Using the same bone density reference database for men and women provides a simpler estimation of fracture risk

Although low bone mineral density (BMD) predicts fractures, there are postulated sex differences in the fracture “threshold.” Some studies demonstrate a higher mean BMD for men with fractures than for women, whereas others note similar absolute risk at the same level of BMD. Our objective was to test the preceding observations in the population‐based Canadian Multicentre Osteoporosis Study (CaMOS). We included participants 50+ years of age at baseline. Mean BMD in men was higher than in women among both fracture cases and noncases. Three methods of BMD normalization were compared in age‐adjusted Cox proportional hazards models. In a model using the same reference population mean and standard deviation (SD), there were strong effects of age and total‐hip BMD for prediction of fractures but no significant effect of sex [hazard ratio (HR) = 0.97, 95% confidence interval (CI) 0.78–1.20] for men versus women. In a model using sex‐specific reference means but a common SD, an apparent sex difference emerged (HR = 0.66, 95% CI 0.54–0.81) for men versus women. The sex term in the second model counterbalanced the higher risk introduced by the lower normalized BMD in men. A third model using sex‐specific reference means and SDs gave nearly identical results. Parallel results for the three methods of normalization were seen when adjusting for clinical risk factors, excluding antiresorptive users and considering death as a competing risk. We conclude that no adjustment for sex is necessary when using common reference data for both men and women, whereas using sex‐specific reference data requires a substantial secondary adjustment for sex. © 2010 American Society for Bone and Mineral Research.     

Bone Stress Injuries Are Associated With Differences in Bone Microarchitecture in Male Professional Soldiers

Bone stress injuries are commonly due to repetitive loading, as often described in competitive athletes or military recruits. The underlying pathophysiology of bone stress injuries is multifactorial. The present cross‐sectional study investigated (i) cortical and trabecular bone microstructure as well as volumetric bone mineral density in subjects with bone stress injuries at the tibial diaphysis, measured at the distal tibia and the distal radius by means of high‐resolution peripheral quantitative computed tomography (CT), (ii) areal bone mineral density using dual‐energy X‐ray absorptiometry as well as calcaneal dual X‐ray absorptiometry and laser, and (iii) the influence on bone turnover markers of formation and resorption at the early phase after injury. A total of 26 Caucasian male professional soldiers with post‐training bone stress injury at the tibial diaphysis were included (case group). A total of 50 male, Caucasian professional soldiers from the same military institution served as controls (control group). High‐resolution peripheral quantitative CT revealed a higher total area at the radius within the case group. Cortical bone mineral density was reduced at the radius and tibia within the case group. The trabecular number and trabecular thickness were reduced at the tibia in the case group. The trabecular network was more inhomogeneous at the radius and tibia within the case group. Calcaneal dual X‐ray absorptiometry and laser was significantly reduced in the case group. This study quantified differences in bone microstructure among otherwise healthy individuals. Differences in bone microarchitecture may impair the biomechanical properties by increasing the susceptibility to sustain bone stress injuries. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 37:2516–2523, 2019     

Algorithm‐Based Qualitative and Semiquantitative Identification of Prevalent Vertebral Fracture: Agreement Between Different Readers,Imaging Modalities,and Diagnostic Approaches

