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The prevalence of vertebral fractures on routine chest radiographs of elderly Caucasian women was only 1.3 times higher than in African American (AA) women, a difference considerably smaller than reported in population studies. AAs with medical problems may have higher risk of vertebral fractures than previously suspected.IntroductionEarlier studies noted a 1.9- to 3.7-fold higher prevalence of vertebral fractures in Caucasian (CA) compared to African American (AA) women. These studies, however, may have suffered from selection bias. We reported that among women referred for bone density testing, the prevalence of vertebral fractures in AA was the same as in CA women. Suspecting that the latter might have been due to a referral bias, we examined the racial difference in the prevalence of vertebra fractures on chest radiographs of patients seeking general medical care, not selected for osteoporosis.MethodsConsecutive chest radiographs (N = 1,200) of women over age 60 were evaluated using Genant's semi-quantitative method. Patients' race and the presence of diseases or medications associated with increased fracture risk were ascertained from the electronic medical records.ResultsAmong 1,011 women (76% AA) with usable radiographs, 11% had moderate or severe vertebral fractures. The prevalence of vertebral fractures was 10.3% in 773 AA and 13% in 238 CA women (p = 0.248 for difference between races). The lack of difference persisted after controlling for age, smoking, use of glucocorticoids, or presence of cancer, rheumatoid arthritis, organ transplantation, and end-stage renal disease. Among all subjects, CA women were more likely to be diagnosed and treated for osteoporosis (p

Neural stem cells have exhibited efficacy in pre-clinical models of spinal cord injury (SCI) and are on a translational path to human testing. We recently reported that neural stem cells must be driven to a spinal cord fate to optimize host axonal regeneration into sites of implantation in the injured spinal cord, where they subsequently form neural relays across the lesion that support significant functional improvement. We also reported methods of deriving and culturing human spinal cord neural stem cells derived from embryonic stem cells that can be sustained over serial high passage numbers in vitro, providing a potentially optimized cell source for human clinical trials. We now report further optimization of methods for deriving and sustaining cultures of human spinal cord neural stem cell lines that result in improved karyotypic stability while retaining anatomical efficacy in vivo. This development improves prospects for safe human translation., Competing Interests: Declaration of competing interest The authors declare no competing interests., (Copyright © 2024. Published by Elsevier Inc.)

Context: Chronic hypoparathyroidism is conventionally treated with oral calcium and active vitamin D to reach and maintain targeted serum calcium and phosphorus levels, but some patients remain inadequately controlled., Objective: To assess long-term safety and efficacy of recombinant human parathyroid hormone (1-84) (rhPTH(1-84)) treatment., Methods: This was an open-label extension study at 12 US centers. Adults (n = 49) with chronic hypoparathyroidism were included. The intervention was rhPTH(1-84) for 6 years. The main outcome measures were safety, biochemical measures, oral supplement doses, bone indices., Results: Thirty-eight patients (77.6%) completed the study. Throughout 72 months, mean albumin-adjusted serum calcium was within 2.00 to 2.25 mmol/L (8.0-9.0 mg/dL). At baseline, 65% of patients with measurements (n = 24/37) were hypercalciuric; of these, 54% (n = 13/24) were normocalciuric at month 72. Mean serum phosphorus declined from 1.6 ± 0.19 mmol/L at baseline (n = 49) to 1.3 ± 0.20 mmol/L at month 72 (n = 36). Mean estimated glomerular filtration rate was stable. rhPTH(1-84)-related adverse events were reported in 51.0% of patients (n = 25/49); all but 1 event were mild/moderate in severity. Mean oral calcium supplementation reduced by 45% ± 113.6% and calcitriol by 74% ± 39.3%. Bone turnover markers declined by month 32 to a plateau above pretreatment values; only aminoterminal propeptide of type 1 collagen remained outside the reference range. Mean bone mineral density z score fell at one-third radius and was stable at other sites., Conclusion: 6 years of rhPTH(1-84) treatment was associated with sustained improvements in biochemical parameters, a reduction in the percentage of patients with hypercalciuria, stable renal function, and decreased supplement requirements. rhPTH(1-84) was well tolerated; no new safety signals were identified., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society.)

Background: The PARADIGHM registry of adult and pediatric patients with chronic hypoparathyroidism evaluates the long-term safety and effectiveness of treatment with recombinant human parathyroid hormone, rhPTH(1-84), and describes the clinical disease course under conditions of routine clinical practice. In this first report, we detail the registry protocol and describe the baseline characteristics of two adult patient cohorts from an interim database analysis. One cohort after study entry were prescribed rhPTH(1-84), and the other cohort received conventional therapy of calcium and active vitamin D., Methods: An observational study of patients with chronic hypoparathyroidism in North America and Europe, collecting data for ≥10 years per patient. Main outcome measures were baseline patient demographics, clinical characteristics, medications, and disease outcome variables of symptoms, biochemical parameters, and health assessments. Baseline is the enrollment assessment for all variables except biochemical measurements in patients treated with rhPTH(1-84); those measurements were the most recent value before the first rhPTH(1-84) dose. Exclusion criteria applied to the analysis of specified outcomes included pediatric patients, patients who initiated rhPTH(1-84) prior to enrollment, and those who received rhPTH(1-34). Clinically implausible biochemical outlier data were excluded., Results: As of 30 June 2019, data of 737 patients were analyzed from 64 centers; 587 (80%) were women, mean ± SD age 49.1±16.45 years. At enrollment, symptoms reported for patients later prescribed rhPTH(1-84) (n=60) and those who received conventional therapy (n=571), respectively, included fatigue (51.7%, 40.1%), paresthesia (51.7%, 29.6%), muscle twitching (48.3%, 21.9%), and muscle cramping (41.7%, 33.8%). Mean serum total calcium, serum phosphate, creatinine, and estimated glomerular filtration rate were similar between cohorts. Health-related quality of life (HRQoL) 36-item Short Form Health Survey questionnaire scores for those later prescribed rhPTH(1-84) were generally lower than those for patients in the conventional therapy cohort., Conclusions: At enrollment, based on symptoms and HRQoL, a greater percentage of patients subsequently prescribed rhPTH(1-84) appeared to have an increased burden of disease than those who received conventional therapy despite having normal biochemistry measurements. PARADIGHM will provide valuable real-world insights on the clinical course of hypoparathyroidism in patients treated with rhPTH(1-84) or conventional therapy in routine clinical practice., Trial Registration: EUPAS16927, NCT01922440., (© 2021. The Author(s).)

