Glucocorticoids mediate circadian timing in peripheral osteoclasts resulting in the circadian expression rhythm of osteoclast-related genes

Circadian rhythms are prevalent in bone metabolism. However, the molecular mechanisms involved are poorly understood. Recently, we suggested that output signals from the suprachiasmatic nucleus (SCN) are transmitted from the master circadian rhythm to peripheral osteoblasts through β-adrenergic and glucocorticoid signaling. In this study, we examined how the master circadian rhythm is transmitted to peripheral osteoclasts and the role of clock gene in osteoclast. Mice were maintained under 12-hour light/dark periods and sacrificed at Zeitgeber times 0, 4, 8, 12, 16 and 20. mRNA was extracted from femur (cancellous bone) and analyzed for the expression of osteoclast-related genes and clock genes. Osteoclast-related genes such as cathepsin K (CTSK) and nuclear factor of activated T-cells, cytoplasmic 1 (NFATc1) showed circadian rhythmicity like clock genes such as period 1 (PER1), PER2 and brain and muscle Arnt-like protein 1 (BMAL1). In an in vitro study, not β-agonist but glucocorticoid treatment remarkably synchronized clock and osteoclast-related genes in cultured osteoclasts. Chromatin immunoprecipitation (ChIP) assay showed the interaction between BMAL1 proteins and promoter region of CTSK and NFATc1. To examine whether endogenous glucocorticoids influence the osteoclast circadian rhythms, mice were adrenalectomized (ADX) and maintained under 12-hour light/dark periods at least two weeks before glucocorticoid injection. A glucocorticoid injection restarted the circadian expression of CTSK and NFATc1 in ADX mice. These results suggest that glucocorticoids mediate circadian timing to peripheral osteoclasts and osteoclast clock contributes to the circadian expression of osteoclast-related genes such as CTSK and NFATc1.     

The epigenetically active small chemical N-methyl pyrrolidone (NMP) prevents estrogen depletion induced osteoporosis

Currently, there are several treatments for osteoporosis however; they all display some sort of limitation and/or side effects making the need for new treatments imperative. We have previously demonstrated that NMP is a bioactive drug which enhances bone regeneration in vivo and acts as an enhancer of bone morphogenetic protein (BMP) in vitro. NMP also inhibits osteoclast differentiation and attenuates bone resorption.In the present study, we tested NMP as a bromodomain inhibitor and for osteoporosis prevention on ovariectomized (OVX) induced rats while treated systemically with NMP. Female Sprague–Dawley rats were ovariectomized and weekly NMP treatment was administrated 1 week after surgery for 15 weeks. Bone parameters and related serum biomarkers were analyzed. 15 weeks of NMP treatment decreased ovariectomy-induced gained weight in average by 43% and improved bone mineral density (BMD) and bone volume over total volume (BV/TV) in rat femur on average by 25% and 41% respectively. Moreover, mineral apposition rate and bone biomarkers of bone turnover in the treatment group were at similar levels with those of the Sham group.Due to the function of NMP as a low affinity bromodomain inhibitor and its mechanism of action involving osteoblasts/osteoclasts balance and inhibitory effect on inflammatory cytokines, NMP is a promising therapeutic compound for the prevention of osteoporosis.     

Relationships between bone geometry,volumetric bone mineral density and bone microarchitecture of the distal radius and tibia with alcohol consumption

PurposeChronic heavy alcohol consumption is associated with bone density loss and increased fracture risk, while low levels of alcohol consumption have been reported as beneficial in some studies. However, studies relating alcohol consumption to bone geometry, volumetric bone mineral density (vBMD) and bone microarchitecture, as assessed by high-resolution peripheral quantitative computed tomography (HR-pQCT), are lacking.MethodsHere we report an analysis from the Hertfordshire Cohort Study, in which we studied associations between HR-pQCT measures at the distal radius and tibia and alcohol consumption in 376 participants (198 men and 178 women) aged 72.1–81.4 years.ResultsA total of 30 (15.2%), 90 (45.5%) and 78 (39.4%) men drank minimal/none (< 1 unit/week), low (≥ 1 unit/week and < 11 units/week) and moderate/high (≥ 11 units/week) amounts of alcohol respectively. These figures were 74 (41.8%), 80 (45.2%) and 23 (13.0%) respectively in women for minimal/none (< 1 unit/week), low (≥ 1 unit/week and < 8 units/week) and moderate/high (≥ 8 units/week). At the distal radius, after adjustment for confounding factors (age, BMI, smoking status, dietary calcium intake, physical activity and socioeconomic status and years since menopause and HRT use for women), men that drank low alcohol had lower cortical thickness (p = 0.038), cortical vBMD (p = 0.033), and trabecular vBMD (p = 0.028) and higher trabecular separation (p = 0.043) than those that drank none/minimal alcohol. Similar differences were shown between minimal/none and moderate/high alcohol although these only reached statistical significance for the cortical parameters. Interestingly, after similar adjustment, women showed similar differences in the trabecular compartment between none/minimal alcohol and low alcohol at the distal tibia. However, women that drank moderate/high alcohol had significantly higher trabecular vBMD (p = 0.007), trabecular thickness (p = 0.026), and trabecular number (p = 0.042) and higher trabecular separation (p = 0.026) at the distal radius than those that drank low alcohol.ConclusionsOur results suggest that alcohol consumption (low and moderate/high) may have a detrimental impact on bone health in men in both the cortical and trabecular compartments at the distal radius with similar results in women in the trabecular compartment between none/minimal alcohol and low alcohol at the distal tibia suggesting that avoidance of alcohol may be beneficial for bone health.     