We compared SQ and ABQ diagnosis of VF imaged by radiography and X‐ray absorptiometry. Mild ABQ VF had stronger associations with osteoporosis than mild SQ VF. Interobserver agreement (radiographic diagnosis) was better for ABQ. Introduction: Vertebral fracture (VF) assessment from images acquired by X‐ray absorptiometry (VFA) is often based on a semiquantitative approach (SQ); prevalent VF is identified if vertebral height appears reduced by >20%. Algorithm‐based qualitative definition of osteoporotic VF (ABQ) requires evidence of endplate depression, and there is no threshold for reduction in vertebral height. The aims of this study were to (1) compare the prevalence of VFs; (2) compare the characteristics of women with and without VFs; (3) compare interobserver agreement; and (4) compare agreement between methods and imaging modalities for ABQ and SQ definitions of VFs. Materials and Methods: Spine radiographs and absorptiometry images for 203 elderly women were assessed using ABQ (readers ABQ‐1 and ABQ‐2). These readings were compared with SQ assessments (readers SQ‐1 and SQ‐2) of the same images performed in a previous study. Agreement between readers and methods was assessed by kappa (κ) statistics. Results: The prevalence of VF was 15–18% (radiography) and 12–24% (VFA) for ABQ and SQ, respectively. Women with ABQ or SQ fractures were older and had lower BMD than those without fracture (p < 0.01). Mild ABQ (but not SQ) VF was associated with low BMD. κ scores for interobserver agreement for radiography and VFA, respectively, were as follows: ABQ, κ = 0.74 (95% CI, 0.60, 0.87) and 0.65 (95% CI, 0.48, 0.81); SQ, κ = 0.53 (95% CI, 0.46, 0.60) and 0.51 (95% CI, 0.44, 0.58). For agreement between ABQ‐1 and SQ‐1, κ = 0.55 (95% CI, 0.39, 0.72) for radiography and 0.41 (95% CI, 0.25, 0.58 for VFA. Conclusions: The prevalence of radiographic VF identified by ABQ and SQ was similar, but on VFA was 50% higher for SQ. Mild ABQ VF was associated with low BMD. Interobserver agreement for radiographic diagnosis was significantly better for ABQ than for SQ. Agreement between ABQ and SQ was moderate.     

The effects of therapeutic vs. high-intensity ultrasound on the rabbit growth plate.

Six of 6-week-old NZ rabbits underwent ultrasound treatment using a therapeutic dose (0.5 W/cm(2)) and other six were treated with a higher dose (2.2 W/cm(2)) to the lateral aspect of the left knee joint for 20 min per day and a total of six weeks. The right knee joint served as a control. The goal of this study is to see if the therapeutic dose and high dose (approximately 45-fold therapeutic dose) will have toxic effects on the physis. Histological review appeared normal growth plate in the therapeutic group. In the high dosage group three of six cases displayed flattening of the distal femoral epiphysis and wedging of the proximal tibial plateau and indistinct growth plate lines. It is of interest to note that there are opening radiolucent area in the lateral aspect on the femoral metaphysis in five of six cases, where bone resorption has taken place. Histological results showed that there are disordered arrays of the cartilaginous cells in the proliferative zone. The height of the lateral physis in the high dose group is not only greater than that in the therapeutic dose (1083.8 vs. 500.3 micro m), but also greater than that in their contralateral control (530.7 micro m) (P<0.05). This short-term study demonstrates that high dose ultrasound has profound pathologic effects in growing bone. Therapeutic doses of ultrasound do not have an adverse effect on bone growth in the short-term follow-up.     

Positron‐emission tomography/computed tomography (PET/CT) in the initial staging of primary rectal cancer

Objective The aim of this study was to assess the role of ¹⁸flourodeoxyglucose positron‐emission tomography/computed tomography (PET/CT) in the initial staging of primary rectal adenocarcinoma. Method A total of 20 patients with adenocarcinoma of the rectum were assessed with both PET/CT and conventional staging (CT chest/abdomen/pelvis, MRI rectum). Discordance with conventional imaging and incidental findings on PET were recorded and the patients presented to a colorectal cancer multidisciplinary team to assess management changes. Patients were followed up so that discordant or incidental findings could be verified by intra‐operative examination, imaging or histology where possible. Results Positron‐emission tomography/computed tomography correctly identified the primary tumour in all 20 patients. Comparing PET/CT with conventional staging modalities, there were 11 discordant or incidental findings in nine patients (45%). This resulted in a potential change in stage in 30% (four patients downstaged and two upstaged). PET/CT suggested additional neoplastic pathology in three patients and excluded the same in two patients. The incidental neoplastic findings were of minor clinical significance and one was eventually deemed false positive. While PET/CT resulted in potential management changes in five patients (25%), no changes in surgical management occurred. When tumours were grouped according to conventional stage, PET/CT resulted in fewer changes in stage in stage I (0%), compared with stages II to IV (43%) (P = 0.08). Conclusion Positron‐emission tomography/computed tomography provides additional information to conventional staging in primary rectal cancer. This information produced minor management changes in this study and did not effect surgical management. PET/CT may be most appropriately used selectively in more advanced stages and where indeterminate findings exist with conventional staging.     

