ASBMR 2011 SU0046

Evaluation of QCT Cortical Hip Parameters in a Clinical Trial With Rosiglitazone: Potential for a New Study Endpoint
C.G. Miller,1 J.P. Bilezikian,2 A.J. Nino,3 B.G. Kravitz,3 G. Paul,3 A.R. Cobitz,3 A.R. Northcutt,4 L.A. Fitzpatrick3
1BioClinica,

Colin G. Miller, PhD, FICR, CSci BioClinica, Inc. 826 Newtown-Yardley Rd Newtown, PA 18940 Tel: (267) 757-3144 E-mail: colin.miller@bioclinica.com

Inc., Newtown, PA; 2Columbia University College of Physicians & Surgeons, New York, NY; 3GlaxoSmithKline, King of Prussia, PA; 4GlaxoSmithKline, Research Triangle Park, NC

Introduction
Quantitative computated tomography (QCT) measurements provide 3-dimensional data that are useful in ascertaining bone quality and bone density.1 QCT may be distinguished from dual-energy X-ray absorptiometry (DXA) for its ability to provide separate bone mineral density (BMD) assessments for trabecular and cortical bone We previously demonstrated that use of rosiglitazone (RSG) in postmenopausal women with type 2 diabetes mellitus (T2DM) resulted in decreased volumetric bone mineral density (vBMD) and decreased cortical thickness at 52 weeks compared with baseline, as analyzed by QCT at a threshold of 350 mg/cm3.2 A partial volume effect in this study may have resulted in over-estimation of cortical thickness and poor precision at low BMD Presented herein is an expanded analysis of femoral neck vBMD and cortical thickness data obtained after a 24-week open-label extension with metformin (MET). The objective of this analysis was to evaluate the effect of RSG on vBMD and cortical thickness exploring the use of additional thresholds (375 mg/cm3 and 400 mg/cm3) to gain a better understanding of cortical edge detection by QCT

Results
Patient Disposition and Demographics A total of 226 women were enrolled in the study; 225 who completed at least 1 dose of study drug were included in the safety population. Of these, a subset of 79 patients underwent QCT scans of the hip at baseline, week 52, and week 76 Baseline demographics were similar between treatment groups Hip Cortical vBMD Measured at the Femoral Neck by QCT RSG group (Table 1) From baseline to week 52 Decreased in all 4 quadrants for all 3 thresholds From week 52 to week 76 Increased in all 4 quadrants for all 3 thresholds MET group (Table 1) From baseline to week 52 Increased in all 4 quadrants at the 350 mg/cm3 threshold Increased in the superior-anterior and inferior-anterior quadrants and showed a minor decrease in the superior-posterior and inferior-posterior quadrants at the 375 mg/cm3 and 400 mg/cm3 thresholds From week 52 to week 76 Increased in the inferior-posterior and inferior-anterior quadrants and decreased in the superior-posterior and superioranterior quadrants at the 350 mg/cm3 threshold Decreased in all 4 quadrants at the 375 mg/cm3 and 400 mg/cm3 thresholds Mean adjusted % change in cortical vBMD for all 4 quadrants (Table 1) Hip Cortical Thickness Measured at the Femoral Neck by QCT Results RSG group (Figure 2) From baseline to week 52 Decreased in all 4 quadrants for all 3 thresholds From week 52 to week 76 Increased in all quadrants for all 3 thresholds, except in the superioranterior quadrant, where a decrease was observed for all 3 thresholds MET group (Figure 2) From baseline to week 52 Rosiglitazone N=114 350 mg/cm3 Threshold 375 mg/cm3 Threshold Adjusteda % Change, Mean (SE) Metformin N=111 Rosiglitazone N=114 Metformin N=111 Rosiglitazone Metformin N=114 N=111 400 mg/cm3 Threshold

