Oral daily PTH(1-34) tablets (EB613) in postmenopausal women with low BMD or osteoporosis: a randomized, placebo-controlled, six-month, phase 2 study.

Anabolic treatment is indicated for high and very-high risk patients with osteoporosis, but acceptance is limited because current anabolic medications require subcutaneous injections. The purpose of this study was to assess the effects of a novel orally administered parathyroid hormone (PTH) tablet on serum markers of bone formation [N-terminal propeptide of Type I procollagen (PINP) and osteocalcin (OC)] and bone resorption [crosslinked C-telopeptide (CTX)], bone mineral density (BMD) and safety in postmenopausal women with low BMD or osteoporosis. In this 6-month, double-blind, placebo-controlled study, 161 patients were randomized to oral PTH tablets containing 0.5, 1.0, 1.5, or 2.5 mg or placebo daily. Biochemical markers were assessed at 1, 2, 3 and 6 months and BMD of lumbar spine, total hip and femoral neck was measured at 6 months. Biochemical marker changes were dose dependent with minimal or no effect at the two lowest doses. At the highest dose (2.5 mg once daily), serum PINP and OC levels increased 30% within 1 month after oral PTH initiation (p < 0.0001), remained elevated through 3 months and were back to baseline at 6 months. In contrast, serum CTX levels declined 16% and 21% below baseline at 3 and 6 months respectively (both p ≤ 0.02). At 6 months, 2.5 mg tablets increased mean BMD vs placebo of the lumbar spine by 2.7%, total hip by 1.8%, and femoral neck by 2.8% (all p ≤ 0.01). There were no drug-related serious adverse events. The most common adverse events were headache, nausea, and dizziness. In contrast to subcutaneous PTH, the oral PTH tablet appears to increase BMD rapidly by the dual mechanism of stimulating formation and inhibiting bone resorption. This might be the first effective oral anabolic alternative to subcutaneous administration for the treatment of low BMD or osteoporosis.

Despite the superior benefits of bone building (anabolic) agents and guidelines supporting their use, these medications are used in a minority of patients for whom they are appropriate, in part because they require daily or monthly injections, which limit patient acceptance. An oral anabolic tablet has potential to address this substantial treatment gap. In this double-blind, placebo controlled, dose-finding randomized study, 161 postmenopausal women with low bone mineral density or osteoporosis were treated with varying doses of the active part of parathyroid hormone [PTH(1-34)] or placebo given in daily oral tablets for 6 months. The highest oral PTH tablet dose (2.5 mg), produced an increase in markers of bone formation while simultaneously decreasing the markers of bone breakdown. Significant gains in bone mineral density of the spine and hip were observed at the end of the 6-month study and there were no significant safety concerns. The 2.5 mg oral PTH tablet dose was well tolerated when patients were instructed to titrate up to the full dose. We conclude that this PTH tablet might be the first effective orally administered bone building medication and should be studied further in treatment of women with osteoporosis.

Assessing Change in Spine Bone Density from Different Numbers and Combinations of Lumbar Vertebrae: The Manitoba BMD Registry.

INTRODUCTION: Change in bone mineral density (BMD) is considered significant when it exceeds the 95 % least significant change (LSC) derived from that facility's precision study. The lumbar spine is often affected by structural artifact such that not all four lumbar vertebrae are evaluable. Guidelines suggest using a site-matched LSC when omitting vertebrae from the BMD measurement. The current study describes significant BMD change related to intervening anti-osteoporosis treatment for different numbers and combinations of lumbar vertebrae using site-matched LSC values. METHODOLOGY: We identified 10,526 untreated adult women mean age 59.6 years with baseline and repeat spine BMD testing (mean interval 4.7 years) where all 4 lumbar vertebrae were evaluable. Change in spine BMD for different combinations of lumbar vertebrae was assessed in relation to intervening anti-resorptive treatment, contrasting women with high treatment exposure (medication possession ratio, MPR ≥ 0.8) versus women who remained untreated. Site-matched LSC values were derived from 879 test-retest precision measurements. RESULTS: There was consistent linear trend between increasing MPR and BMD change exceeding the LSC for all lumbar vertebral combinations, positive with BMD increase and negative with BMD decrease (all p-trend <0.001). In the high treatment exposure group, mean percent increases in spine BMD were similar for all vertebral combinations, from L1-4 to a single vertebra. In untreated women, mean percent decreases in spine BMD were also similar for all vertebral combinations. The net treatment response (proportion of women with treatment-concordant changes minus proportion with treatment-discordant changes exceeding the LSC) was 29.7 % for 4 vertebrae, 27.5-30.0 % for 3 vertebrae, 22.4-28.5 % for 2 vertebrae, and 18.1-21.9 % for a single vertebra. CONCLUSIONS: All numbers and combinations of lumbar vertebrae, when used in conjunction with site-matched LSC values, can provide clinically meaningful follow-up in treated and untreated patients, even when spine BMD is based on a single vertebral body.

