Original ArticleVertebral Fracture Diagnosis in the Multinational BONE Study of Oral Ibandronate: Quality Management in Radiology
Introduction
As in all osteoporosis fracture trials, the quality of the study results relies on X-ray technique standardization and fracture diagnosis reproducibility and accuracy. The use of conventional spinal radiographs to reproducibly measure vertebral deformity (morphometric or quantitative diagnosis) requires 2 high-quality images of the lateral spine produced under standardized conditions and specifications. The radiographs are reviewed for quality control and then subsequently digitized and subjected to computer-assisted evaluation. Therefore, it is important that this step is performed consistently throughout clinical trials. This view is supported by clinical trial guidelines from the US Food and Drug Administration (FDA) (1) and the National Osteoporosis Foundation (NOF) Working Group on Vertebral Fractures (2). These guidelines recommend that vertebral fractures are diagnosed by experienced radiologists using both morphometric and qualitative assessments of standardized lateral views of the thoracic and lumbar spine. In addition, it is suggested that multicenter clinical studies use a single center to assess all radiographs, although this is not always logistically possible.
Ibandronate is a highly potent, nitrogen-containing bisphosphonate developed specifically to provide antifracture efficacy with convenient, less-frequent than daily administration (3). The efficacy of oral ibandronate given daily (2.5 mg) or intermittently with a between-dose interval of >2 mo (20 mg every other day for 12 doses every 3 mo) was demonstrated in a randomized, double-blind, placebo-controlled study involving 73 centers in Europe and North America (BONE: oral iBandronate Osteoporosis vertebral fracture trial in North America and Europe) (4).
All women gave written informed consent to participate and the study was carried out according to the Helsinki II Declaration and the European Guidelines for Good Clinical Practice and in adherence with local drug regulations. Local Ethics Committees/Institutional Review Board approved the study protocol.
A total of 2946 women aged 55–80 yr were enrolled in the study. Inclusion criteria required that participants were ≥5 yr postmenopausal, with a bone mineral density (BMD) T-score of −2.0 to −5.0 in at least 1 lumbar (L1–L4) vertebra and 1–4 prevalent vertebral fractures (T4–L4). These criteria differed from those used in the registration trials for daily alendronate and risedronate. The treatment effect of alendronate was studied separately in women with and without prevalent vertebral fractures. Inclusion criteria for the study in women with prevalent vertebral fractures required the presence of 1 or more existing fracture, with no upper limit (5). Prevalent fractures were defined as any ratio of vertebral heights more than 3 standard deviations below the population norm for that vertebral level. Femoral neck BMD was required to be ≤0.68 g/cm2 (T-score approx −2.1). Of the 2 studies of daily risedronate, 1 required 2 or more radiologically identified prevalent vertebral fractures (T4–L4) with no low BMD criterion (6), whereas the other required either 2 or more radiologically identified prevalent vertebral fractures (T4–L4) or 1 prevalent vertebral fracture plus low lumbar spine BMD (L1–L4) of ≤0.83 g/cm2 (T-score of −2) (7). In both risedronate studies, prevalent vertebral fractures were identified both quantitatively and semiquantitatively. In the BONE study, both oral daily and intermittent ibandronate administered over 3 yr significantly reduced the risk of new vertebral fractures. The BONE study established ibandronate as the first oral bisphosphonate drug with prospectively proven lasting antifracture efficacy when administered in an intermittent regimen with a dosing interval of >2 mo in the overall population of a randomized-controlled trial.
Before BONE, a clinical study of an intravenous formulation of ibandronate (8) had also been initiated. The radiographs of both the BONE and intravenous studies would be read in 2 different centers (1 in Europe and the other in North America). Therefore, to ensure that radiographs were being taken and read consistently and to achieve the necessary high standard of consistency, rigorous processes for fracture diagnosis were established that adhered closely to the FDA/NOF guidelines. The methodology included techniques for obtaining and evaluating radiographs, computer-aided morphometric analysis of radiographs, differential diagnosis of osteoporotic fractures, and instructions designed to achieve standardization of this process (see Methods).
Specific attention was also paid to intra-and intercenter consistency through a series of validation processes, which evaluated consistency of reading films and diagnosis of prevalent and incident vertebral fractures at the 2 study centers. The validation processes used films from both trials and ensured the methodology was being consistently implemented across both centers, and highlighted any aspects of the methodology that required further improvement to achieve maximum cross-center consistency.
The present report describes the standardized methodology for diagnosing prevalent and incident vertebral osteoporotic fractures used in the BONE study, and reports results from the cross-validation exercises for maximizing fracture diagnostic accuracy. The amendments made to the BONE study protocol to ensure high-quality reproducible results and the findings from the validation exercises of the BONE radiographs are also reported.
Section snippets
Inclusion Criteria
To be eligible for the BONE trial, women were required to have 1–4 prevalent vertebral fractures (T4–L4) and a lumbar spine BMD T-score of −2 to −5 in at least 1 vertebra (4). These criteria were chosen because a prevalent fracture increases the risk of incident vertebral fracture and studies in higher-risk populations are more feasible because they require a smaller number of patients to meet their primary objective of establishing fracture efficacy. Patients with more than 4 fractures were
Results of the Validation Processes of the Morphometric and Qualitative Analyses
The first process demonstrated excellent concordance in reading of radiographs between the radiologists. In the consensus analysis, all Kappa coefficients exceeded 0.80 except for a single comparison between 2 of the readers on anterior height (Kappa coefficient, 0.76). No inferiority of agreement in mid-height measurement compared with anterior or posterior height was evident.
Good intercenter agreement in qualitative differential diagnosis of osteoporotic fracture was demonstrated in the
Discussion
In the BONE study (4), oral intermittent and daily ibandronate significantly reduced the risk of new morphometric vertebral fractures by 50% (p = 0.0006) and 62% (p = 0.0001), respectively, vs placebo. These findings confirmed antifracture efficacy with ibandronate when administered either daily or less frequently than daily or weekly over a 3-yr period. Consequently, ibandronate is the first bisphosphonate with prospectively proven lasting antifracture efficacy when given with a dosing interval of
Conclusions
The rigorous methodology used in the BONE study achieved excellent agreement between the 2 radiograph-assessment centers in diagnosing prevalent and incident fractures, even though using 1 center is generally recommended. Excellent diagnostic agreement was also achieved between morphometric and qualitative assessment methods. In addition, the quality and reproducibility of the methodology increased the proportion of enrolled patients who conformed to the prevalent fracture inclusion criteria
Acknowledgment
The authors would like to thank G. Parker, medical writer, for her assistance in drafting the manuscript.
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