‐sulfonyl chitosan micelles (NSC‐OST), which has not previously been reported in the literature, was synthesized in order to overcome the defects and obtain better efficacy. In this study, we found that NSC‐OST inhibited on the formation and resorption activity of osteoclasts through using a bone marrow macrophage (BMM)‐derived osteoclast culture system in vitro, rather than affecting the viability of cells. We also found that NSC‐OST inhibited osteoclast formation, hydroxyapatite resorption and RANKL‐induced osteoclast marker protein expression. In terms of mechanism, NSC‐OST suppressed the NFATc1 transcriptional activity and the activation of NF‐κB signalling pathway. In vivo, ovariectomized (OVX) rat models were established for further research. We found that NSC‐OST can attenuate bone loss in OVX rats through inhibiting osteoclastogenesis. Consistent with our hypothesis, NSC‐OST is more effective than OST in parts of the results. Taken together, our findings suggest that NSC‐OST can suppress RANKL‐induced osteoclastogenesis and prevents ovariectomy‐induced bone loss in rats and could be considered a safe and more effective anti‐osteoporosis drug than OST.

Surgical choice of posterior osteotomy way for senile osteoporotic thoracolumbar fracture with kyphosis

To investigate the surgical choice of posterior osteotomy way by the observation of clinical outcome of Smith-Petersen osteotomy (SPO), pedicle subtraction osteotomy (PSO) and vertebral column re-section (VCR) for senile osteoporotic thoracolumbar fracture with kyphosis. From June 2015 to August 2017, an amount of 8 elderly patients with thoracolumbar kyphosis caused by osteoporotic vertebral fracture underwent osteotomy approach for posterior osteotomy. All patients were old osteoporotic vertebral fracture more than 6 months and received invalid conservative treatment for 3 months including nonsteroidal anti-inflammatory and analgesic drugs, anti-osteoporosis drugs and acupuncture, etc. There were 3 males and 5 females, with an average age of 73.4 years (66 to 83 years), with an average course of the disease of 34.6 months (8 to 60 months). Eight patients had a total of 8 vertebral fractures, and fracture segment was in T10 of 1 case, T11 of 1 case, T12 of 3 cases, L1 of 2 cases, L2 of 1 case. Eight patients showed kyphosis caused by wedge deformation of single segmental vertebral fractures. The thoracolumbar kyphosis and symptoms were progressively developing into central sagittal imbalance. SPO osteotomy was performed in 3 cases, PSO osteotomy in 3 cases, and VCR osteotomy in 2 cases. Orthopaedic effects were analyzed by imaging measurements, including pre- and post-operative kyphosis Cobb angle, localized kyphosis (LK), thoracic kyphosis (TK), lumbar lordosis (LL), sacral tilt angle (ST) and sagittal vertical axis (SVA). Visual analogue scale (VAS) and Oswestry Disability Index (ODI) were used to evaluate the pain and lumbar function. All the eight patients were followed up from 8 to 24 months with an average of 13.5 months and all the symptoms of low back pain have significantly reduced or disappeared. The VAS score decreased from 5-8 points (mean 6.5 points) before surgery to 1-4 points (mean 1.88 points) at the final follow-up, and the score was significantly improved. The ODI score decreased from 36-78 points (mean 60.25 points) before surgery to 10-32 points (mean 20.38 points) at the final follow-up, and the functional score improved significantly. During the follow-up period, X-ray examination showed that some patients had a slight decrease in the height of the intervertebral fusion, and the bone graft was healed. There was no obvious corrected degree loss and internal fixation loosening, and the thoracolumbar kyphosis was significantly improved. The mean Cobb angle of T10-L2 was reduced from 25.3° to 2.8° with corrected rate of 89.3% ; LK was reduced from 43.4° to 7.1° with corrected rate of 86.2% ; TK was reduced from 49.9° to 30.6°, LL was reduced from 43.6° to 30.8°, and ST was changed from 24.0° to 32.1°, SVA was changed from 6.23 cm to 2.40 cm. For the different pathological features and deformities of senile osteoporotic thoracolumbar fracture combined with kyphosis, SPO, PSO or VCR can achieve good orthopedic effect and clinical efficacy.

Oral Bisphosphonate Use and All-Cause Mortality in Patients With Moderate-Severe (Grade 3B-5D) Chronic Kidney Disease: A Population-Based Cohort Study.

