A further two centres contributed similar individuals identified prospectively (Hologic: Guy’s London, Yeovil). Previous case studies of LRP5 HBM used Z-score thresholds to define HBM [13]; however, as Hologic DXA scanner databases store T- but not Z-scores, our search was of T- and/or Z-score ≥ +4. All DXA images were visually inspected by clinicians or clinical

scientists trained in the interpretation of DXA, and those with identifiable explanations for a high BMD value, such as osteoarthritis, were excluded. Evidence of significant VX-770 manufacturer osteoarthritis on lumbar DXA scans is common. To reduce contamination of our remaining DXA scans by more moderate osteoarthritis, we aimed to refine our case definition based upon restriction to specific lumbar verterba(e).

At our largest centre, 562 scans with T-/Z-score ≥ +4 were graded for OA severity by Kellgren and Lawrence scores and examined in relation to BMD at lumbar vertebral levels [17, 18]. In contrast to other lumbar vertebrae, L1 Z-score was not associated with the presence of OA, reflecting the recognised pattern of progressive OA changes seen in descending sequential lumbar vertebrae [19], nor did total hip Z-score reflect lumbar spine OA. A generalized HBM trait would be expected to affect both spine and hip BMD, though not necessary to the same extent. Hence, we refined our definition of HBM index cases Palbociclib as having either (a) L1 Z-score of ≥+3.2 plus a total hip Z-score no lower than +1.2 or (b) a total hip Z-score ≥ +3.2 plus a L1 Z-score no lower than +1.2. A threshold of +3.2 was in keeping with the only published precedent for identifying HBM previously described using DXA [13] and most appropriately differentiated very generalized HBM from artefact. Z rather than T-score was used to limit age bias. A standard deviation of +3.2 would be expected to identify a tail of 0.069% of a normal distribution [20]. Since the prevalence

of HBM on DXA databases is likely to be influenced by motivations for DXA referral, we examined the latter in a subgroup of 22% of scans at the largest centre in Hull, where referral indication was recorded in an adjunctive database linked to their Lunar DXA database. The distribution of BMD amongst relatives Surviving index cases, identified from DXA database searches described above, who were still resident in the area, were invited by letter and follow-up telephone call to attend their local DXA centre for clinical assessment (described below) and in order to construct family pedigrees. BYL719 Elderly, immobile individuals were offered home visits to limit participation bias (n = 2).