Cardiovascular Safety of Romosozumab vs. PTH Analogs for Osteoporosis Treatment: a Propensity Score Matched Cohort Study.

CONTEXT: Romosozumab, a monoclonal sclerostin antibody, is a recently approved highly potent anti-osteoporotic agent with osteoanabolic properties. Clinical use of Romosozumab is hindered by the fear of adverse cardiovascular (CV) events raised following the pivotal ARCH-trial. OBJECTIVE: To assess real-world CV safety of romosozumab vs. alternative osteoanabolic therapies used for treatment of severe osteoporosis. DESIGN: Data was obtained from TriNetX, a global federated health research network including real-time electronic medical records from 113 healthcare organizations with a total of 136,460,930 patients across 16 countries at time of analysis. Inclusion criteria were age ≥ 40 years, a diagnosis of osteoporosis and prescription of romosozumab or a PTH analog (teriparatide/abaloparatide) during 8.2019-8.2022. 1:1 propensity score matched cohorts were created using demographic variables, comorbidities, and medications. Kaplan-Meier analysis was used to estimate the probability of the outcomes. OUTCOMES: Incident 3-point major adverse CV event or death (3P-MACE) during 1-year of follow-up after the initial prescription. RESULTS: 5,626 and 15,986 patients met the criteria for romosozumab and PTH analog cohorts, respectively, with 5,610 patients per group following propensity score matching. 3P-MACE was significantly less frequent in the romosozumab vs. PTH analog cohort (158 vs 211 patients with an outcome, p=0.003) with reductions in the individual components of the composite outcome: myocardial ischemic events (31 vs 58, p=0.003); cerebrovascular events 56 vs 79, p=0.037; deaths (83 vs 104, p=0.099). CONCLUSIONS: In a diverse real-world setting, prescription of romosozumab for osteoporosis is associated with less adverse CV events when compared to PTH analog therapy.

Estimating Lumbar Spine Least Significant Change for Fewer than Four Vertebrae: The Manitoba BMD Registry.

INTRODUCTION: The International Society of Clinical Densitometry recommends omitting lumbar vertebrae affected by structural artifact from spine BMD measurement. Since reporting fewer than 4 vertebrae reduces spine BMD precision, least significant change (LSC) needs to be adjusted upwards when reporting spine BMD change based on fewer than 4 vertebrae. METHODOLOGY: In order to simplify estimating LSC from combinations of vertebrae other than L1-L4 (denoted LSCL1-4 ), we analyzed 879 DXA spine scan-pairs from the Manitoba BMD Program's ongoing precision evaluation. The additional impact on the LSC of performing the second scan on the same day vs different day was also assessed. RESULTS: LSC progressively increased when fewer vertebrae were included, and also increased when the scans were performed on different days. We estimated that the LSCL1-4 should be adjusted upwards by 7 %, 24 % and 65 % to approximate the LSC for 3, 2, or 1 vertebral body, respectively. To additionally capture the greater LSC when the precision study was done on different days, LSCL1-4 derived from a precision study where scans were done on the same day should be adjusted upwards by 39 %, 60 % and 112 % for 3, 2, or 1 vertebral body, respectively. CONCLUSION: LSCL1-4 derived from a precision study where scans are performed on the same day can be used to estimate LSC for fewer than 4 vertebrae and for scans performed on different days.