Oral bisphosphonates (oBPs) have been associated with reduced fractures and mortality. However, their risks and benefits are unclear in patients with moderate-severe CKD. This study examined the association between oBPs and all-cause mortality in G3B-5D CKD. This is a population-based cohort study including all subjects with an estimated glomerular filtration rate (eGFR) <45/mL/min/1.73 m2 (G3B: eGFR <45/mL/min/1.73 m2 G4: eGFR 15-29/mL/min/1.73 m2 G5: eGFR <15/mL/min/1.73 m2 G5D: hemodialysis) aged 40+ years from the UK Clinical Practice Research Datalink (CPRD) and the Catalan Information System for Research in Primary Care (SIDIAP). Previous and current users of other anti-osteoporosis drugs were excluded. oBP use was modeled as a time-varying exposure to avoid immortal time bias. Treatment episodes in oBP users were created by concatenating prescriptions until patients switched or stopped therapy or were censored or died. A washout period of 180 days was added to (date of last prescription +180 days). Propensity scores (PSs) were calculated using prespecified predictors of mortality including age, gender, baseline eGFR, socioeconomic status, comorbidities, previous fracture, co-medications, and number of hospital admissions in the previous year. Cox models were used for PS adjustment before and after PS trimming (the first and last quintiles). In the CPRD, of 19,351 oBP users and 210,954 non-oBP users, 5234 (27%) and 85,105 (40%) deaths were recorded over 45,690 and 915,867 person-years of follow-up, respectively. oBP users had 8% lower mortality risk compared to non-oBP users (hazard ratio [HR] 0.92; 95% CI, 0.89 to 0.95). Following PS trimming, this became nonsignificant (HR 0.98; 95% CI, 0.94 to 1.04). In the SIDIAP, of 4146 oBP users and 86,127 non-oBP users, 1330 (32%) and 36,513 (42%) died, respectively. oBPs were not associated with mortality in PS adjustment and trimming (HR 1.04; 95% CI, 0.99 to 1.1 and HR 0.95; 95% CI, 0.89 to 1.01). In this observational, patient-based cohort study, oBPs were not associated with increased mortality among patients with moderate-severe CKD. However, further studies are needed on other effects of oBPs in CKD patients. © 2020 American Society for Bone and Mineral Research.

Construction of multilayered molecular reservoirs on a titanium alloy implant for combinational drug delivery to promote osseointegration in osteoporotic conditions

In this study, β-cyclodextrin (β-CD) molecules are used as molecular reservoirs and grafted onto chitosan molecules for calcitriol (VD3) loading, which is a hormonally active metabolite of vitamin D. The resultant molecular complex is co-assembled with an antiosteoporosis drug calcitonin (CT) to form bio-functional multilayer structure on Ti6Al7Nb substrate via layer-by-layer self-assembly, which is capable of releasing VD3 and calcitonin in a sustained manner to modulate osteoblasts, osteoclasts, and macrophages at the bone-implant interface. In vitro results show that the released VD3 and CT individually upregulated the expression of calcium-binding protein (including Calbindin D9k and Calbindin D28k) and BMP2 in osteoblasts in peri-implant regions to stimulate their Ca deposition and differentiation. RAW264.7 cells (a murine macrophage) on the biofunctional implant displayed improved M2 phenotypical differentiation and expression of BMP2 and VEGF genes, but M1 phenotypical differentiation potential and MCF and TRAP gene expression levels are evidently lower. Results from in vivo micro-CT and histological analysis also demonstrate that VD3/CT co-loaded implant can dramatically enhance the bone remodeling under osteoporotic conditions with significantly enhanced interfacial shear strength and improved osseointegration as compared to other groups. The insights in this study offer new avenues for the rational functionalization of titanium implants to effectively repair osteoporotic fractures. Statement of SignificanceA promising strategy to enhance the recovery rate of osteoporotic fractures is to immobilize antiosteoporotic drugs onto the surface of titanium-based implants. In this study, we grafted beta-cyclodextrin (β-CD) onto chitosan (Chi) molecules to load VD3, which was co-assembled with calcitonin (CT) onto Ti6Al7Nb implants by the layer-by-layer assembly technique. The obtained functional titanium alloy implant (Ti6Al7Nb/LBL/Chi-CD@VD3/ CT) could stably release VD3 and calcitonin agents in a sustained manner. RAW264.7 cells grown on Ti6Al7Nb/LBL/Chi-CD@VD3/CT showed superior M2 phenotypical differentiation efficiency, but lower MCF/TRAP gene expression levels. In vitro and in vivo results showed that the released VD3 and CT individually upregulated the expression of calcium binding proteins and BMP2 in osteoblasts, promoting new bone formation in the peri-implant region.

