Sustained Modeling‐Based Bone Formation During Adulthood in Cynomolgus Monkeys May Contribute to Continuous BMD Gains With Denosumab

Denosumab (DMAb) administration to postmenopausal women with osteoporosis is associated with continued bone mineral density (BMD) increases and low fracture incidence through 8 years, despite persistently reduced bone turnover markers and limited fluorochrome labeling in iliac crest bone biopsies. BMD increases were hypothesized to result from additional accrual of bone matrix via modeling‐based bone formation—a hypothesis that was tested by examining fluorochrome labeling patterns in sections from ovariectomized (OVX) cynomolgus monkeys (cynos) treated with DMAb for 16 months. Mature OVX or Sham cynos were treated monthly with vehicle for 16 months, whereas other OVX cynos received monthly 25 or 50 mg/kg DMAb. DMAb groups exhibited very low serum bone resorption and formation biomarkers and near‐absent fluorochrome labeling in proximal femur cancellous bone. Despite these reductions, femoral neck dual‐energy X‐ray absorptiometry (DXA) BMD continued to rise in DMAb‐treated cynos, from a 4.6% increase at month 6 to 9.8% above baseline at month 16. Further examination of cortical bone in the proximal femur demonstrated consistent and prominent labeling on the superior endocortex and the inferior periosteal surface, typically containing multiple superimposed labels from month 6 to 16 over smooth cement lines, consistent with continuous modeling‐based bone formation. These findings were evident in all groups. Quantitative analysis at another modeling site, the ninth rib, demonstrated that DMAb did not alter the surface extent of modeling‐based labels, or the cortical area bound by them, relative to OVX controls, while significantly reducing remodeling‐based bone formation and eroded surface. This conservation of modeling‐based formation occurred concomitantly with increased femoral neck strength and, when coupled with a reduction in remodeling‐based bone loss, is likely to contribute to increases in bone mass with DMAb treatment. Thus, this study provides preclinical evidence for a potential mechanism that could contribute to the clinical observations of continued BMD increases and low fracture rates with long‐term DMAb administration. © 2015 American Society for Bone and Mineral Research.     

Myelosuppressive Therapies Significantly Increase Pro‐Inflammatory Cytokines and Directly Cause Bone Loss

Skeletal‐related events resulting from accelerated bone loss are common complications in patients treated for a range of cancers. However, the mechanisms and rate of bone loss after myelosuppression are unclear. We, therefore, investigated this in mice and humans. We treated mice with different myelosuppressive therapies (chemotherapy or irradiation with or without transplantation) and studied their effects on bone structure. Myelosuppression of mice rapidly caused an increase in bone resorption that was not matched by bone formation. The resultant significant and persistent bone loss early after therapy was associated with increased inflammatory cytokines, in particular, monocyte chemoattractant protein 1 (MCP1). Therapy‐induced bone loss was prevented with a single dose of the bisphosphonate zoledronic acid (ZA), administered before myelosuppression. Importantly, ZA treatment of mice did not impair hematopoiesis, including hematopoietic stem cell function. Furthermore, examination of serum from patients before and after autologous or allogeneic stem cell transplantion (SCT) revealed altered levels of bone turnover markers and elevated inflammatory cytokines. MCP1 levels in serum obtained between days 7 and 14 post‐SCT positively correlated with bone loss observed at 100 days after allogeneic SCT. Similar to that observed in our studies in mice, the bone loss was long term, persisting at 12 months post‐SCT. Furthermore, patients who received chemotherapy less than 100 days before SCT had significantly more bone loss at the hip. In these patients, serum levels of MCP1, but not routine biomarkers of bone turnover, including C‐terminal cross‐linking telopeptide of type‐1 collagen (β‐CTx), positively correlated with their bone loss. Hence, myelosuppressive therapies increase inflammation and directly contribute to bone loss. Administration of an osteoclast inhibitor before the initiation of cancer therapy is likely to have the best outcome in preventing bone loss in patients with cancer. © 2014 American Society for Bone and Mineral Research.     