Objectives: Falls represent a significant cause of morbidity and mortality in older adults, and are more common among those living alone. We aimed to determine if there is an association between loneliness and falls. Methods: Participants were surveyed in three waves separated by 5 years. We used the three-item UCLA Loneliness Scale to measure loneliness. Results: Data from 2337 respondents, with both loneliness and fall data in at least two consecutive waves, were included. Over three waves, 51% respondents reported a fall and 23% reported ≥ two falls. In multivariate analysis, the odds of having ≥ one fall 5 years later increased by a factor of 1.11 per one point increase on the loneliness scale (OR = 1.11, 95% CI 1.04, 1.19; p  < .01). Discussion: Lonely older adults have increased odds of future falls. Strategies for combating loneliness in older adults may help reduce fall-related morbidity and mortality., Competing Interests: Declaration of Conflicting Interests: The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: TJV is an investigator, advisor and speaker for Radius Health, an advisor and investigator for Takeda, and an investigator for Ascendis. All other authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2021.)

Context: Conventional hypoparathyroidism treatment with oral calcium and active vitamin D is aimed at correcting hypocalcemia but does not address other physiologic defects caused by PTH deficiency., Objective: To evaluate long-term safety and tolerability of recombinant human PTH (1-84) [rhPTH(1-84)]., Design: Open-label extension study; 5-year interim analysis., Setting: 12 US centers., Patients: Adults (N = 49) with chronic hypoparathyroidism., Intervention(s): rhPTH(1-84) 25 or 50 µg/d initially, with 25-µg adjustments permitted to a 100 µg/d maximum., Main Outcome Measure(s): Safety parameters; composite efficacy outcome was the proportion of patients with ≥50% reduction in oral calcium (or ≤500 mg/d) and calcitriol (or ≤0.25 µg/d) doses, and albumin-corrected serum calcium normalized or maintained compared with baseline, not exceeding upper limit of normal., Results: Forty patients completed 60 months of treatment. Mean albumin-corrected serum calcium levels remained between 8.2 and 8.7 mg/dL. Between baseline and month 60, levels ± SD of urinary calcium, serum phosphorus, and calcium-phosphorus product decreased by 101.2 ± 236.24 mg/24 hours, 1.0 ± 0.78 mg/dL, and 8.5 ± 8.29 mg2/dL2, respectively. Serum creatinine level and estimated glomerular filtration rate were unchanged. Treatment-emergent adverse events (AEs) were reported in 48 patients (98.0%; hypocalcemia, 36.7%; muscle spasms, 32.7%; paresthesia, 30.6%; sinusitis, 30.6%; nausea, 30.6%) and serious AEs in 13 (26.5%). At month 60, 28 patients (70.0%) achieved the composite efficacy outcome. Bone turnover markers increased, peaked at ∼12 months, and then declined to values that remained above baseline., Conclusion: Treatment with rhPTH(1-84) for 5 years demonstrated a safety profile consistent with previous studies and improved key biochemical parameters., (Copyright © 2019 Endocrine Society.)

Patients with hypoparathyroidism have a multitude of physical, emotional, and cognitive complaints consistent with reduced quality of life (QOL). Impaired QOL in patients treated with conventional therapy with calcium and active vitamin D has been documented in epidemiologic (registry) studies, case-controlled studies, and surveys, and at baseline in clinical trials of parathyroid hormone (PTH). Treatment with PTH has been shown to improve QOL in some but not all studies., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Context: Reduced health-related quality of life (HRQoL) is common in patients with hypoparathyroidism treated conventionally with calcium and active vitamin D supplements., Objective: To examine the effects of recombinant human parathyroid hormone [rhPTH(1-84)] on HRQoL as measured by the 36-Item Short-Form Health Survey (SF-36) during a multinational, randomized, placebo-controlled study., Patients: Adults (N = 122) with chronic hypoparathyroidism., Intervention(s): After an optimization period when calcium and/or active vitamin D supplements were adjusted to reach target serum calcium levels (8.0 to 9.0 mg/dL; 2.0 to 2.2 mmol/L), patients were randomly assigned to receive placebo (n = 39) or rhPTH(1-84) (n = 83) (starting dose, 50 μg/d, could be titrated up to 100 μg/d); supplement doses were adjusted to maintain target serum calcium levels., Main Outcome Measure(s): Change from baseline (postoptimization, at randomization) to week 24 in HRQoL as assessed by the SF-36., Results: Overall, the between-group differences were not statistically significant. However, in the rhPTH(1-84) group, there were significant improvements in the physical component summary score (P = 0.004), and in body pain (P < 0.05), general health (P < 0.05), and vitality (P < 0.001) domains as compared with baseline values. In the placebo group, there were no significant changes for any domains. The magnitude of change between 0 and 24 weeks in SF-36 scores was negatively correlated with baseline scores, such that patients with lower HRQoL at baseline were more likely to experience improvement in response to treatment., Conclusion: Treatment with rhPTH(1-84) may improve HRQoL in adults with hypoparathyroidism., (Copyright © 2017 Endocrine Society)