Significant deterioration in nanomechanical quality occurs through incomplete extrafibrillar mineralization in rachitic bone: evidence from in-situ synchrotron X-ray scattering and backscattered electron imaging

Bone diseases such as rickets and osteoporosis cause significant reduction in bone quantity and quality, which leads to mechanical abnormalities. However, the precise ultrastructural mechanism by which altered bone quality affects mechanical properties is not clearly understood. Here we demonstrate the functional link between altered bone quality (reduced mineralization) and abnormal fibrillar-level mechanics using a novel, real-time synchrotron X-ray nanomechanical imaging method to study a mouse model with rickets due to reduced extrafibrillar mineralization. A previously unreported N-ethyl-N-nitrosourea (ENU) mouse model for hypophosphatemic rickets (Hpr), as a result of missense Trp314Arg mutation of the phosphate regulating gene with homologies to endopeptidase on the X chromosome (Phex) and with features consistent with X-linked hypophosphatemic rickets (XLHR) in man, was investigated using in situ synchrotron small angle X-ray scattering to measure real-time changes in axial periodicity of the nanoscale mineralized fibrils in bone during tensile loading. These determine nanomechanical parameters including fibril elastic modulus and maximum fibril strain. Mineral content was estimated using backscattered electron imaging. A significant reduction of effective fibril modulus and enhancement of maximum fibril strain was found in Hpr mice. Effective fibril modulus and maximum fibril strain in the elastic region increased consistently with age in Hpr and wild-type mice. However, the mean mineral content was ～21% lower in Hpr mice and was more heterogeneous in its distribution. Our results are consistent with a nanostructural mechanism in which incompletely mineralized fibrils show greater extensibility and lower stiffness, leading to macroscopic outcomes such as greater bone flexibility. Our study demonstrates the value of in situ X-ray nanomechanical imaging in linking the alterations in bone nanostructure to nanoscale mechanical deterioration in a metabolic bone disease.     

A free‐hand technique for pedicle screw placement in the lower cervical spine

Objective: To describe a free‐hand method for pedicle screw placement in the lower cervical spine with no intraoperative imaging monitors, and to evaluate the safety of this technique. Methods: A study of the free‐hand technique of cervical pedicle screw placement was conducted by postoperative radiological review and follow‐up. Thirty‐six patients who had had cervical reconstruction with posterior plate utilizing pedicle screw fixation, and been followed for a minimum of 2 years, were studied. The position of the pedicle screw was evaluated by postoperative oblique radiographs and axial computed tomograms. Clinical outcomes were measured by Odem's criteria. Results: A total of 144 screws of diameter 3.5 or 4.0 mm were inserted into the cervical pedicles in 36 patients. Postoperative images showed that 16 (11.1%) of the screws had penetrated the pedicle walls. Among them, 10 (6.9%) screws had penetrated the lateral, 4 (2.8%) the superior and 2 (1.3%) the inferior walls. However, there were no neurological or vascular complications related to the malpositioned screws during a minimum of 2 years follow‐up. In addition, Odem's scores were applied postoperatively in all patients except one with complete neurological deficit. Conclusion: Based on 144 screw placements, cervical pedicle screw insertion utilizing a free‐hand technique without intraoperative imaging guidance seems to be safe and reliable. However, solid knowledge of the anatomy of the cervical pedicle and adjacent neurovascular bundles, and careful preoperative review of cervical images, are imperative for successful screw placement in the cervical spine.     