Evaluation of patients with pathological fractures treated by standard trauma principles but neglecting the underlying malign bone disease

IntroductionThere are several studies in the literature about pathological fractures but almost no information about patients whose pathological fracture caused by a malignant lesion misdiagnosed and treated as a simple fracture. The aim of this study was to investigate patient and fracture characteristics, and outcomes in cases where fractures occurred in the presence of a malign pathology but were treated as simple fractures.Patients and MethodsCases of malign bone lesions between 2000 and 2020 were retrospectively reviewed. Patients with a final diagnosis of malign bone lesion but whose pathological fractures were treated ignoring the underlying malign bone disease were included. Demographic, clinical and outcome data were collected from patient's medical records and analyzed.ResultsSix patients met the inclusion criteria. Three of the patients were female and the cohort mean age was 56.8 ± 21.8 years at the time of admission. Patient diagnoses were: renal cell carcinoma metastasis (n = 1); colon cancer metastasis (n = 1); chondrosarcoma (n = 2); osteosarcoma (n = 1); and undifferentiated pleomorphic sarcoma of bone (n = 1). In all cases surgical management differed from those that should have been applied if the pathological fracture had been identified. Furthermore, surgical management after definitive histological diagnosis were more aggressive compared to if the malignancy had been identified at first admission. All patients died after a mean follow-up of 16.67 ± 11.7 months and the complication rate was 100%.ConclusionWhen a pathological fracture is misdiagnosed and managed as a simple bone fracture, outcomes are extremely poor. In these situations, remedial surgery is more extensive, with increased complication rates and there is poor life expectancy.     

Risk factors for loss to follow up of pelvis and acetabular fractures

IntroductionPelvic and acetabular fracture incidence is increasing worldwide for more than four decades. There is currently no evidence examining risk factors for loss to follow up in patients with these injuries.MethodsPatients presenting with pelvic and/or acetabular fractures at our institution between 2015 and 2020 were included. Demographic, injury, treatment, and follow up information was included. Excluded patients were those who sustained a pathologic fracture, has a course of treatment prior to transfer to our centre, or expired prior to discharge.Results446 patients, 263 with a pelvic ring injury, 172 with an acetabular fracture, and 11 with combined injuries were identified. 271 (61%) of patients in our cohort followed up in Orthopaedic clinic (p = 0.016). With an odds ratio of 2.134, gunshot wound mechanism of injury was the largest risk factor for loss to follow up (p = 0.031) followed by male sex (OR= 1.859) and surgery with general trauma surgery (OR=1.841). The most protective risk factors for follow up with Orthopaedic surgery were operatively treated pelvic and acetabular fractures (OR=0.239) and Orthopaedic Surgery as the discharging service (OR=0.372).DiscussionNumerous risk factors exist for loss to follow up including male sex, ballistic mechanism, and discharging service. Investigation into interventions to improve follow up in these patients are warranted.     

Are current DRG-based bundled payment models for lumbar fusions risk-adjusting adequately? An analysis of Medicare beneficiaries