Osteoporosis is a highly prevalent condition, resulting in significant morbidity and mortality. Nevertheless, it is frequently untreated. Vertebral fractures often do not come to clinical attention, yet, their presence is diagnostic of osteoporosis, helps to predict the risk of future fractures, and may alter the choice of pharmacotherapy. The addition of lateral spine imaging technology to the densitometer, for vertebral fracture assessment (VFA), represented a major advancement in the ability to diagnose vertebral fractures and osteoporosis. VFA is an under-utilized and highly effective imaging tool to enhance osteoporosis detection and fracture prevention. Several factors make VFA an ideal technology to evaluate for vertebral fractures. These include: the ability to obtain the image at the same time the bone density is done, with significantly lower radiation exposure than with spine radiography, and at a lower cost. This review provides an overview of the clinical significance of identifying vertebral fractures, the origins of the VFA, its clinical indications, a review of the methods used to diagnose vertebral fracture, an overview on interpreting the VFA, and the strengths and limitations of this technique., (Copyright © 2017 Elsevier Inc. All rights reserved.)

This corrects the article DOI: 10.1038/nrdp.2017.55.

Trabecular bone score (TBS), a noninvasive textural analysis of the lumbar spine dual-energy X-ray absorptiometry (DXA) image, has been shown to predict fractures in Caucasian (CA) populations but has not been thoroughly studied in African-American (AA) populations. The aim of this study was to compare the TBS in AAs and CAs and to assess whether TBS can be used to refine fracture risk stratification in AA patients. Eight hundred twenty-five women (390 AAs, 435 CAs) referred for bone mineral density (BMD) as part of their clinical care had measurements of the TBS, the BMD of the lumbar spine, total hip, and femoral neck, and vertebral fracture assessment for detection of vertebral fractures. Unadjusted TBS was higher in CA than AA (1.275 vs 1.238, p < 0.001), but this was no longer true after adjusting for age and tissue thickness. Interestingly, differences in TBS were still highly significant in those under 60 yr of age even with adjustment for tissue thickness, but not in older subjects. There were 74 CAs and 56 AAs with vertebral fractures on vertebral fracture assessment (17% vs 14%, p = 0.30). In CA, the odds ratio (OR) for prevalent vertebral fracture per SD decrease in TBS was 2.33 (p < 0.001), whereas in AA, the OR was 1.43 (p = 0.02). In a multivariate logistic regression model that also included age, BMD T-score, and glucocorticoid use, the association between TBS and prevalent vertebral fractures was still highly significant in CAs (OR 1.54, p = 0.008) but not in AAs (OR 1.23, p = 0.21). Our results suggest that TBS may be less discriminatory in regard to fracture risk in AAs than in CAs and that TBS may need to be used differently in these 2 ethnic groups., (Copyright © 2016 International Society for Clinical Densitometry. Published by Elsevier Inc. All rights reserved.)

Trabecular bone score, an indirect measure of bone structure, may differ between ethnicities. We found that African Americans had lower trabecular bone score than do whites referred for densitometry, even when controlling for age and abdominal soft tissue thickness., Purpose: Trabecular bone score (TBS), an indirect measure of bone structure, has been shown to predict fractures in predominantly white populations. Analysis of NHANES data revealed lower TBS in African Americans than in whites. However, it is not clear if this is true in patients referred for densitometry (where fracture risk stratification is most pertinent) or if ethnic differences in TBS may be related to differences in abdominal soft tissue (tissue thickness), which was not controlled for in the NHANES study., Methods: We retrospectively analyzed all BMD scans obtained at a university hospital in Chicago between 2011 and 2016., Results: There were 3187 women (51 % African American) and 675 men (32 % African American). African American women were older (69.6 ± 10.4 vs. 64.8 ± 1.3) and heavier (BMI 28.3 ± 4.7 vs. 25.4 ± 4.5) than whites were, while men were of similar age and BMI. African American women had higher T-scores at all sites (the lowest of T-scores, termed LowT, -1.5 ± 1.2 vs. -1.9 ± 1.0, p < 0.001) but lower TBS than white women even when adjusting for age and tissue thickness (1.231 ± 0.130 versus 1.251 ± 0.130, p < 0.001). While LowT was higher in African American men (-1.1 ± 1.2 vs. -1.5 ± 1.4, p < 0.001), TBS was lower than in white men even after adjusting for age and tissue thickness (1.232 ± 0.144 vs. 1.275 ± 0.144, p < 0.001)., Conclusions: African Americans had lower TBS than whites did, even with adjustment for age and tissue thickness. Ethnic differences in TBS should be considered when assessing fracture risk in clinical practice.