Proteolytic processing of osteopontin by PHEX and accumulation of osteopontin fragments in Hyp mouse bone,the murine model of X‐linked hypophosphatemia

X‐linked hypophosphatemia (XLH/HYP)—with renal phosphate wasting, hypophosphatemia, osteomalacia, and tooth abscesses—is caused by mutations in the zinc‐metallopeptidase PHEX gene (phosphate‐regulating gene with homologies to endopeptidase on the X chromosome). PHEX is highly expressed by mineralized tissue cells. Inactivating mutations in PHEX lead to distal renal effects (implying accumulation of a secreted, circulating phosphaturic factor) and accumulation in bone and teeth of mineralization‐inhibiting, acidic serine‐ and aspartate‐rich motif (ASARM)‐containing peptides, which are proteolytically derived from the mineral‐binding matrix proteins of the SIBLING family (small, integrin‐binding ligand N‐linked glycoproteins). Although the latter observation suggests a local, direct matrix effect for PHEX, its physiologically relevant substrate protein(s) have not been identified. Here, we investigated two SIBLING proteins containing the ASARM motif—osteopontin (OPN) and bone sialoprotein (BSP)—as potential substrates for PHEX. Using cleavage assays, gel electrophoresis, and mass spectrometry, we report that OPN is a full‐length protein substrate for PHEX. Degradation of OPN was essentially complete, including hydrolysis of the ASARM motif, resulting in only very small residual fragments. Western blotting of Hyp (the murine homolog of human XLH) mouse bone extracts having no PHEX activity clearly showed accumulation of an ～35 kDa OPN fragment that was not present in wild‐type mouse bone. Immunohistochemistry and immunogold labeling (electron microscopy) for OPN in Hyp bone likewise showed an accumulation of OPN and/or its fragments compared with normal wild‐type bone. Incubation of Hyp mouse bone extracts with PHEX resulted in the complete degradation of these fragments. In conclusion, these results identify full‐length OPN and its fragments as novel, physiologically relevant substrates for PHEX, suggesting that accumulation of mineralization‐inhibiting OPN fragments may contribute to the mineralization defect seen in the osteomalacic bone characteristic of XLH/HYP. © 2013 American Society for Bone and Mineral Research.     

Bone mineral content and density of the lumbar spine of infants and toddlers: Influence of age,sex, race,growth, and human milk feeding

Little is known about factors that affect bone mass and density of infants and toddlers and the means to assess their bone health owing to challenges in studying this population. The objectives of this study were to describe age, sex, race, growth, and human milk feeding effects on bone mineral content (BMC) and areal density (aBMD) of the lumbar spine, and determine precision of BMC and aBMD measurements. We conducted a cross‐sectional study of 307 healthy participants (63 black), ages 1 to 36 months. BMC and aBMD of the lumbar spine were measured by dual‐energy X‐ray absorptiometry. Duplicate scans were obtained on 76 participants for precision determination. Age‐specific Z‐scores for aBMD, weight, and length (BMDZ, WAZ, LAZ) were calculated. Information on human milk feeding duration was ascertained by questionnaire. Between ages 1 and 36 months, lumbar spine BMC increased about fivefold and aBMD increased twofold (p < 0.0001). BMC was greater (5.8%) in males than in females (p = 0.001), but there was no difference in aBMD (p = 0.37). There was no difference in BMC or aBMD between whites and blacks (p ≥ 0.16). WAZ and LAZ were positively associated with BMDZ (r = 0.34 and 0.24, p < 0.001). Duration of human milk feeding was negatively associated with BMDZ in infants <12 months of age (r = ?0.42, p < 0.001). Precision of BMC and aBMD measurements was good, 2.20% and 1.84%, respectively. Dramatic increases in BMC and aBMD of the lumbar spine occur in the first 36 months of life. We provide age‐specific values for aBMD of healthy infants and toddlers that can be used to evaluate bone deficits. Future studies are needed to identify the age when sex and race differences in aBMD occur, and how best to account for delayed or accelerated growth in the context of bone health assessment of infants and toddlers. © 2013 American Society for Bone and Mineral Research     

Clonality studies in giant cell tumor of bone.