BACKGROUND CONTEXTCurrent bundled payment programs in spine surgery, such as the bundled payment for care improvement rely on the use of diagnosis-related groups (DRG) to define payments. However, these DRGs may not be adequate enough to appropriately capture the large amount of variation seen in spine procedures. For example, DRG 459 (spinal fusion except cervical with major comorbidity or complication) and DRG 460 (spinal fusion except cervical without major comorbidity or complication) do not differentiate between the type of fusion (anterior or posterior), the levels/extent of fusion, the use of interbody/graft/BMP, indication of surgery (primary vs. revision) or even if the surgery was being performed for a vertebral fracture.PURPOSEWe carried out a comprehensive analysis to report the factors responsible for cost-variation in a bundled payment model for spinal fusions.STUDY DESIGNRetrospective review of a 5% national sample of Medicare claims from 2008 to 2014 (SAF5).OUTCOME MEASURESTo understand the independent marginal cost impact of various patient-level, geographic-level, and procedure-level characteristics on 90-day costs for patients undergoing spinal fusions under DRG 459 and 460.METHODSThe 2008 to 2014 Medicare 5% standard analytical files (SAF) were used to retrieve patients undergoing spinal fusions under DRG 459 and DRG 460 only. Patients with missing gender, age, and/or state-level data were excluded. Only those patients who had complete data, with regard to payments/costs/reimbursements, starting from day 0 of surgery up to 90 days postoperatively were included to prevent erroneous collection. Multivariate linear regression models were built to assess the independent marginal cost impact (decrease/increase) of each patient-level, state-level, and procedure-level characteristics on the average 90-day cost while controlling for other covariates.RESULTSA total of 21,367 patients (DRG-460=20,154; DRG-459=1,213) were included in the study. The average 90-day cost for all lumbar fusions was $31,716±$18,124, with the individual 90-day payments being $54,607±$30,643 (DRG-459) and $30,338±$16,074 (DRG-460). Increasing age was associated with significant marginal increases in 90-day payments (70–74 years: +$2,387, 75–79 years: +$3,389, 80–84 years: +$2,872, ≥85: +$1,627). With regards to procedure-level factors—undergoing an anterior fusion (+$3,118), >3 level fusion (+$5,648) vs. 1 to 3 level fusion, use of interbody device (+$581), intraoperative neuromonitoring (+$1,413), concurrent decompression (+$768) and undergoing surgery for thoracolumbar fracture (+$6,169) were associated with higher 90-day costs. Most individual comorbidities were associated with higher 90-day costs, with malnutrition (+$12,264), CVA/stroke (+$5,886), Alzheimer's (+$4,968), Parkinson's disease (+$4,415), and coagulopathy (+$3,810) having the highest marginal 90-day cost-increases. The top five states with the highest marginal cost-increase, in comparison to Michigan (reference), were Maryland (+$12,657), Alaska (+$11,292), California (+$10,040), Massachusetts (+$8,800), and the District of Columbia (+$8,315).CONCLUSIONSUnder the proposed DRG-based bundled payment model, providers would be reimbursed the same amount for lumbar fusions regardless of the surgical approach (posterior vs. anterior), the extent of fusion (1–3 level vs. >3 level), use of adjunct procedures (decompressions) and cause/indication of surgery (fracture vs. degenerative pathology), despite each of these factors having different resource utilization and associated costs. When defining and developing future bundled payments for spinal fusions, health-policy makers should strive to account for the individual patient-level, state-level, and procedure-level variation seen within DRGs to prevent the creation of a financial dis-incentive in taking care of sicker patients and/or performing more extensive complex spinal fusions.     

肌肉骨骼系统慢性疼痛管理专家共识

肌肉骨骼系统慢性疼痛是临床最常见的慢性疼痛。目前,国内外医师对慢性疼痛的认识、临床实践环境、镇痛药物种类/使用经验/了解程度、医保药品收录均有差异,故有效、规范化的慢性疼痛管理显得尤为必要。因此,亟待制定完善的、基于生物-心理-社会医学等因素的跨学科慢性疼痛管理共识,提高广大医务人员对慢性疼痛的认识与重视、规范指导慢性疼痛的管理,提高医疗质量、降低医疗成本,消除患者感觉、情感、认知和社会维度的痛苦体验,在治疗患者原发疾病的同时,改善患者的心理需求和社会功能需求。通过查阅文献,本共识专家组遵循循证医学原则,经过反复讨论和通信修改,对肌肉骨骼系统慢性疼痛管理达成共识,供广大骨科医师在临床工作中参考。     

The utilization of decellularized tendon slices to provide an inductive microenvironment for the proliferation and tenogenic differentiation of stem cells

The extracellular matrix (ECM) microenvironment for the stem cell niches, including but not limited to the biochemical composition, matrix topography, and stiffness, is crucial to stem cell proliferation and differentiation. The purpose of this study was to explore the capacity of the decellularized tendon slices (DTSs) to induce stem cell proliferation and tenogenic differentiation. Rat adult stem cells, including tendon-derived stem cells (TDSCs) and bone marrow-derived stem cells (BMSCs), were identified to have universal stem cell characteristics. The DTSs were found to retain the native tendon ECM microenvironment cues, including the inherent surface topography, well-preserved tendon ECM biochemical composition and similar stiffness to native tendon. When the TDSCs and BMSCs were cultured on the DTSs respectively, the LIVE/DEAD assay, alamarBlue^® assay, scanning electron microscopy examination and qRT-PCR analysis demonstrated that the DTSs have the capacity to support these stem cells homogeneous distribution, alignment, significant proliferation and tenogenic differentiation. Taken together, the findings of this study indicate that the DTSs can provide a naturally inductive microenvironment for the proliferation and tenogenic differentiation of TDSCs and BMSCs, supporting the use of decellularized tendon ECM as a promising and valuable approach for tendon repair/reconstruction.