In hypoparathyroidism, inappropriately low levels of parathyroid hormone lead to unbalanced mineral homeostasis. The objective of this study was to determine the effect of recombinant human parathyroid hormone, rhPTH(1-84), on phosphate and vitamin D metabolite levels in patients with hypoparathyroidism. Following pretreatment optimization of calcium and vitamin D doses, 124 patients in a phase III, 24-week, randomized, double-blind, placebo-controlled study of adults with hypoparathyroidism received subcutaneous injections of placebo or rhPTH(1-84) (50 µg/day, titrated to 75 and then 100 µg/day, to permit reductions in oral calcium and active vitamin D doses while maintaining serum calcium within 2.0-2.2 mmol/L). Predefined endpoints related to phosphate homeostasis and vitamin D metabolism were analyzed. Serum phosphate levels decreased rapidly from the upper normal range and remained lower with rhPTH(1-84) (P < 0.001 vs. placebo). At week 24, serum calcium-phosphate product was lower with rhPTH(1-84) vs. placebo (P < 0.001). rhPTH(1-84) treatment resulted in significant reductions in oral calcium dose compared with placebo (P < 0.001) while maintaining serum calcium. After pretreatment optimization, baseline serum 25-hydroxyvitamin D (25[OH]D) and 1,25-dihydroxyvitamin D (1,25[OH] 2 D) levels were within the normal range in both groups. After 24 weeks, 1,25(OH) 2 D levels were unchanged in both treatment groups, despite significantly greater reductions in active vitamin D dose in the rhPTH(1-84) group. In hypoparathyroidism, rhPTH(1-84) reduces serum phosphate levels, improves calcium-phosphate product, and maintains 1,25(OH) 2 D and serum calcium in the normal range while allowing significant reductions in active vitamin D and oral calcium doses., Competing Interests: BLC, JPB, and DMS have received institutional research grants from and served as advisory group members for NPS Pharmaceuticals, Inc.; MM and TJV have served as advisory group members for NPS Pharmaceuticals, Inc.; HL was an employee of NPS Pharmaceuticals, Inc., at the time the study was conducted and the manuscript was written. Ethical approval All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards. Informed consent Informed consent was obtained from all individual participants included in the study.

No studies have compared how well different prediction models discriminate older men who have a radiographic prevalent vertebral fracture (PVFx) from those who do not. We used area under receiver operating characteristic curves and a net reclassification index to compare how well regression-derived prediction models and nonregression prediction tools identify PVFx among men age ≥65 yr with femoral neck T-score of -1.0 or less enrolled in the Osteoporotic Fractures in Men Study. The area under receiver operating characteristic for a model with age, bone mineral density, and historical height loss (HHL) was 0.682 compared with 0.692 for a complex model with age, bone mineral density, HHL, prior non-spine fracture, body mass index, back pain, grip strength, smoking, and glucocorticoid use (p values for difference in 5 bootstrapped samples 0.14-0.92). This complex model, using a cutpoint prevalence of 5%, correctly reclassified only a net 5.7% (p = 0.13) of men as having or not having a PVFx compared with a simple criteria list (age ≥ 80 yr, HHL >4 cm, or glucocorticoid use). In conclusion, simple criteria identify older men with PVFx and regression-based models. Future research to identify additional risk factors that more accurately identify older men with PVFx is needed., (Copyright © 2014 The International Society for Clinical Densitometry. All rights reserved.)

The 2013 Position Development Conference of the International Society for Clinical Densitometry (ISCD) has adopted simplified indications for vertebral fracture assessment (VFA) based on an analysis of the Study of Osteoporotic Fractures (SOF). This showed that a simpler regression model, which included only age, bone mineral density (BMD), and height loss, was able to differentiate women with vertebral fractures from those without vertebral fractures almost as well as more complex models. We aimed to verify these findings in 1228 women referred for BMD testing and determine if the 2013 ISCD indications for VFA would perform as well the 2007 indications. The simple and complex SOF-based models were similar in terms of sensitivity (88.4% vs 89.4%), specificity (44.4% vs 45.5%), positive (25.9% vs 26.5%) and negative (94.5% vs 95.1%) predictive values, and area under the receiver operating characteristics curve (AUROC) (0.664 vs 0.674). The 2013 and 2007 ISCD VFA indications did not differ significantly in terms of sensitivity (88.2% vs 91.3%), specificity (41.3% vs 37.5%), positive (25.3% vs 22.9%) and negative (93.9% vs 95.5%) predictive values, and AUROC (0.648 vs 0.644). Our study provides support for the use of the simplified 2013 ISCD VFA indications as a practical approach to VFA testing., (Copyright © 2014 The International Society for Clinical Densitometry. Published by Elsevier Inc. All rights reserved.)

It is unknown how well prediction models incorporating multiple risk factors identify women with radiographic prevalent vertebral fracture (PVFx) compared with simpler models and what their value might be in clinical practice to select older women for lateral spine imaging. We compared 4 regression models for predicting PVFx in women aged 68 y and older enrolled in the Study of Osteoporotic Fractures with a femoral neck T-score ≤ -1.0, using area under receiving operator characteristic curves (AUROC) and a net reclassification index. The AUROC for a model with age, femoral neck bone mineral density, historical height loss (HHL), prior nonspine fracture, body mass index, back pain, and grip strength was only minimally better than that of a more parsimonious model with age, femoral neck bone mineral density, and historical height loss (AUROC 0.689 vs 0.679, p values for difference in 5 bootstrapped samples <0.001-0.35). The prevalence of PVFx among this older population of Caucasian women remained more than 20% even when women with low probability of PVFx, as estimated by the prediction models, were included in the screened population. These results suggest that lateral spine imaging is appropriate to consider for all Caucasian women aged 70 y and older with low bone mass to identify those with PVFx., (Copyright © 2014 The International Society for Clinical Densitometry. All rights reserved.)