Self-sacrificial MOFs for ultra-long controlled release of bisphosphonate anti-osteoporotic drugs.

In this paper we report drug delivery systems that are based on phosphonate MOFs. These employ biologically-acceptable metal ions (e.g. Ca2+ and Mg2+) and several anti-osteoporosis bisphosphonate drugs (etidronate, pamidronate, alendronate and neridronate), as the organic linkers. These materials have been synthesized, structurally characterized, and studied for the self-sacrificial release (by pH-driven dissolution) of the bisphosphonate active ingredient. They exhibit variable release rates and final % release, depending on the actual structure of the metal-bisphosphonate material. Their cytotoxicity profiles match those of the active ingredients.

Current status of anti-osteoporosis drug utilization for hip fracture

Current status of anti-osteoporosis drug utilization for hip fracture

In Vitro Antiosteoporosis Activity and Hepatotoxicity Evaluation in Zebrafish Larvae of Bark Extracts of Prunus jamasakura Medicinal Plant.

Osteoporosis is one of the main health problems in the world today characterized by low bone mass and deterioration in bone microarchitecture. In recent years, the use of natural products approach to treat it has been in the increase. In this study, in vitro antiosteoporosis activity and hepatotoxicity of P. jamasakura bark extracts were evaluated. Methods. Mouse bone marrow macrophage (BMM) cells were incubated with tartrate-resistant acid phosphate (TRAP) buffers and p-nitrophenyl phosphate and cultured with different P. jamasakura bark extracts at concentrations of 0, 6.25, 12.5, 25, and 50 μg/ml in the presence of the receptor activator of nuclear factor kappa-Β ligand (RANKL) for 6 days. The osteoclast TRAP activity and cell viability were measured. Nitric oxide (NO) assay was conducted using murine macrophage-like RAW 264.7 cells treated with P. jamasakura ethanolic and methanolic bark extracts at concentrations of 0, 6.25, 12.5, 25, 50, 100, and 200 μg/ml. For hepatotoxicity assessment, zebrafish larvae were exposed to P. jamasakura bark extracts, 0.05% dimethyl sulfoxide as a negative control, and 5 μM tamoxifen as a positive control. The surviving larvae were anesthetized and assessed for hepatocyte apoptosis. Results. TRAP activity was significantly inhibited (p < 0.001) at all concentrations of P. jamasakura extracts compared to the control treatment. At 50 μg/ml, both ethanolic and methanolic extracts of P. jamasakura exhibited significant (p < 0.01) BMM cell viability compared to the control treatment. P. jamasakura ethanolic and methanolic extracts had significant inhibitory (p < 0.01) effects on lipopolysaccharide (LPS)-induced NO production at 200 μg/ml and exhibited significant (p < 0.01) and (p < 0.05) stimulative effects, respectively, on RAW 264.7 cell viability. No overt hepatotoxicity was observed in the liver of zebrafish larvae in any of the treatments. Conclusion. The TRAP activity of P. jamasakura bark gives a foundation for further studies to enhance future development of antiosteoporosis drug.

Therapeutic effect of percutaneous kyphoplasty combined with anti-osteoporosis drug on postmenopausal women with osteoporotic vertebral compression fracture and analysis of postoperative bone cement leakage risk factors: a retrospective cohort study

BackgroundThe purpose of this study is to explore the therapeutic effect of percutaneous kyphoplasty (PKP) combined with anti-osteoporosis drug, zoledronic acid, on postmenopausal women with osteoporotic vertebral compression fracture (OVCF) and to perform an analysis of postoperative bone cement leakage risk factors.MethodsA total of 112 OVCF patients, according to therapeutic regimens, were divided into control group (n = 52, treated with PKP) and observation group (n = 60, treated with PKP and zoledronic acid injection).ResultsPostoperative tumor necrosis factor-α and interleukin-6 levels were significantly decreased in the two groups, compared with those before treatment (both P < 0.05); bone mineral density (BMD), serum bone gla protein (BGP), and vertebral height ratio of injured vertebrae were significantly increased, and procollagen type I N-terminal propeptide (PINP), Cobb angle, visual analogue scale/score (VAS), and Oswestry disability index (ODI) were significantly decreased compared with those before treatment (all P < 0.05). There were significantly higher changes in difference value of BMD, PINP, BGP, vertebral height ratio of injured vertebrae, Cobb angle, VAS, and ODI levels and significantly better therapeutic effect in the observation group than those in the control group (all P < 0.05). Multivariate logistic regression analysis showed that the use of zoledronic acid, vertebral height ratio of injured vertebrae, and ODI were independent factors affecting the therapeutic effect, and that the dosage of bone cement, and peripheral vertebrae wall damage were independent risk factors causing postoperative bone cement leakage. There were no significant differences in postoperative bone cement leakage rate between the two groups.ConclusionsPeripheral vertebrae wall damage and the dosage of bone cement are independent risk factors causing bone cement leakage in OVCF patients treated with PKP. PKP combined with zoledronic acid has an improvement effect on the condition of postmenopausal women with OVCF and reduces the inflammation and pain in patients, which is beneficial to clinical treatment.