中医肿瘤疗效评价标准在晚期非小细胞肺癌的应用

[目的]探讨<实体瘤的中医肿瘤疗效评定(草案)>(简称<草案>)在中医药治疗晚期非小细胞肺癌(NSCLC)疗效评价应用中的客观性和全面性.[方法]采用回顾性临床时照研究方法,收集Ⅲ～Ⅳ期NSCLC病例共104例,其中中医组53例,西医组51例,同时采用<草案>和实体瘤疗效评价标准(RECIST) 对2组进行疗效评定,分析、比较两种不同标准评定的结果.[结果](1)按照<草案>标准,中医组瘤体缓解有效率明显低于西医组(P<0.05),瘤体稳定率2组无显著性差异(P>0.05);中医组乏力症状明显改善,疗效优于西医组(P<0.01);中医组卡氏评分疗效显著优于西医组(P<0.01);总疗效方面,中医组总有效率、总稳定率略高于西医组,.但无显著性差异(P>0.05).(2)生存情况方面,中医组中位生存期为(8.0 ±1.2)个月,半年、1年、2年生存率分别为60.38%、24.53%、3.77%.西医组中位生存期为(5.9±0.4)个月,半年、1年、2年生存率分别为41.18%、15.69%、1.96%. (3)两种标准评定结果.按照RECIST标准总有效率为9.62%,总稳定率为72.12%;按照<草案>标准总有效率为34.62%,总稳定率为84.62%.两种标准评定结果比较,差异有显著性意义(P<0.01).两种标准评定结果的一致性分析表明其评价结果存在一致性.但一致程度不够理想.[结论]以<草案>标准评价中医药治疗晚期NSCLC疗效,其结果能较好地反映中医疗效特点和优势,较之RECIST标准更为客观和全面,建议逐步完善后在临床推广应用.     

Lipopolysaccharide-Induced Bone Loss in Rodent Models: A Systematic Review and Meta-Analysis

Osteoporosis has traditionally been characterized by underlying endocrine mechanisms, though evidence indicates a role of inflammation in its pathophysiology. Lipopolysaccharide (LPS), a component of gram-negative bacteria that reside in the intestines, can be released into circulation and stimulate the immune system, upregulating bone resorption. Exogenous LPS is used in rodent models to study the effect of systemic inflammation on bone, and to date a variety of different doses, routes, and durations of LPS administration have been used. The study objective was to determine whether systemic administration of LPS induced inflammatory bone loss in rodent models. A systematic search of Medline and four other databases resulted in a total of 110 studies that met the inclusion criteria. Pooled standardized mean differences (SMDs) and corresponding 95% confidence intervals (CI) with a random-effects meta-analyses were used for bone volume fraction (BV/TV) and volumetric bone mineral density (vBMD). Heterogeneity was quantified using the I² statistic. Shorter-term (<2 weeks) and longer-term (>2 weeks) LPS interventions were analyzed separately because of intractable study design differences. BV/TV was significantly reduced in both shorter-term (SMD = −3.79%, 95% CI [−4.20, −3.38], I² 62%; p < 0.01) and longer-term (SMD = −1.50%, 95% CI [−2.00, −1.00], I² 78%; p < 0.01) studies. vBMD was also reduced in both shorter-term (SMD = −3.11%, 95% CI [−3.78, −2.44]; I² 72%; p < 0.01) and longer-term (SMD = −3.49%, 95% CI [−4.94, −2.04], I² 82%; p < 0.01) studies. In both groups, regardless of duration, LPS negatively impacted trabecular bone structure but not cortical bone structure, and an upregulation in bone resorption demonstrated by bone cell staining and serum biomarkers was reported. This suggests systemically delivered exogenous LPS in rodents is a viable model for studying inflammatory bone loss, particularly in trabecular bone. © 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).     

Sexing Bones: Improving Transparency of Sex Reporting to Address Bias Within Preclinical Studies