Vertebral fracture assessment (VFA) is a low-cost method of accurately identifying individuals who have clinically unrecognized or undocumented vertebral fractures at the time of bone density test. Because prevalent vertebral fractures predict subsequent fractures independent of bone mineral density and other clinical risk factors, their recognition is an important part of strategies to identify those who are at high risk of fracture, so that prevention therapies for those individuals can be implemented. The 2007 Position Development Conference developed detailed guidelines regarding the indications for acquisition of, and interpretation and reporting of densitometric VFA tests. The purpose of the 2013 VFA Task Force was to simplify the indications for VFA yet keep them evidence based. The Task Force reviewed the literature published since the 2007 Position Development Conference and developed prediction models based on 2 large cohort studies (the Study of Osteoporotic Fractures and the Osteoporotic Fractures in Men Study) and the densitometry database of the University of Chicago. Based on these prediction models, indications for VFA were reduced to a simplified set of criteria based on age, historical height loss, use of systemic glucocorticoid therapy, and self-reported but undocumented prior vertebral fracture., (Copyright © 2013 The International Society for Clinical Densitometry. Published by Elsevier Inc. All rights reserved.)

Dual-energy X-ray absorptiometry (DXA) is the method of choice to assess fracture risk for women 65 yr and older and men 70 yr and older. The 2007 International Society for Clinical Densitometry Official Positions had developed guidelines for assessing bone density in younger women during and after the menopausal transition and in men 50-69 yr and the 2008 National Osteoporosis Foundation (NOF) guidelines recommended testing in postmenopausal women younger than 65 yr and men 50-69 yr only in the presence of clinical risk factors. The purpose of the 2013 DXA Task Force was to reassess the NOF guidelines for ordering DXA in postmenopausal women younger than 65 yr and men 50-69 yr. The Task Force reviewed the literature published since the 2007 Position Development Conference and 2008 NOF, reviewing clinical decision rules such as the Osteoporosis Screening Tool and FRAX and sought to keep recommendations simple to remember and implement. Based on this assessment, the NOF guidelines were endorsed; DXA was recommended in those postmenopausal women younger than 65 yr and men 50-69 yr only in the presence of clinical risk factors for low bone mass, such as low body weight, prior fracture, high-risk medication use, or a disease or condition associated with bone loss., (Copyright © 2013 The International Society for Clinical Densitometry. Published by Elsevier Inc. All rights reserved.)

Summary: Vertebral fracture assessment (VFA) is a new method for imaging thoracolumbar spine on bone densitometer. Among patients referred for bone densitometry, the selection of patients for VFA testing can be optimized using an index derived from clinical risk factors and bone density measurement., Purpose: VFA, a method for imaging thoracolumbar spine on bone densitometer, was developed because vertebral fractures, although common and predictive of future fractures, are often not clinically diagnosed. The study objective was to develop a strategy for selecting patients for VFA., Methods: A convenience sample from a university hospital bone densitometry center included 892 subjects (795 women) referred for bone mineral density (BMD) testing. We used questionnaires to capture clinical risk factors and dual-energy X-ray absorptiometry to obtain BMD and VFA., Results: Prevalence of vertebral fractures was 18% in women and 31% in men (p = 0.003 for gender difference). In women, age, height loss, glucocorticoid use, history of vertebral and other fractures, and BMD T-score were significantly and independently associated with vertebral fractures. A multivariate model which included above predictors had an area under the receiver operating curve of 0.85 with 95% confidence interval (CI) of 0.81 to 0.89. A risk factor index was derived from the above multivariate model. Using a level of 2 as a cut-off yielded 93% sensitivity (95% CI 87, 96) and 48% specificity (95% CI 69, 83). Assuming a 15% prevalence of vertebral fractures, this cut-off value had a 24% positive and 97% negative predictive value and required VFA scanning of three women at a cost of $60 (assuming a $20 cost/VFA scan) to detect one with vertebral fracture(s)., Conclusions: Selecting patients for VFA can be optimized using an index derived from BMD measurement and easily obtained clinical risk factors.

Summary: The utility of vertebral fracture assessment (VFA) by DXA to detect prevalent vertebral fracture in a multicenter setting was investigated by comparison to conventional radiography. While limited by lower image quality, overall performance of VFA was good but had a tendency to miss mild prevalent fractures., Introduction: In osteoporosis clinical trials standardized spine radiographs are used to detect vertebral fractures as a study endpoint. Lateral spine imaging with dual X-ray absorptiometry (DXA) scanners, known as vertebral fracture assessment (VFA) by DXA, presents a potential alternative to conventional radiography with lower radiation dose and greater patient convenience., Methods: We investigated in a multicenter setting the ability of VFA to detect fractures in comparison with conventional radiography. The study examined 203 postmenopausal women who had imaging of the spine by DXA and radiography. Three radiologists experienced in vertebral fracture assessment independently read the VFA scans and radiographs using the Genant semiquantitative method on two occasions., Conclusions: Analyzing the data from all readable vertebrae, the kappa statistic, sensitivity, and specificity ranged from 0.64-0.77, 0.65-0.84, and 0.97-0.98, respectively. Considering only moderate and severe fractures improved the kappa statistic (0.80-0.91) and sensitivity (0.70-0.86). While image quality of VFA is inferior to radiography, the detection of vertebral fractures using visual scoring is feasible. However, VFA underperformed due to unreadable vertebrae and reduced sensitivity for mild fractures. Nevertheless, VFA correctly identified most moderate and severe vertebral fractures. Despite this limitation, VFA by DXA provides an important tool for clinical research.