Reporting of Full-Length Femur Imaging to Detect Incomplete Atypical Femur Fractures: 2023 Official Positions of the International Society for Clinical Densitometry.

Incomplete atypical femur fractures (iAFFs) are associated with the long-term use of anti-resorptive therapies. Although X-rays are typically used to screen for iAFFs, images from dual-energy X-ray absorptiometry (DXA) offer an alternate method for detecting iAFFs. Although a previous 2019 ISCD Official Position on this subject exists, our task force aimed to update the literature review and to propose recommendations on reporting findings related to iAFFs that may be observed on DXA images. The task force recommended that full-length femur imaging (FFI) from DXA can be used as a screening tool for iAFFs. The presence of focal lateral cortical thickening and transverse lucencies should be reported, if identified on the FFI. This task force proposed a classification system to determine the likelihood of an iAFF, based on radiographic features seen on the FFI. Lastly, the task force recommended that the clinical assessment of prodromal symptoms (pain) is not required for the assessment of FFI.

Executive Summary of the 2023 Adult Position Development Conference of the International Society for Clinical Densitometry: DXA Reporting, Follow-up BMD Testing and Trabecular Bone Score Application and Reporting.

After 15 months of preparation by task force chairs and teams, ISCD's 9th Position Development Conference (PDC) convened in Northbrook, IL, USA on March 28th and 29th, 2023 to approve new ISCD Official Positions in the topic areas of DXA Reporting, Follow-up BMD Testing and TBS Application and Reporting. Three teams of participants work to bring the PDC to fruition: the Steering Committee, Task Forces and Chairs, and the Expert Panel. To reach agreement on draft Official Positions, the PDC follows a scripted process with the UCLA/RAND Appropriateness Method (UCLA/RAM) as its foundation. Multiple rounds of data review, public debate and voting resulted in 32 new or modified Official Positions. Six companion position papers are also published along with this Executive Summary, serving as the detailed substantiation for the Official Positions. This Executive Summary reviews the personnel groups, activities and products of the 2023 PDC, with the entirety of the updated 2023 Official Positions presented in Appendix A. New Official Positions are highlighted in bold.

DXA Reporting Updates: 2023 Official Positions of the International Society for Clinical Densitometry.

INTRODUCTION: Professional guidance and standards assist radiologic interpreters in generating high quality reports. Initially DXA reporting Official Positions were provided by the ISCD in 2003; however, as the field has progressed, some of the current recommendations require revision and updating. This manuscript details the research approach and provides updated DXA reporting guidance. METHODS: Key Questions were proposed by ISCD established protocols and approved by the Position Development Conference Steering Committee. Literature related to each question was accumulated by searching PubMed, and existing guidelines from other organizations were extracted from websites. Modifications and additions to the ISCD Official Positions were determined by an expert panel after reviewing the Task Force proposals and position papers. RESULTS: Since most DXA is now performed in radiology departments, an approach was endorsed that better aligns with standard radiologic reports. To achieve this, reporting elements were divided into required minimum or optional. Collectively, required components comprise a standard diagnostic report and are considered the minimum necessary to generate an acceptable report. Additional elements were retained and categorized as optional. These optional components were considered relevant but tailored to a consultative, clinically oriented report. Although this information is beneficial, not all interpreters have access to sufficient clinical information, or may not have the clinical expertise to expand beyond a diagnostic report. Consequently, these are not required for an acceptable report. CONCLUSION: These updated ISCD positions conform with the DXA field's evolution over the past 20 years. Specifically, a basic diagnostic report better aligns with radiology standards, and additional elements (which are valued by treating clinicians) remain acceptable but are optional and not required. Additionally, reporting guidance for newer elements such as fracture risk assessment are incorporated. It is our expectation that these updated Official Positions will improve compliance with required standards and generate high quality DXA reports that are valuable to the recipient clinician and contribute to best patient care.

Reporting Fewer Than Four Vertebrae: 2023 Official Positions of the International Society for Clinical Densitometry.