Simultaneous determination of illegal drug substances in dietary supplements for gout and osteoporosis using ultra-performance liquid chromatography and liquid chromatography-quadrupole-time-of-flight mass spectrometry

The aim of this study was to simultaneously determine the presence of unauthorized drug substances in health foods and herbal products used in the treatment of conditions such as gout and anti-osteoporosis. Therefore, we developed and optimised a rapid and accurate method to simultaneously measure 20 anti-gout and anti-osteoporosis drug substances using an ultra-high-performance liquid chromatography (UPLC) system equipped with a photodiode array (PDA) detector. The method was validated to fully meet internationally accepted standards. LODs and LOQs spiked in solid and liquid negative samples were ranged from 0.12 to 1.50 μg/mL, and ranged from 0.36 to 4.50 μg/mL. Linearities (R2> 0.999), stabilities (RSD ≤ 2.92%), accuracies (84.25∼106.62%, intra-day; 84.56∼105.85%, inter-day), precisions (RSD ≤ 3.71% on the intra-day; RSD ≤ 3.47% on the inter-day), recoveries spiked in various type of blank samples such as powder, liquid, tablet, and capsule were determined within 81.20–116.20 %, respectively. From a confirmation of matrix effects (88.06∼110.50% in solid blank; 89.16∼110.52% in liquid blank), it was confirmed that this method was not significantly affected by a sample matrix. The validated method was used to analyse 116 samples containing health foods, herbal products, and seized forensic samples advertised to be effective anti-gout and anti-osteoporosis agents. Of the 20 drug substances screened, dexamethasone was detected and confirmed by comparing the tandem mass spectrometry (MS/MS) fragment ion patterns of a reference standard and the sample using LC-quadrupole-time-of-flight (Q-TOF)/MS. The concentrations of adulterants in seized forensic samples ranged from 0.013 to 0.022 %.

Inequalities in prescription rates of anti-osteoporosis drugs in primary care in England: A practice-level prescribing data analysis in 2013-2018.

To investigate potential variations in prescription rates of anti-osteoporosis drugs at the general practitioner (GP) practice level in England, analysing associations of prescription rates with key demographic and socio-economic variables, and its evolution over time. A retrospective database analysis was conducted using prescription data from all GP practices in England between April 2013 and September 2018. Potential associations between prescription rates and other variables (sex, age, ethnicity, rural-urban classification and income deprivation) were analysed using mixed-effects Poisson regressions and concentration indices. Alendronic acid was the most frequently prescribed anti-osteoporosis drug. Exploratory and regression analyses showed the association between GP prescriptions and the characteristics of the population they serve. Income deprivation had a statistically significant and negative effect on prescription levels of alendronic acid, denosumab, ibandronic acid and risedronate sodium. Since 2013, denosumab prescriptions exhibited a steep surge in the least income-deprived areas, compared with a modest rise in the most income-deprived areas. Concentration indices indicated a disproportionate concentration of denosumab and, to a lesser extent, ibandronic acid prescriptions among the least income-deprived. The analyses demonstrated that different prescribing behaviours may exist across GPs according to the Clinical Commissioning Group (CCG) to which they belong. Variation in the prescription of anti-osteoporosis drugs exists across GPs and CCGs in England, this being more prominent for certain drugs (e.g. denosumab) compared with others (e.g. alendronic acid). Inequalities exist in English primary healthcare and we advocate our findings could support the efforts of decision-makers towards a more equitable system.

Osteoporosis: long-term treatment versus drug holiday-what is the evidence?