Despite knowledge that sexually dimorphic mechanisms regulate bone homeostasis, sex often remains unreported and unconsidered in preclinical experimental design. Failure to report sex could lead to inappropriate generalizations of research findings and less effective translation into clinical practice. Preclinical sex bias (preferential selection of one sex) is present across other fields, including neuroscience and immunology, but remains uninvestigated in skeletal research. For context, we first summarized key literature describing sexually dimorphic bone phenotypes in mice. We then investigated sex reporting practices in skeletal research, specifically how customary it is for murine sex to be included in journal article titles or abstracts and then determined whether any bias in sex reporting exists. Because sex hormones are important regulators of bone health (gonadectomy procedures, ie, ovariectomy [OVX] and orchidectomy [ORX], are common yet typically not reported with sex), we incorporated reporting of OVX and ORX terms, representing female and male mice, respectively, into our investigations around sex bias. Between 1999 and 2020, inclusion of sex in titles or abstracts was low in murine skeletal studies (2.6%–4.06%). Reporting of OVX and ORX terms was low (1.44%–2.64%) and reporting of OVX and ORX with sex uncommon (0.4%–0.3%). When studies were combined to include both sexes and OVX (representing female) and ORX terms (representing male), a bias toward reporting of female mice was evident. However, when the terms OVX and ORX were removed, a bias toward the use of male mice was identified. Thus, studies focusing on sex hormones are biased toward female reporting with all other studies biased in reporting of male mice. We now call upon journal editors to introduce consistent guidance for transparent and accessible reporting of murine sex in skeletal research to better monitor preclinical sex bias, to diversify development of treatments for bone health, and to enable global skeletal health equity. © 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).     

Sex-Specific Associations Between Cardiac Workload,Peripheral Vascular Calcification,and Bone Mineral Density: The Gambian Bone and Muscle Aging Study

Noncommunicable diseases (NCD) are rapidly rising in Africa, with multimorbidity increasing the burden on health and social care. Osteoporosis and cardiovascular disease (CVD) share common risk factors; both often remain undiagnosed until a major life-threatening event occurs. We investigated the associations between cardiac workload, peripheral vascular calcification (PVC), and bone parameters in Gambian adults. The Gambian Bone and Muscle Aging Study (GamBAS) recruited 249 women and 239 men aged 40 to 75+ years. Body composition and areal bone mineral density (aBMD) were measured using dual-energy X-ray absorptiometry; peripheral quantitative computed tomography (pQCT) scans were performed at the radius and tibia. Supine blood pressure and heart rate were measured and used to calculate rate pressure product and pulse pressure. Presence of PVC was determined from tibia pQCT scans. Sex interactions were tested (denoted as p-int); adjustments were made for residuals of appendicular lean mass (ALM) and fat mass (FM). There were negative associations between rate pressure product and aBMD in women only, all p-int < .05; after adjustment for ALM residuals, for every 10% increase in rate pressure product, aBMD was lower at the whole body (−0.6% [−1.2, −0.1]), femoral neck (−0.9% [−1.8, −0.05]), L₁ to L₄ (−0.6% [−1.7, 0.5]), and radius (−1.9% [−2.8, −0.9]); there were similar associations when adjusted for FM residuals. Similar negative associations were found between pulse pressure and aBMD in women only. PVC were found in 26.6% men and 22.5% women; women but not men with calcification had poorer cardiac health and negative associations with aBMD (all sites p-int < .001). There were consistent associations with cardiac parameters and pQCT outcomes at the radius and tibia in women only. Multiple markers of cardiac health are associated with poorer bone health in Gambian women. In the context of epidemiological transition and changing NCD burden, there is a need to identify preventative strategies to slow/prevent the rising burden in CVD and osteoporosis in Sub-Saharan Africa. © 2020 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).     

Impact of Genetic and Pharmacologic Inhibition of Myostatin in a Murine Model of Osteogenesis Imperfecta