The precision for spine bone mineral density (BMD) worsens as vertebrae are excluded, so recommendations are needed for least significant change (LSC) for spine BMDs based on fewer than 4 vertebrae. The task force recommends re-analysis of each facility's L1-L4 in-house precision study to determine the precision in order to calculate the LSC for each combination of 2 or 3 reported vertebrae. The task force recommended not reporting spine BMDs based on single vertebral bodies for either the diagnosis or monitoring of osteoporosis. Specific data for studies assessing the precision of two non-contiguous vertebrae are mixed, but ultimately the task force recommended that spine BMD based on 2 non-contiguous vertebrae can be used for the diagnosis and monitoring of osteoporosis.

Bilateral hip DXA Reporting: 2023 Official Positions of the International Society for Clinical Densitometry.

INTRODUCTION: This position development conference (PDC) Task Force examined the use and reporting of bilateral hip bone mineral density (BMD) measurements. This was deemed appropriate as increased availability of Dual-energy X-ray Absorptiometry (DXA) technology offering bilateral hip measurement resulted in more routine clinical use. The International Society for Clinical Densitometry Official Positions accept bilateral hip BMD measurement for clinical use but currently do not include recommendations for reporting those studies. METHODS: Four key questions regarding bilateral hip reporting were proposed by the PDC Steering Committee. Relevant literature was identified using PubMed. Questions included whether bilateral hip measurements are appropriate for diagnostic classification or monitoring, as well as which bilateral hip regions of interest should be reported for diagnosis and monitoring. Additionally, the appropriate nomenclature for bilateral hip acquisition was defined. RESULTS: The literature review demonstrated that bilateral hip measurement is appropriate and diagnostic classification should be based on the lowest T-score at the right or left side femoral neck or total hip; the mean T-score should not be used for diagnostic purposes. Mean bilateral total hip is preferred for BMD monitoring. The terms hip, or total hip were deemed appropriate nomenclature instead of femur or total proximal femur. CONCLUSION: Bilateral hip acquisition is clinically appropriate and reporting and nomenclature standards are offered herein when a bilateral hip study is acquired. In terms of future research, the impact of discordant hips on diagnosis and monitoring was identified as a significant knowledge gap.

GCM2 p.Tyr394Ser variant in Ashkenazi Israeli patients with suspected familial isolated hyperparathyroidism.

Context: A germline mutation can be identified in up to 10% of patients with primary hyperparathyroidism (PHPT). In 2017, a high frequency of the GCM2 [(NM_ 004752.4) c.1181A> C; p.Tyr394Ser; rs142287570] variant was reported in PHPT Ashkenazi Jews (AJ). Objective: To evaluate the presence of the GCM2 p.Tyr394Ser variant in Israeli patients addressed for genetic evaluation to characterize their phenotype and clinical management. Method: Patients with PHPT who underwent addressed for genetic screening for suspected familial hypocalciuric hypercalcemia (FHH), a family history of isolated hyperparathyroidism (FIHP), or failed parathyroidectomy with persistent PHPT were recruited. Those with normal initial selected gene sequencing or hyperparathyroid genetic panel completed the GCM2 p.Tyr394Ser variant sequencing. The prevalence of this variant was evaluated using our local genomic database. Results: A total of 42 single individuals from unrelated kindreds were evaluated. A disease-causing mutation was found in 11 (26.1%) patients: 10 were diagnosed with FHH (eight CASR and two AP2S1 mutations), and one patient had a CKN2B mutation. In 28 of the remaining patients, the GCM2 p.Tyr394Ser variant was positive in three (10.7%), and all were AJ. Within AJ (15/28, 53.5%), the rate of the p.Tyr394Ser variant was 3/15 (20%), and of those, two had a history of familial isolated hyperparathyroidism. Multi-glandular parathyroid adenoma/hyperplasia was also observed in two of these patients. No clinical or laboratory findings could discriminate patients with the GCM2 p.Tyr394Ser variant from those with FHH. Cinacalcet normalized the calcium levels in one patient. The prevalence of the GCM2 p.Tyr394Ser variant in 15,407 tests in our local genomic database was 0.98%. Conclusion: In contrast to previous observations, the GCM2 p.Tyr394Ser variant-associated phenotype may be mild in AJ with FIHP, sometimes mimicking FHH. Because surgery may be curative, surgeons should be aware of the possibility of multiple gland diseases in these patients. The clinical spectrum and clinical utility of screening for this variant warrant further investigation.