The occurrence of multiple vertebral fractures after discontinuation of denosumab in the treatment of osteoporosis has reopened the debate on the optimal treatment duration and drug holidays.In principle, there is a difference in this regard between the discontinuation of medications such as bisphosphonates and substances without bone retention such as selective estrogen receptor modulators (SERMs), denosumab or teriparatide. Even after the end of application bisphosphonates have avery long half-life in the bones. After cessation of drug intake there is a slow, slight increase of bone turnover markers. Even after cessation of the SERM raloxifene, a decline in bone density can be observed, as with the termination of teriparatide. In contrast to these osteoporosis medications, after cessation of denosumab, asteep and rapid increase in markers of bone resorption above baseline levels ("rebound") and a reduction in bone mineral density to initial values can be observed.Osteoporosis is a disease that carries an increased risk of fracture, which is reduced for the duration of osteoporosis treatment. In certain situations, the fracture risk is only temporarily raised. In these situations, cessation of the osteoporosis treatment is possible. Beyond these special clinical situations, however, osteoporosis needs to be addressed as achronic disease with a permanently increased fracture risk and the indication for therapy should be evaluated according to the extent of the risk of fracture.What happens after discontinuation of anti-osteoporosis drugs? The various effects on bone turnover markers, bone mineral density and fracture incidence of the individual drug groups are presented in detail, as are the resulting recommendations of the task forces of the American Society of Bone and Mineral Research (ASBMR) and the European Calcified Tissue Society (ECTS).

Potential risks of rare serious adverse effects related to long-term use of bisphosphonates: An overview of systematic reviews.

There have been concerns about a potential link between long-term use of bisphosphonates (BPs) for the treatment of osteoporosis and rare serious adverse effects, such as atypical femoral fractures. However, many reviews exist with conflicting conclusions about this issue. The aim of this overview of reviews was to systematically evaluate the risk of rare serious adverse effects of long-term use of BPs for the treatment of osteoporosis. We identified systematic reviews with meta-analyses of randomized controlled trials (RCTs) and (or) observational studies published in English or Chinese that evaluated the safety of BPs through to December 2018. The Cochrane library, PubMed, Web of Science and hand-searching of reference lists and clinical practice guidelines were electronically searched for data sources. Carcinogenicity, atypical fracture, osteonecrosis of jaw (ONJ) and fracture union time were specified as the primary outcomes. The methodological quality of each systematic review was assessed by two reviewers using the Assessment of Multiple Systematic Reviews (AMSTAR) tool, and the quality of evidence for key outcomes was assessed using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach. In total, 1376 potentially relevant citations were identified, of which only 8 systematic reviews with meta-analyses met the eligibility criteria. All the included reviews were published between 2012 and 2015 and documented the pooled estimates of effect size (relative risk [RR], odds ratio [OR] or hazard ratio [HR] and their 95% confidence intervals [95% CI]) for the incidence of adverse events. All included systematic reviews were of moderate or high quality. The median AMSTAR score was 7.5 (interquartile range, 5-10). However, evidence of the key outcomes was mainly of very low or moderate quality. BP treatment only increased the risk of atypical fracture and ONJ, and prolonged union time compared with placebo or other anti-osteoporosis drugs (P＜.05). This study indicated that long-term use of BPs could increase the risk of rare serious adverse effects, but the relationship between long-term use of BPs and carcinogenicity was often uncertain. Therefore, high-quality research and more complete inclusion criteria are needed.

Moderate osteoporosis itself is beneficial for bones

There have been increasing numbers of reports that anti-osteoporosis drugs cause osteonecrosis. A typical example is medication-related osteonecrosis of the jaws (MRONJ) which can cause massive necrosis and defects of the jaws. Thus, the dosage and effects of anti-osteoporosis drugs should be re-examined. Our hypothesis is that primary moderate osteoporosis itself is beneficial for bones and should not be excessively treated other than vitamin D, calcium supplementation and functional exercises. The self-repair and anti-infection abilities of bone depend on its organic tissues including stem cells, blood vessels, osteoclastic and osteogenic factors in bone, which jointly fight against invading pathogens and repair bone damage. Recent evidence supports age-related changes in mesenchymal stem cell including loss of self-renewal and increases in senescent cell numbers. Thus, the number of MSCs and vessels need to be increased to achieve functions similar to those in young people. This requires dissolving a portion of inorganic materials and providing extra space to hold more cells and blood vessels. In contrast, anti-osteoporosis drugs prevent bone destruction, and increase mineralization that occupies the space of organic materials, reduces bone immunity and self-repair. Moreover, long term use of anti-osteoporosis drugs also have negative effects on long bones and cartilages. Therefore, moderate age-related osteoporosis is natural in humans to protect bones. Excessive treatment of osteoporosis weakens immunity and self-repair.