Radiographic texture analysis (RTA) is a computerized analysis of the spatial pattern of radiographic images used as a way of evaluating bone structure. We have shown that RTA performed on high-resolution heel images obtained using a portable densitometer differentiates subjects with and without osteoporotic fractures. In the present study, short-term precision of RTA was examined on densitometric heel images obtained from 33 subjects scanned 8 times each, with 3 observers placing a region of interest (ROI) 3 times on each image. The long-term precision was examined on images obtained from 10 subjects 3 times on each of 3 days separated by 1 week, with 2 observers placing an ROI on each image. The RTA features examined included the root mean square (RMS) variation, a measure of the contrast between the light and dark areas of the image, the first moment of the power spectrum, a measure of the spatial frequency of the trabecular pattern, and Minkowski fractal (MINK), a measure of roughness/smoothness of the trabecular pattern. The precision of the RTA features expressed as coefficient of variation ranged between the lowest of 0.5-0.7% for MINK and the highest of 14-16% for RMS. The short- and long-term precision was similar, and was not significantly influenced by repositioning and rescanning, or by ROI placement by the same or different observers. Significant sources of variability of RTA were the between-subject differences and differences between regions of the heel, but not differences due to repositioning, rescanning in the same position, or ROI placement by the same or different observers. We conclude that technical aspects of image acquisition and processing are adequate to allow further development of RTA of the densitometric images for clinical application as a method for noninvasive assessment of bone structure.

This cross-sectional study compared risk factors for prevalent vertebral fractures (diagnosed using densitometric spine image Vertebral Fracture Assessment [VFA]) in 176 black and 345 white women recruited during their clinical bone mineral density (BMD) testing at the University of Chicago Hospitals. We used logistic regression to assess the association of prevalent vertebral fractures and risk factors (age, height loss, history of nonvertebral fractures, BMD, and use of corticosteroids). The prevalence of vertebral fractures was 21% for both races. All risk factors of interest were significantly associated with vertebral fractures in white women. Among black women, only age and corticosteroid use were found to be significant predictors of presence of vertebral fracture(s). In women without history of corticosteroid use, the probability of having vertebral fracture(s) given age was lower (p=0.02) in black subjects. In 77 patients with a history of corticosteroid use, the probability of having vertebral fracture(s) was higher in black than in white women after adjustment for age (p=0.045), BMD (p=0.045), or cumulative corticosteroid dose (p=0.08). Fewer black women were prescribed pharmacologic therapy for osteoporosis, regardless of their BMD level and corticosteroid use. We conclude that use of corticosteroids may be associated with relatively greater vertebral fracture risk in blacks than in whites.

Introduction: Bone fragility is determined by bone mass, measured as bone mineral density (BMD), and by trabecular structure, which cannot be easily measured using currently available noninvasive methods. In previous studies, radiographic texture analysis (RTA) performed on the radiographic images of the spine, proximal femur, and os calcis differentiated subjects with and without osteoporotic fractures. The present cross-sectional study was undertaken to determine whether such differentiation could also be made using high-resolution os calcis images obtained on a peripheral densitometer., Methods: In 170 postmenopausal women (42 with and 128 without prevalent vertebral fractures) who had no secondary causes of osteoporosis and were not receiving treatment for osteoporosis, BMD of the lumbar spine, proximal femur, and os calcis was measured using dual energy x-ray absorptiometry. Vertebral fractures were diagnosed on densitometric spine images. RTA, including Fourier-based and fractal analyses, was performed on densitometric images of os calcis., Results: BMD at all three sites and all texture features was significantly different in subjects with and without fractures, with the most significant differences observed for the femoral neck and total hip measurements and for the RTA feature Minkowski fractal (p<0.001). In univariate logistic regression analysis, Minkowski fractal predicted the presence of vertebral fractures as well as femoral neck BMD (p<0.001). In multivariate logistic regression analysis, both femoral neck BMD and Minkowski fractal yielded significant predictive effects (p=0.001), and when age was added to the model, the effect of RTA remained significant (p=0.002), suggesting that RTA reflects an aspect of bone fragility that is not captured by age or BMD. Finally, when RTA was compared in 42 fracture patients and 42 nonfracture patients matched for age and BMD, the RTA features were significantly different between the groups (p=0.003 to p=0.04), although BMD and age were not., Conclusion: This study suggests that RTA of densitometer-generated calcaneus images provides an estimate of bone fragility independent of and complementary to BMD measurement and age.

It is not clear how bone mineral density (BMD) measurements from several regions of lumbar spine and proximal femur should be utilized in assessing fracture risk. We examined how well the newest ISCD recommendations differentiate subjects with and without prevalent vertebral fractures in 187 postmenopausal women presenting for routine bone densitometry. The association between T-scores from proximal femur and lumbar spine sites and the probability of having a vertebral fracture was modeled via logistic regression with adjustment for age. The lowest T-score of any hip or spine sites (the current ISCD recommendation) and the proximal femur measurements, particularly the femoral neck and total hip, displayed the strongest association with the probability of vertebral fractures.Subjects with a T-score < -2.5 at multiple hip sites had a higher probability of having a vertebral fracture. The sensitivity and specificity associated with particular T-score cutoff values varied greatly depending on the site of measurement.Consequently, T-score values from different sites that had comparable sensitivity/specificity for detecting the presence of vertebral fractures differed by as much as 1.5 T-score units. This finding implies that a single cutoff value, such as -2.5, might not be clinically acceptable when applied to T-scores from different sites.