Trabecular Bone Score Preceding and during a 2-Year Follow-Up after Sleeve Gastrectomy: Pitfalls and New Insights.

Bariatric surgery (BS) can have negative effects on bone health. Bone microarchitecture quality evaluation using the trabecular bone score (TBS) has not been described in patients after sleeve gastrectomy (SG). To test the hypothesis that the TBS is clinically useful for this population, we evaluated changes in bone mineral density (BMD) and the TBS in a longitudinal cohort study following SG. The measurements before surgery and after 12 and 24 postoperative months were as follows: weight, height, BMI, waist circumference (WC), BMD and TBS. The results at baseline showed the following: a mean BMI of 43 ± 0.56, TBS of 1.25 ± 0.02, lumbar spine BMD T-score of -0.4 ± 0.93, TBS T-score of -2.30 ± 0.21, significantly lower than BMD-T-score, and associated with a BMD-T-TBS-T gap (T-gap) of -2.05 ± 1.26 (-0.24 ± 0.13). One year after surgery, the TBS had significantly improved (+12.12% ± 1.5), leading to a T-gap of -0.296 ± 0.14, which remained stable at 2 years post-surgery. A correlation analysis revealed a significant negative correlation between the T-gap and WC (r = -0.43 p = 0.004). Our interpretation is that abdominal fat may interfere with image acquisition via increased tissue thickness, leading to a false low TBS at baseline. In conclusion, TBS should be interpreted with caution in patients with obesity and elevated WC. Additionally, we show that after SG, the LS microarchitecture measured using the TBS is partially degraded in up to 25% of patients. Further studies are warranted to assess hip bone microarchitecture changes after bariatric surgery.

Deliberate Compensated Vasoplegia-A Novel Pharmaceutical Approach for Controlling Blood Pressure During Surgery for Pheochromocytoma.

BACKGROUND: The most dreaded adverse event of pheochromocytoma surgery is operative severe blood pressure fluctuations. Preoperative protocols with alpha-blockade have achieved controversial results. No study to date evaluated the use of operative protocols in pheochromocytoma patients. Deliberated compensated vasoplegia (DCV) is a novel pharmaceutical regimen developed at our institution to decrease severe hypertensive events. The aim of this study is to compare outcomes of pheochromocytoma resection with and without DCV protocol. METHODS: A retrospective analysis of all pheochromocytoma resections between the years 2012 and 2021 was performed. Resections performed with and without DCV protocol were compared. The primary outcome measured was the incidence of severe hypertension (MAP > 150 mmHg) during surgery. Secondary outcomes included other abnormal blood pressure measurements as well as perioperative data and complications. RESULTS: A total of 41 resections were included, 21 performed under DCV protocol, and 20 without the protocol. Analysis demonstrated no significant difference in preoperative parameters including tumor size, catecholamine levels, and preoperative alpha-blockade protocol. The use of DCV protocol resulted in significant decrease in severe hypertension incidence from 1.95 ± 3.6 to 0.03 ± 0.13 events/h, p = 0.008. Application of the DCV protocol was not associated with any other adverse events. CONCLUSIONS: This study suggests that DCV anesthesia protocol significantly decreases the incidence of severe hypertensive episodes during pheochromocytoma resection. This is the first study that describes a highly effective protocol for controlling hypertension in pheochromocytoma patients.

Changes in bone mineral density following laparoscopic sleeve gastrectomy: 2-year outcomes.

