Barbara A. Blunt

Accurate assessment of precision errors: how to measure the reproducibility of bone densitometry techniques.

Assessment of precision errors in bone mineral densitometry is important for characterization of a techniques ability to detect logitudinal skeletal changes. Short-term and long-term precision errors should be calculated as root-mean-square (RMS) averages of standard deviations of repeated measurements (SD) and standard errors of the estimate of changes in bone density with time (SEE), respectively. Inadequate adjustment for degrees of freedom and use of arithmetic means instead of RMS averages may cause underestimation of true imprecision by up to 41% and 25% (for duplicate measurements), respectively. Calculation of confidence intervals of precision errors based on the number of repeated measurements and the number of subjects assessed serves to characterize limitations of precision error assessments. Provided that precision error are comparable across subjects, examinations with a total of 27 degrees of freedom result in an upper 90% confidence limit of +30% of the mean precision error, a level considered sufficient for characterizing technique imprecision. We recommend three (or four) repeated measurements per individual in a subject group of at least 14 individuals to characterize short-term (or long-term) precision of a technique.

What is the role of serial bone mineral density measurements in patient management

The ability of dual X-ray absorptiometry (DXA) to monitor bone mineral density (BMD) has been well documented in epidemiologic and pharmaceutical trials. However, its application to monitoring of patients in clinical practice has been subject to recent controversies. Despite these controversies, most clinical centers rely on DXA for monitoring of patients, and therefore guidance is needed. In this article, we report the positions developed by an expert panel of the International Society for Clinical Densitometry on the use of densitometry for the serial measurement of bone mass for monitoring change in BMD. The panel found DXA to be a precise method of measuring change in BMD if used with an appropriate level of least significant change (LSC), at anatomic sites with good precision and response to therapy, and at 1- to 2-yr time intervals. Monitoring is acceptable for determining when therapy is indicated, and if an agent is not therapeutically effective (i.e., when bone loss occurs despite treatment). Each densitometry center should perform an in vivo precision study on individuals similar to the patient population at the center and determine LSC at a 95% confidence level. If such a precision study cannot be performed, benchmark precision might be used, although there was no agreement on what values should be used. The PA spine is the preferred anatomic site for monitoring. The total hip can be used when the spine study is technically invalid. We conclude with recommendations for further research.

Neurogenic hypotension in patients with severe head injuries

OBJECTIVEnTo examine the occurrence of hypotensive episodes in patients with severe traumatic brain injuries that are not of hypovolemic origin and to investigate possible neurogenic or iatrogenic causes of such episodes.nnnMETHODSnWe reviewed Traumatic Coma Data Bank (TCDB) records of the 248 patients with early hypotension. We attempted to eliminate episodes related to hemorrhagic hypovolemia by excluding patients with (1) extracranial injuries of Abbreviated Injury Scale scores > 3 (n = 99, 40%); (2) postresuscitation hematocrit levels < 35% (n = 76, 30.6%); (3) hematocrit levels decreasing to < 35% during the first 24 hours after injury (n = 47, 19%); and (4) patients with conflicting data (n = 5, 2%). This left 21 patients (8.5%) without discernible extracranial causes for their hypotension.nnnRESULTSnOf these 21 patients, 4 had no extracranial injuries and 4 had only a single injury with Abbreviated Injury Scale score = 1. Hypotensive episodes were not associated with terminal or unsalvageable status. Mortality was 43%. Of the multiple factors investigated, the only two that were strongly associated with these unexplained hypotensive episodes were the presence of a diffuse injury pattern on computed tomography (n = 15, 71%) and the early use of mannitol or furosemide (n = 16, 76%) (It was policy at TCDB centers that hypotensive patients not receive diuretics until they were resuscitated.)nnnCONCLUSIONSn(1) Some episodes of severe traumatic brain injury-related hypotension may be of neurogenic origin. (2) The risk/benefit ratio of early diuretic use in patients with severe traumatic brain injuries may be too high to support liberal use. These data strongly support the need for a study involving prospective collection of data describing the early blood pressure courses in such patients.