Genetic studies including chromosome analysis, telomere reduction and telomere activity, DNA microsatellites and loss of heterozygosity (LOH) studies have been performed on giant cell tumor (GCT) of bone however whether this primary skeletal neoplasm represents a monoclonal or polyclonal proliferation is unknown. Utilizing a new assay to study the polymorphic human androgen receptor locus (HUMARA), the ratio of maternal inactive X-chromosome to the paternal inactive X (Lyon hypothesis) is determined via a methylation--specific polymerase chain reaction (PCR) technique to detect X-chromosome polymorphisms. Characterization of the genetic tumorigenesis of this unpredictable neoplasm may lend insight into its biological behavior and offer improvements in therapeutic intervention, as new information emerges regarding osteoclastic bone resorption. Seventeen female patients with giant cell tumor of bone had their DNA harvested and their X-chromosome inactivation pattern and polymorphisms determined and compared to control. A polyclonal proliferation pattern was identified in all informative samples studied.     

Multilocular cystic renal cell carcinoma: clinicopathological features and preoperative prediction using multiphase computed tomography

Study Type – Diagnostic (exploratory cohort) Level of Evidence 2b What’s known on the subject? and What does the study add? Multilocular cystic renal cell carcinoma (MCRCC), defined according to the 2004 WHO classification, has good prognosis, which is not affected adversely by large tumour size or advanced stage. Thus nephron‐sparing surgery is proposed when MCRCC is suspected by preoperative radiologic criteria. The present study confirms the low malignant potential of MCRCC. Additionally, the results of the present study provide a simple, useful criteria using a Bosniak classification and Hounsfield unit on multiphase computed tomography images to differentiate MCRCC from other cystic RCC.

OBJECTIVE

? To analyse the clinicopathological and radiological features of multilocular cystic renal cell carcinoma (MCRCC) and to determine the preoperative factors differentiating MCRCC from other cystic RCC (CRCC).

PATIENTS AND METHODS

? The medical records of 53 patients with complex cystic renal masses evaluated by multiphase computed tomography (CT), surgically removed and confirmed as sporadic RCC were reviewed. ? Of these 53 patients, 23 were classified as having MCRCC and 30 as other CRCCs, defined as RCCs with extensive cystic change or cystic necrosis. ? Another 22 patients were treated for complex cystic renal masses presumed to be RCC and diagnosed as having benign cyst.

RESULTS

? Benign cysts and MCRCCs were significantly more likely to be of Bosniak classification III than other CRCCs (77% vs 61% vs 27%, P= 0.001). ? The mean Hounsfield unit (HU) during the corticomedullary phase (CMP) was significantly higher in other CRCCs, with HU ≥38 having 83% sensitivity and 80% specificity for predicting other CRCCs. ? In a multiple regression model, Bosniak classification and mean HU during CMP were independent factors predictive of other CRCCs. ? In the 41 patients with masses >4 cm in diameter, the combination of Bosniak classification IV and HU ≥38 during CMP showed 63% sensitivity, 96% specificity, 91% positive predictive value and 80% negative predictive value, yielding 2% false‐positive and 15% false‐negative rates.

CONCLUSIONS

? The mean HU during CMP and Bosniak classification can differentiate MCRCC from other CRCCs. ? This could help in selecting an appropriate surgical method, such as nephron‐sparing surgery, for complex cystic renal masses >4 cm.     