BACKGROUND: Emerging evidence suggests that sleeve gastrectomy (SG) leads to significant bone mineral density (BMD) losses, but there is a paucity of studies evaluating skeletal consequences beyond 12-months post-operatively. OBJECTIVES: To evaluate BMD changes 2 years postoperatively. SETTING: A university hospital. METHODS: Thirty-three women (mean age: 34.4 ± 12.3 years) who underwent SG and completed 24 months of follow-up were evaluated prospectively at baseline and at 3 (M3), 6 (M6), 12 (M12), and 24 (M24) months postoperatively. Data collected included BMD at the total hip, femoral neck, and lumbar spine measured by dual-energy x-ray absorptiometry and anthropometrics, biochemical, nutritional, and physical activity parameters. RESULTS: At M24, patients achieved a mean body mass index and excess weight loss of 32.4 ± 5.1 kg/m2 and 64.5 ± 21.4%, respectively; however, weight stabilized at M12. Femoral neck BMD decreased significantly from baseline to M24 (.924 ± .124 versus .870 ± .129 g/cm2, P < .001), with no change between M12 and M24 (P = .273). Total hip BMD decreased significantly from baseline to M24 (1.004 ± .105 versus .965 ± .132 g/cm2, P < .001) but increased between M12 and M24 (P = .001). No significant changes were noted in lumbar spine BMD. The percentage of changes in the femoral neck and the total hip BMD from baseline to M24 positively correlated with postoperative excess weight loss (r = .352, P = .045, and r = .416, P = .018, respectively). CONCLUSION: Despite notable weight loss, women who underwent SG experienced significant bone loss at the total hip and femoral neck more than 2 years postoperatively. Future studies should investigate intervention strategies to attenuate skeletal deterioration after SG.

Successful parathyroidectomy improves cognition in patients with primary hyperparathyroidism: A prospective study in a tertiary medical center and comprehensive review of the literature.

Context: The recent American and European guidelines on management of patients with primary hyperparathyroidism (PHPT) did not endorse neurocognitive evaluation as part of standard work-up and did not consider it as a surgery criterion.The neurocognitive deleterious effects of hyperparathyroidism and impact of parathyroidectomy on PHPT patients is yet to be elucidated. Objective: To evaluate specific neurocognitive functions in PHPT patients prior to parathyroidectomy and describe the changes during follow-up with serial evaluations. Design: A prospective case-control study including parathyroidectomy candidates evaluated at a tertiary teaching university hospital. Thorough neurocognitive evaluation was conducted before and 1- & 6-months following parathyroidectomy: Rey Auditory Verbal Learning Test (RAVLT), Rey-Osterrieth Complex Figure Test (ROCF), Trail Making Test A, Trail Making Test B, Addenbrooke's Cognitive Examination-III (ACE), Frontal Assessment Battery (FAB), Beck Depression Inventory (BDI). Results: 18 consecutive patients underwent successful parathyroidectomy. Various neurocognitive functions improved significantly after successful parathyroidectomy: long term auditory memory (RAVLT, p=0.008), short- and long-term visual memory (ROCF, p=0.006 and p=0.002 respectively), visual attention and complex concentration skills (trail making A, p<0.001) and executive abilities (trail making B, p=0.005). No change was identified in frontal-lobe abilities. Depression symptoms were absent or minimal prior to surgery and no significant change was observed after surgery. Conclusions: PHPT is associated with significant various neurocognitive dysfunctions when mindfully evaluated before surgery. Successful parathyroidectomy results in several neurocognitive aspect improvements. The data suggest that neurocognitive deterioration may be considered an added parathyroidectomy criterion when surgical decision is not straightforward.

Safety and Efficacy of Oral Human Parathyroid Hormone (1-34) in Hypoparathyroidism: An Open-Label Study.

