679 vertebral fracture assessment 724/730 DXA of right/left hip 777 DXA of lumbar spine
Excluded:
23 578 patients at 7 NoFRACT hospitals 2015-2017
496 women
496 filled in questionnaires 496 trabecular bone score
496 DXA of hip and lumbar spine 423 vertebral fracture assessment 839 women and men included in the sub-study of NoFRACT
Paper I
Paper II 614 women and men 614 trabecular bone score
614 vertebral fracture assessment 614 DXA of hip and lumbar spine
Paper III
Excluded:
6 trabecular bone score
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Of the 771 patients who had TBS calculated, 41 of these were excluded in paper I and 35 were excluded in paper II. Twenty-six patients were excluded due to BMI > 37 kg/m² (TBS values are not recommended for use in patients with BMI
> 37 kg/m² because of the influence of soft tissue) and 15 patients were excluded due to fractures or anatomical aberrations in two or more vertebrae in paper I which did not give TBS result of L1-L4. In paper II, reanalysis of the TBS in six patients who did not have TBS calculated initially, lead exclusion of only 9 patients due to this. Unfortunately, this is wrongly explained in the method of paper II. Further, 679 of the patients had a lateral thoracolumbar scan performed for VFA.
Of the 725/731 patients with DXA scan of right/left hip, one patient was excluded because of poor image quality of the DXA scans, resulting in 777 patients with valid BMD measurement of at least one hip. Of the 785 patients with a DXA scan of the lumbar spine, 8 patients were excluded because of less than two evaluable vertebrae, hence 777 patients had valid BMD measurement of the lumbar spine. Exclusion of six more patients due to TBS (as described above) explained that 608 patients had valid values for both DXA and TBS and with VFA performed in paper I and 614 patients in paper II. Hence, 724/730 patients with DXA scans of the right/left hip, 777 with DXA of the lumbar spine, 679 with VFA and 730 with TBS calculated were included in the analyses of Paper I. The proportion of vertebrae that could not be assessed due to low imaging quality was 8.4%. They were mainly located in the upper thoracic region (Th4-Th6). No patients were excluded due to conditions known to affect bone metabolism, such as chronic kidney disease, use of AOD, hormone replacement therapy (HRT) or premenopausal status.
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3.2 Ethics
All patients in the sub-study provided written informed consent and they were informed about the opportunity to withdraw the consent at any time. The study was approved by The Regional Committee for Medical and Health Research Ethics (REK 2014/2260) and was conducted in accordance with the World Medical Association Declaration of Helsinki. The NoFRACT main study (NCT02536898) and the sub-study (NCT02608801) were both registered separately in ClinicalTrials.gov. Data security was ensured by using a research platform for sensitive data at the University of Oslo.
3.3 Design
The NoFRACT sub-study was designed as a prospective observational study, with clinical examination and questionnaire at baseline, telephone interview, questionnaire and measurement of bone turnover markers (BTM) at 1-year follow-up and clinical examination, questionnaire and BTM at 2-year follow-up.
All three papers in this thesis used baseline data on fracture patients with a cross-sectional design; with no fracture-free control group or follow-up.
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3.4 Data from questionnaires
The participants answered a self-administered questionnaire at the time of inclusion concerning: years of age, ethnicity, number and site of fractures after the age of 50 years, parental history of hip fracture, type of comorbidity, medication and supplementation of calcium and vitamin D, number of falls the last 12 months, height loss, need of walking aids, frequency and duration of exercise, number of daily units dairy products, alcohol intake, current smoking, working status, home situation, self-reported health status and health related quality of life (EQ-5D). Men were asked about treatment for prostate cancer.
Women were asked about use of HRT at menopause, current or previous use of aromatase inhibitors, postmenopausal status, number of children born and total number of months of breastfeeding (Appendix).
Exercise was reported as mean frequency of exercise per week (mean): never (0 times/week), 1 time/week (1 time/week), 2-3 times/week (2.5 times/week) and 4-7 times/week (5.5 times/week). Additionally the duration of each workout (mean) was reported: < 15 minutes (7.5 minutes), 15-29 minutes (22.5 minutes), 30-60 minutes (45 minutes) and > 60 minutes (75 minutes). Based on this information, we estimated hours of exercise as mean exercise time/week x mean minutes/workout. Consumption of dairy products was reported in unit dairy products per day (mean): 0 = none, 1-2 units/day (1.5 units per day), 3-4 units per day (3.5 units/day) and ≥ 5 units/day (6 units/day).
The study nurse registered additional clinical data at baseline: site and date of index fracture, date of baseline visit, use and type of AOD, calcium and vitamin D supplementation at baseline, type of AOD, calcium and vitamin D supplementation started after assessment, 10-year risk of hip fracture, MOF and osteoporotic fracture estimates calculated by FRAX and Garvan nomogram.
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3.5 Bone mineral density
Height (m) and weight (kg) were measured in light clothing without shoes before BMD measurement. BMI was calculated as weight per square meter height (kg/m²).
BMD was measured at the femoral neck and total hip at both sides and at lumbar spine (L1-L4), using iDXA Pro in Drammen (Fig. 5A) and DXA Prodigy Pro in Tromsø (Fig. 5B) (both GE Lunar, Madison, WI, USA). Phantom Quality Assurance (QA) of the DXA equipment was performed daily.
Fig. 5. Dual energy x-ray absorptiometry devices used for measurement of bone mineral density. IDXA Pro (A) and DXA Prodigy Pro (B).
A B
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The patients were positioned lying straight on the back in the center of the table (Fig. 6). The scan extended from the lowest vertebrae with ribs to the pelvic brim including all the vertebrae in total from L1 to L4. The hips were positioned with the femora straight on the table, parallel to the edge on the DXA image. The femora were rotated 15-25° inwards, achieved by using a position device placed between the ankles.
Fig. 6. Positioning of patient for BMD measurements of femoral neck, total hip and lumbar spine.
All fractured lumbar vertebrae were excluded. BMD T-scores were calculated using NHANES III reference population of female Caucasians aged 20–29 years for femoral neck and total hip (5) and Lunar female reference database for lumbar spine in both women and men, as recommended by ISCD (59).
The patients were categorized into those with normal BMD, osteopenia or osteoporosis at femoral neck or at the site with the lowest BMD T-score using the WHO classification (Table 2) (121):
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Table 2 WHO diagnostic categorization of osteoporosis based on bone mineral density (BMD) T-score.
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3.6 Trabecular bone score
TBS was analyzed using TBS iNsight software (Medimaps, Geneva, Switzerland) Version 3.0.1 with processing of the DXA image of L1-L4. Standard mode was used. Fractured vertebrae were excluded. Patients with BMI below 15 kg/m² or above 37 kg/m² were excluded because of the influence of soft tissue, as recommended by MediMaps (122). TBS was analyzed directly after DXA scanning of the participants from Drammen, and after admission to a temporary license from MediMaps for images of the Tromsø participants. The European reference population was used for women and men.
TBS values were divided into 3 categories according to risk of major osteoporotic fracture: ≥ 1.310: low risk of fracture, between 1.230 and 1.310 medium risk for fracture and ≤ 1.230 high risk of fracture. This division is recommended in the TBS manual, and it is based on results from a meta-analysis of 14 population-based studies (Table 3) (103).
Table 3 Trabecular bone score (TBS) values with associated microarchitecture degradation and fracture risk.
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