Gnathodiaphyseal dysplasia (GDD) is a rare skeletal syndrome characterized by bone fragility, sclerosis of tubular bones, and cemento-osseous lesions of the jawbone. By linkage analysis of a large Japanese family with GDD, we previously mapped the GDD locus to chromosome 11p14.3-15.1. In the critical region determined by recombination mapping, we identified a novel gene (GDD1) that encodes a 913-amino-acid protein containing eight putative transmembrane-spanning domains. Two missense mutations (C356R and C356G) of GDD1 were identified in the two families with GDD (the original Japanese family and a new African American family), and both missense mutations occur at the cysteine residue at amino acid 356, which is evolutionarily conserved among human, mouse, zebrafish, fruit fly, and mosquito. Cellular localization to the endoplasmic reticulum suggests a role for GDD1 in the regulation of intracellular calcium homeostasis.

Osteoporosis is a disease that results in an increased risk of bone fracture due to a loss of bone mass and deterioration of bone structure. Bone mineral density (BMD) provides a measure of bone mass and is frequently measured by bone densitometry systems to diagnose osteoporosis. In addition, computerized radiographic texture analysis (RTA) is currently being investigated as a measure of bone structure and as an additional diagnostic predictor of osteoporosis. In this study, we assessed the ability of a peripheral bone densitometry (PD) system to yield images useful for RTA. The benefit of such a system is that it measures BMD by dual-energy x-ray absorptiometry and therefore provides high- and low-energy digital radiographic images. The bone densitometry system investigated was the GE/Lunar PIXI, which provides 512 x 512 digital images of the heel or forearm (0.2 mm pixels). We compared texture features of heel images obtained with this PD system to those obtained on a Fuji computed radiography (CR) system (0.1 mm pixels). Fourier and fractal-based texture features of images from 24 subjects who had both CR and BMD exams were calculated, and correlation between the two systems was analyzed. Fourier-based texture features characterize the magnitude, frequency content, and orientation of the trabecular bone pattern. Good correlation was found between the two modalities for the first moment (FMP) with r=0.71 (p value<0.0001) and for minimum FMP with r=0.52 (p value=0.008). Root-mean-square (RMS) did not correlate with r=0.31 (p value>0.05), while the standard deviation of the RMS did correlate with r=0.79 (p value<0.0001). Good correlation was also found between the two modalities for the fractal-based texture features with r=0.79 (p value<0.0001) for the global Minkowski dimension and r=0.63 (p value=0.0007) for the fractal dimension from a box counting method. The PD system therefore may have the potential for yielding heel images suitable for RTA.

Osteoporosis is a disease characterized by a loss of bone mass and a deterioration of bone structure. Bone mineral density (BMD) measures bone mass and is currently the method used to diagnose osteoporosis, while computerized radiographic texture analysis (RTA) is being investigated as a measure of bone structure. The GE/Lunar PIXI peripheral bone densitometer (PD) system, which uses dual-energy subtraction to measure BMD, also provides a digital image of the heel or forearm. The goal of our current research was to evaluate the physical imaging properties of the PIXI system (pixel size of 0.2 mm) compared to a Fuji computed radiography (CR) system (pixel size of 0.1 mm) to determine its suitability for texture analysis from image data. Contrast was measured using a series of uniform images covering the useful clinical exposure range. Spatial resolution was characterized by the presampling modulation transfer function (MTF) determined by an edge method. Noise power spectra (NPS) for different exposures were calculated using a two-dimensional Fourier analysis method. The expectation modulation transfer function was measured and combined with the NPS data to calculate the noise-equivalent number of quanta. The slope of the characteristic curve of the peripheral densitometer (PD) system was found to be position dependent across the image, although this dependence was substantially reduced by use of the system's clinical-settings corrections. An MTF value of 0.5 was found at 0.5 cycles/mm for the densitometry system compared to the same value at 1.6 cycles/mm for the CR system. Unlike the CR system, the NPS of the densitometry system was found not to be directionally dependent and did not drop off at higher spatial frequencies.

The current study was undertaken to evaluate the clinical utility of DVA, a system for imaging the lateral spine on the Lunar Prodigy densitometer. DVA images were obtained and bone density of the lumbar spine and proximal femur measured in 297 subjects (272 women), aged 64+/-13 years. The images were classified as: normal (N) if no fractures were detected and all vertebrae between T6 and L4 were visualized, fracture (F) if any vertebra had a fracture (defined as 25% or more reduction in the vertebral height) even if some of the other vertebrae could not be visualized, and un-interpretable (U) if at least one of the vertebra between T6 and L4 could not be classified and no fractures were detected in the visualized vertebrae. A subset of 66 patients also had standard radiographs of the thoracic and lumbar spine. Compared to radiographs, DVA had a 95% sensitivity to detect fractures and 82% specificity (to exclude them). Among all 297 subjects studied, DVAs were interpretable in 87%. They were classified as N in 204 (68%), F in 55 (19%) and U in 38 (13%). The reasons for un-interpretability were: scoliosis, scapular or rib shadow, severe arthritic changes and multiple vertebral compression fracture with severe spinal deformities. Only 11% of F subjects gave a history of a vertebral fracture, and only 56% of F subjects met the BMD criteria for osteoporosis (T score <-2.5). These results indicate that adding DVA, a low radiation and relatively low cost "point of service" procedure, to BMD measurement provides the clinician with a more comprehensive fracture risk assessment than that afforded by clinical evaluation and BMD measurement alone.

Bone fragility is determined by bone mass and trabecular structure. While bone mass can be readily measured as bone density, bone trabecular structure cannot be easily assessed by currently available methods. The realization of the importance of bone structure in determining fracture risk has led to the development of several imaging modalities aimed at evaluating the contribution of bone quality to its biomechanical strength and fragility. High-resolution magnetic resonance imaging and computed tomography have limited spatial resolution and high cost but have a potential to generate true three-dimensional images of trabecular structure in vivo. Bone radiographs subjected to various forms of texture analysis have higher resolution and lower cost but provide only a two-dimensional representation of bone structure. Both two- and three-dimensional methods have been shown to predict biomechanical strength in vitro and to differentiate between subjects with and without fractures in vivo. Therefore, all of these methods deserve closer evaluation and also need further technical improvements before they can be considered for use in clinical practice.