Current methods and advances in bone densitometry

Bone mass is the primary, although not the only, determinant of fracture. Over the past few years a number of noninvasive techniques have been developed to more sensitively quantitate bone mass. These include single and dual photon absorptiometry (SPA and DPA), single and dual X-ray absorptiometry (SXA and DXA) and quantitative computed tomography (QCT). While differing in anatomic sites measured and in their estimates of precision, accuracy, and fracture discrimination, all of these methods provide clinically useful measurements of skeletal status. It is the intent of this review to discuss the pros and cons of these techniques and to present the new applications of ultrasound (US) and magnetic resonance (MRI) in the detection and management of osteoporosis.

Spinal bone mineral density by quantitative CT in a normal Italian population

The purpose of this study was to describe the normal cross-sectional pattern of spinal bone loss associated with aging in an Italian population and to compare these values to the American normative database. A group of 472 healthy subjects (382 females and 90 males) were recruited for bone mineral density (BMD) assessment by quantitative computed tomography (QCT). To eliminate technique-related differences in a comparison of Italian and American normal values obtained with two different scanners we performed a cross-calibration analysis scanning the same computerized imaging reference system (CIRS) phantom at both centers. The results of the cross-calibration study using the CIRS phantom were used to compare regression slopes of BMD with age and age-adjusted mean BMD of American men and women vs cross-calibrated Italian men and women. American men and women decrease more rapidly vs Italian men and women, and Italian men have significantly lower age-adjusted mean BMD than American men. For these reasons we recommend normal values to be locally obtained for an Italian population.

Magnetic resonance imaging of the calcaneus: Preliminary assessment of trabecular bone-dependent regional variations in marrow relaxation time compared with dual X-ray absorptiometry

RATIONALE AND OBJECTIVESnMarrow transverse relaxation time (T2*) in magnetic resonance (MR) imaging may be related to the density and structure of the surrounding trabecular network. We investigated regional variations of T2* in the human calcaneus and compared the findings with bone mineral density (BMD), as measured by dual X-ray absorpiometry (DXA). Short- and long-term precisions were evaluated first to determine whether MR imaging would be useful for the clinical assessment of disease status and progression in osteoporosis.nnnMETHODSnGradient-recalled echo MR images of the calcaneus were acquired at 1.5 T from six volunteers. Measurements of T2* were compared with BMD and (for one volunteer) conventional radiography.nnnRESULTSnT2* values showed significant regional variation; they typically were shortest in the superior region of the calcaneus. There was a linear correlation between MR and DXA measurements (r = .66 for 1/T2* versus BMD). Differences in T2* attributable to variations in analysis region-of-interest placement were not significant for five of the six volunteers. Sagittal MR images had short- and long-term precision errors of 4.2% and 3.3%, respectively. For DXA, the precision was 1.3% (coefficient of variation).nnnCONCLUSIONnMR imaging may be useful for trabecular bone assessment in the calcaneus. However, given the large regional variations in bone density and structure, the choice of an ROI is likely to play a major role in the accuracy, precision, and overall clinical efficacy of T2* measurements.

Good Clinical Practice and Audits for Dual X-ray Absorptiometry and X-ray Imaging Laboratories and Quality Assurance Centers Involved in Clinical Drug Trials, Private Practice, and Research

Good Clinical Practice (GCP) guidelines, with an emphasis on quality and validation of processes and data, must be applied to the use of imaging in clinical drug development. All participants, including the sponsor, principal investigator, site staff, quality assurance centers, and contract research organizations, must be cognizant of the need for application of these principles to their activities related to the imaging programs. This article discusses the various aspects of GCP as they need to be applied to the use of dual X-ray absorptiometry (DXA) for bone densitometry and X-rays for vertebral fracture assessment in clinical trials for osteoporosis, as well as research and private practice settings. The theory of proper audit conduct to verify clinical trial data is presented.