The standard treatment of primary hypoparathyroidism (hypoPT) with oral calcium supplementation and calcitriol (or an analog), intended to control hypocalcemia and hyperphosphatemia and avoid hypercalciuria, remains challenging for both patients and clinicians. In 2015, human parathyroid hormone (hPTH) (1-84) administered as a daily subcutaneous injection was approved as an adjunctive treatment in patients who cannot be well controlled on the standard treatments alone. This open-label study aimed to assess the safety and efficacy of an oral hPTH(1-34) formulation as an adjunct to standard treatment in adult subjects with hypoparathyroidism. Oral hPTH(1-34) tablets (0.75 mg human hPTH(1-34) acetate) were administered four times daily for 16 consecutive weeks, and changes in calcium supplementation and alfacalcidol use, albumin-adjusted serum calcium (ACa), serum phosphate, urinary calcium excretion, and quality of life throughout the study were monitored. Of the 19 enrolled subjects, 15 completed the trial per protocol. A median 42% reduction from baseline in exogenous calcium dose was recorded (p = .001), whereas median serum ACa levels remained above the lower target ACa levels for hypoPT patients (>7.5 mg/dL) throughout the study. Median serum phosphate levels rapidly decreased (23%, p = .0003) 2 hours after the first dose and were maintained within the normal range for the duration of the study. A notable, but not statistically significant, median decrease (21%, p = .07) in 24-hour urine calcium excretion was observed between the first and last treatment days. Only four possible drug-related, non-serious adverse events were reported over the 16-week study, all by the same patient. A small but statistically significant increase from baseline quality of life (5%, p = .03) was reported by the end of the treatment period. Oral hPTH(1-34) treatment was generally safe and well tolerated and allowed for a reduction in exogenous calcium supplementation, while maintaining normocalcemia in adult patients with hypoparathyroidism. © 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).

Pathogenic Stress Induces Human Monocyte to Express an Extracellular Web of Tunneling Nanotubes.

Actin-based tunneling nanotubes are a means of intercellular communication between remote cells. In the last decade, this type of nanotube was described in a wide variety of cell types and it became widely accepted that communication through these nanotubes is related to response to environmental changes. Few reports, however, are available regarding the expression of similar nanotubes in vivo or in primary cells. Moreover, the functional significance of this intercellular communication for health and disease is largely unknown. In this context, and as a first step in unraveling these questions, we examined the formation of similar nanotubes in primary peripheral human monocytes. To that end, we combined the use of a live cell imaging system along with advanced methods of fluorescent and scanning electron microscopy. This experimental approach reveals for the first time that the bacterial lipopolysaccharide endotoxin induces a transient expression of an unexpected abundance of actin-based tunneling nanotubes associated with vesicles. In addition, it was found that a similar response can be achieved by treating human monocytes with various bacterial and yeast membrane components, as well as with a viral component analog. In all these cases, this response is mediated by distinct complexes of toll-like receptors. Therefore, we suggest that the observed phenomena are related to a broad type of monocyte pathogen response, and raise the possibility that the phenomena described above may be involved in many clinical situations related to inflammation as a new topic of study.

Opportunistic screening for osteoporosis and osteopenia by routine computed tomography scan: A heterogeneous, multiethnic, middle-eastern population validation study.

PURPOSE: We aimed define thresholds for HU values observed on opportunistic CT scans that suggest abnormal bone mineral density (BMD) in a heterogeneous Middle Eastern population. METHODS: Consecutive patients who had undergone CT and dual-energy X-ray absorptiometry (DXA) test of the lumbar spine within 6 months were included in this retrospective study. Hounsfield units (HU) on lateral lumbar spine CT and BMD at the spine and hip on DXA were compared. Potential HU thresholds suggestive of abnormal BMD were established using receiver operating characteristic (ROC) analysis. RESULTS: 246 patients (mean age of 64 ±â€¯11.6 years; 83 % female) were included. On DXA, 27 % had osteoporosis, 56 % had osteopenia, and 17 % had normal BMD. To distinguish osteoporosis from non-osteoporosis (osteopenia, normal BMD), a threshold of HU160 had sensitivity 95 % and the balanced threshold was HU121 (sensitivity 74 %, specificity 61 %). To distinguish normal from abnormal BMD (osteoporosis, osteopenia), a threshold of HU110 had specificity 93 % and the balanced threshold was HU149 (sensitivity 76 %, specificity 74 %). CONCLUSIONS: In a heterogeneous Middle-Eastern population, our study supports the reported correlation between HU values on lumbar spine CT and BMD on DXA. In this population, HU > 160 correlates with low probability of osteoporosis on DXA, and screening examination is not warranted unless a vertebral fracture is detected; for HU ≤ 110 there is high probability of abnormal (osteoporosis or osteopenia) BMD, DXA examination is warranted; Finally, for HU 110-160, there is an intermediate chance of abnormal BMD, DXA examination may be warranted in specific patients with other risk factors.