Osteogenesis imperfecta (OI) is a genetic connective tissue disorder characterized by compromised skeletal integrity, altered microarchitecture, and bone fragility. Current OI treatment strategies focus on bone antiresorptives and surgical intervention with limited effectiveness, and thus identifying alternative therapeutic options remains critical. Muscle is an important stimulus for bone formation. Myostatin, a TGF-β superfamily myokine, acts through ActRIIB to negatively regulate muscle growth. Recent studies demonstrated the potential benefit of myostatin inhibition with the soluble ActRIIB fusion protein on skeletal properties, although various OI mouse models exhibited variable skeletal responses. The genetic and clinical heterogeneity associated with OI, the lack of specificity of the ActRIIB decoy molecule for myostatin alone, and adverse events in human clinical trials further the need to clarify myostatin's therapeutic potential and role in skeletal integrity. In this study, we determined musculoskeletal outcomes of genetic myostatin deficiency and postnatal pharmacological myostatin inhibition by a monoclonal anti-myostatin antibody (Regn647) in the G610C mouse, a model of mild–moderate type I/IV human OI. In the postnatal study, 5-week-old wild-type and +/G610C male and female littermates were treated with Regn647 or a control antibody for 11 weeks or for 7 weeks followed by a 4-week treatment holiday. Inhibition of myostatin, whether genetically or pharmacologically, increased muscle mass regardless of OI genotype, although to varying degrees. Genetic myostatin deficiency increased hindlimb muscle weights by 6.9% to 34.4%, whereas pharmacological inhibition increased them by 13.5% to 29.6%. Female +/mstn +/G610C (Dbl.Het) mice tended to have similar trabecular and cortical bone parameters as Wt showing reversal of +/G610C characteristics but with minimal effect of +/mstn occurring in male mice. Pharmacologic myostatin inhibition failed to improve skeletal bone properties of male or female +/G610C mice, although skeletal microarchitectural and biomechanical improvements were observed in male wild-type mice. Four-week treatment holiday did not alter skeletal outcomes. © 2020 American Society for Bone and Mineral Research (ASBMR).     

Total Hip Bone Mineral Density as an Indicator of Fracture Risk in Bisphosphonate-Treated Patients in a Real-World Setting

Bone mineral density (BMD) is an established measure used to diagnose patients with osteoporosis. In clinical trials, change in BMD has been shown to provide a reliable estimate of fracture risk reduction, and achieved BMD T-score has been shown to reflect the near-term risk of fracture. We aimed to test the association between BMD T-score and fracture risk in patients treated for osteoporosis in a real-world setting. This retrospective, observational cohort study included Swedish females aged ≥55 years who had a total hip BMD measurement at one of three participating clinics. Patients were separated into two cohorts: bisphosphonate-treated and bisphosphonate-naïve prior to BMD measurement, stratified by age and prior nonvertebral fracture status. The primary outcome was cumulative incidence of clinical fractures within 24 months of BMD measurement, with other fracture types included as secondary outcomes. Associations between T-score and fracture risk were estimated using proportional hazards regression and restricted cubic splines. A total of 15,395 patients were analyzed: 11,973 bisphosphonate-naïve and 3422 bisphosphonate-treated. In the 24 months following BMD measurement, 6.3% (95% confidence interval [CI], 5.9–6.7) of bisphosphonate-naïve and 8.4% (95% CI, 7.5–9.4) of bisphosphonate-treated patients experienced a clinical fracture. Strong inverse relationships between BMD T-score and fracture incidence were observed in both cohorts. Among bisphosphonate-naïve patients, this relationship appeared to plateau around T-score −1.5, indicating smaller marginal reductions in fracture risk above this value; bisphosphonate-treated patients showed a more consistent marginal change in fracture risk across the evaluated T-scores (−3.0 to –0.5). Trends remained robust regardless of age and prior fracture status. This real-world demonstration of a BMD–fracture risk association in both bisphosphonate-naïve and bisphosphonate-treated patients extends evidence from clinical trials and recent meta-regressions supporting the suitability of total hip BMD as a meaningful outcome for the clinical management of patients with osteoporosis. © 2021 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).     

严重创伤病人死亡的高危因素

目的为了探讨影响严重创伤病人死亡的高危因素。方法对创伤严重评分≥１６的２３３例严重创伤病人进行了多因素回顾性分析。结果与结论性别、入院时休克和创伤至入院的时间与死亡率无明显关系。而病人的年龄、受伤区域的个数、创伤前并存的慢性疾病和创伤严重度评分与死亡率明显相关，是严重创伤病人死亡的高危因素。     

清开灵注射液治疗急性中风的Meta分析

背景：中医药学几千年来各界了许多治疗中风有产的疗法和方药,如清开灵注射液（）简称清开灵）等,但因临床研究对方法学的重视仍不够,影响了研究结论的推广和国外医学界的承认。循证医学及系统分析的方法和结果日益得到了国际医学界和卫生决策部门的认可与重视,利用循证医学,系统分析的方法,拿出Ｍｅｔａ分析等数据,将极寺地促进中医药走向世界。目的：在严格的质量评价的基础上,对清开灵的临床疗与安全性进行系统评价。