Disorders of thirst and vasopressin secretion present clinically in one of three ways: as hypotonic polyuria (DI), as hypodipsic hyponatremia, and as hyponatremia. In evaluating a patient with DI, the major challenge is to differentiate between primary polydipsia and neurogenic and nephrogenic DI. This is best accomplished through a series of steps that start with simple clinical observation, and progress, as necessary, to more complicated diagnostic procedures (Fig. 1). If the diagnosis is not clear from the clinical setting and the patient's history, the first step is to measure plasma osmolality and sodium under conditions of ad libitum fluid intake. If the results are clearly above the upper limit of normal range, primary polydipsia is excluded and the work-up can proceed directly to administration of vasopressin or DDAVP and/or a measurement of plasma vasopressin levels to differentiate between neurogenic and nephrogenic DI. If basal plasma osmolality and sodium fall within normal range, the standard dehydration test should be performed. If urine osmolality does not increase above that of plasma despite evident dehydration, primary polydipsia is excluded and the effect of vasopressin or DDAVP on urine osmolality should be examined to differentiate between neurogenic and nephrogenic DI. If administration of antidiuretic hormone increases urine osmolality by more than 50 per cent, the patient has severe neurogenic DI. If the increase in urine osmolality is less than 50 per cent, the patient has nephrogenic DI. In patients who do not concentrate urine above that of plasma in response to dehydration, the best approach is to measure plasma vasopressin, osmolality, and sodium after the latter have been increased above normal range by dehydration and/or infusion of hypertonic saline. When these results are plotted on a suitable nomogram (Fig. 2), neurogenic DI can be clearly diagnosed from the relative deficiency of vasopressin. In patients with normal vasopressin levels, primary polydipsia can be differentiated from nephrogenic DI by examining the relationship of urine osmolality to plasma vasopressin (Fig. 3), obtained during dehydration and/or graded vasopressin infusion. In evaluating a patient with sustained hypernatremia, it is only necessary to assess thirst, which can be done by a simple bedside observation. In a patient without obvious neurologic or cognitive impairment, absence of thirst in the face of plasma osmolality above 305 mosm/kg (plasma sodium above 150 mEq/L) is diagnostic for hypodipsic hypernatremia. In a patient who presents with hyponatremia, the main objective is to differentiate between hyper-, hypo-, and euvolemic (SIADH) types

Study Objective: To determine whether antibodies to vasopressin play a role in the development of diabetes insipidus or interfere with diagnosis and treatment., Design: Random plasma or serum samples for determining of antibodies to vasopressin were collected from patients and controls., Setting: Referral university hospital with most patients studied in the clinical research center., Patients: Twenty-nine healthy controls and 113 patients with polyuria (15 with primary polydipsia; 86 with neurogenic diabetes insipidus [60 studied before, 28 during, and 10 after antidiuretic hormone treatment]; and 12 with nephrogenic diabetes insipidus)., Interventions: Antibodies were detected by incubating samples with radiolabeled 125I-arginine vasopressin. The effect of antibodies on diagnosis was studied by examining the relation of plasma vasopressin to osmolality measured during dehydration or infusion of hypertonic saline and the relation of urine osmolality to plasma vasopressin measured during dehydration., Measurements and Main Results: Antibodies to vasopressin were not detected in patients with primary polydipsia, nephrogenic diabetes insipidus, or neurogenic diabetes insipidus studied before therapy with antidiuretic hormone. Antibodies were detected in 6 of 28 patients studied during such treatments. All 6 patients reported decreased antidiuretic response to previously effective therapy with arginine or lysine vasopressin but had normal response to desmopressin or chlorpropamide., Conclusion: Diabetes insipidus does not result from spontaneously occurring antibodies to vasopressin. The antibodies occasionally develop during treatment with antidiuretic hormone and, when they do, almost always result in secondary resistance to its antidiuretic effect. Antibodies usually do not impair the response to other forms of therapy; they only rarely interfere with the diagnosis of diabetes insipidus, by falsely suggesting the presence of the partial nephrogenic form.

Changes in osmoregulation during normal menstrual cycle were examined in 15 healthy women. In 10 women, studied repetitively during two consecutive menstrual cycles, basal plasma osmolality, sodium, and urea decreased by 4 mosmol/kg, 2 meq/l, and 0.5 mM, respectively (all P less than 0.02) from the follicular to luteal phase. Plasma vasopressin, protein, hematocrit, mean arterial pressure, and body weight did not change. In five other women, diluting capacity and osmotic control of thirst and vasopressin release were assessed in follicular, ovulatory, and luteal phases. Responses of thirst and/or plasma vasopressin, urine osmolality, osmolal and free water clearance to water loading, and infusion of hypertonic saline were normal and similar in the three phases. However, the plasma osmolality at which plasma vasopressin and urine osmolality were maximally suppressed as well as calculated osmotic thresholds for thirst and vasopressin release were lower by 5 mosmol/kg in the luteal than in the follicular phase. This lowering of osmotic thresholds for thirst and vasopressin release, which occurs in the luteal phase, is qualitatively similar to that observed in pregnancy and should be taken into account when studying water balance and regulation of vasopressin secretion in healthy cycling women.