Joint analysis of IVD herniation and degeneration by rat caudal needle puncture model

Intervertebral disc (IVD) degeneration is responsible for various spine pathologies and present clinical treatments are insufficient. Concurrently, the mechanisms behind IVD degeneration are still not completely understood, so as to allow development of efficient tissue engineering approaches. A model of rat IVD degeneration directly coupled to herniation is here proposed in a pilot study. Disc injury is induced by needle puncture, using two different needles gauges: a low caliber 25‐G needle and a high caliber 21‐G needle. Histological, biochemical, and radiographic degeneration was evaluated at 2 and 6 weeks post‐injury. We show that the larger caliber needle results in a more extended histological and radiographic degeneration within the IVD, compared to the smaller one. TUNEL quantification indicates also increased cell death in the 21‐G group. Analyses of collagen type I (Picrosirius red staining), collagen type II (immunofluorescence), and GAG content (Blyscan assay) indicate that degeneration features spontaneously recover from 2 to 6 weeks, for both needle types. Moreover, we show the occurrence of hernia proportional to the needle gauge. The number of CD68+ macrophages present, as well as cell apoptosis within the herniated tissue are both proportional to hernia volume. Moreover, hernias formed after lesion tend to spontaneously diminish in volume after 6 weeks. Finally, MMP3 is increased in the hernia in the 21‐G group at 2 weeks. This model, by uniquely combining IVD degeneration and IVD herniation in the same animal, may help to understand mechanisms behind IVD pathophysiology, such as hernia formation and spontaneous regression. © 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:258–268, 2017.

     

Quantifying intra‐osseous growth of osteosarcoma in a murine model with radiographic analysis

The orthotopic murine osteosarcoma model is an excellent representation of the human condition as mice develop rapid growth of ‘primary’ tumor with subsequent lung metastasis. Currently, monitoring tumor growth relies on measuring pulmonary metastases occurring four weeks post injection. Studies show that amputation of the tumor‐bearing limb is required before pulmonary metastases are detectable due to rapid growth causing morbidity. Thus, a method measuring ‘primary’ tumor growth independent of metastasis is required. We hypothesized that serial radiography would allow for longitudinal quantification of ‘primary’ osteosarcoma growth and explored this idea by utilizing the tibial orthotopic model. Tumor growth was monitored weekly by radiography and calipers, and results were compared with µCT and histology. We found that radiographs demonstrate extra and intra‐osseous tumor growth by displaying lytic and blastic lesions and the surrounding radio‐opaque area enlarged significantly (p < 0.0001) allowing for quantification. Additionally, radiographs proved more precise than indirect caliper measurements (intra‐observer error ±6.64%: inter‐observer error ±15.84%). Therefore, we determined that radiography provides accurate, longitudinal quantification of ‘primary’ osteosarcoma tumor that can be performed serially in the same mouse, does not require introduction of bioluminescence to the host or cell, and is more precise than the current caliper method. © 2011 Orthopaedic Research Society Published by Wiley Periodicals, Inc. J Orthop Res 29:1957–1962, 2011     

Clinical imaging characteristics of herniation pits of the femoral neck

Objective: To discuss imaging features of radiographs, computed tomography (CT), magnetic resonance imaging (MRI) and radionuclide imaging of the herniation pit of the femoral neck and their implications for pathogenesis. Methods: Twenty‐seven patients with 31 herniation pits of the femoral neck were analyzed. All patients were examined by plain radiographs, 18 by CT, 16 by MRI, and 8 by radionuclide imaging. Results: Thirty‐one herniation pits located in the anterior part of the femoral neck or the base of the femoral head were round, oval or ‘8’‐shaped subcortical defects. The pits were usually seen as mild radiolucent areas on radiographs, soft‐tissue attenuation with a thin sclerotic rim and a focal cortical perforation on CT and three different signal intensities on MRI. Only one of eight pits revealed mild focal increased uptake on bone radionuclide scans. Conclusion: The occurrence of a herniation pit of the femoral neck correlates closely with the particulars of the structure of the hip joint and corresponding mechanical forces. Round or oval subcortical defects surrounded by a thin sclerotic rim in the superior lateral part of the femoral neck or the anterior lateral base of the femoral head, which are usually normal on radionuclide imaging and have focal cortical perforations on CT, are specific signs for diagnosing herniation pits of the femoral neck.