Conclusions Table 1. Percent Change in Hip Cortical vBMD via QCT at Different Thresholds Figure 2. Absolute Changes in Hip Cortical Thickness (mm) by QCT at 3 Different Thresholds
350 mg/cm 3
Baseline to week 52, Mean (SE) P-value Week 52 to week 76, Mean (SE) P-value 0.03 (0.06) NS RSG (n= 30-32) (n=30-32) -0.10 (0.04) <0.01 0.03 (0.05) 0.04 RSG (n= 30-32) (n=30-32) -0.10 (0.04) 0.01 0.04 (0.05) 0.05 -0.09 (0.05) MET (n=30-34) 0.04 (0.05) -0.11 (0.06) MET (n=30-34) 0.06 (0.05) RSG (n= 30-32) (n=30-32) -0.09 (0.07) NS -0.02 (0.07) MET (n=30-33) 0.05 (0.08)

The findings suggest that reductions in adjusted mean % change in vBMD in cortical thickness occurred with RSG treatment from baseline to week 52. Changes with MET were generally minimal The reductions observed during RSG treatment appeared to partially reverse during the open-label MET phase from week 52 to week 76. During this time, patients in the MET group tended to experience minimal reductions in vBMD and cortical thickness Greater consistency between results appeared to occur with the 375 mg/cm3 and 400 mg/cm3 thresholds The likely partial volume effects seen for vBMD at the 350 mg/cm3 are decreased with the higher thresholds, which is reflected in the decrease in SD The effect of thresholds on the SD for the cortical thickness (measured in mm) was not apparent The default value boundary for the software used for this quadrant analysis is 350 mg/cm3. It is suggested that a 375 mg/cm3 or 400 mg/cm3 threshold may be used vBMD at the 4 quadrants of the femoral neck can be precisely segmented from trabecular bone and appears to be a valuable tool to evaluate therapeutic effect on this bone compartment

350 mg/cm 3
Baseline to week 52, Mean (SE) P-value Week 52 to week 76, Mean (SE) P-value

RSG (n= 30-32) (n=30-32) -0.10 (0.08) NS -0.01 (0.07) NS RSG (n= 30-32) (n=30-32) -0.08 (0.06) NS -0.01 (0.05) NS RSG (n= 30-32) (n=30-32) -0.07 (0.05) NS -0.01 (0.05) NS

MET (n=30-33) -0.02 (0.09)

-0.04 (0.08)

Superior-Posterior Femoral Neck Quadrant Cortical vBMD (cm3) BL to week 52 (n=34)b

375 mg/cm 3
Baseline to week 52, Mean (SE) P-value

375 mg/cm 3
Baseline to week 52, Mean (SE) P-value Week 52 to week 76, Mean (SE) P-value

MET (n=30-34) 0.00 (0.06)

Methods
Overview of Bone Mechanistic Study Phase IV, multinational, double-blind, randomized study, divided into 3 phases: screening, a 52-week double-blind treatment with RSG or MET, and a 24-week follow-up with all patients receiving open-label MET (Figure 1) Main inclusion criteria: women >55 and <80 years with an established clinical diagnosis of T2DM and BMD value consistent with a T-score >-2.5 at the femoral neck, lumbar spine, and total hip as assessed by DXA Drug-nave (glycosylated hemoglobin [HbA1c] 9.0%) or on prior monotherapy (HbA1c 8.5% on submaximal doses; HbA1c 7.0% on maximal doses) Postmenopausal >5 years QCT Analyses Using spiral multi-detector computed tomography (CT) scanners with a standard acquisition technique, QCT scans of the femoral neck were acquired at baseline, after 52 weeks of double-blind treatment with RSG or MET, and after 24 weeks of additional open-label treatment with MET (week 76). The region of acquisition extended from just above the femoral head to at least 1 cm below the lesser trochanter Following standard requirements for QCT acquisition, patients were scanned with both a calibration phantom with known hydroxyapatite concentrations (Mindways Software Inc., Austin, TX) to calibrate QCT values to BMD and a quality assurance phantom (Mindways Software Inc.) to monitor the QCT system performance throughout the study Quality review and analysis of QCT scans occurred at a central image-reading facility (BioClinica, Inc., Newtown, PA) using the QCTPro (version 4.1.3) system (Mindways Software Inc.) Mean cortical vBMD was obtained at the femoral neck for the superior-posterior, superior-anterior, inferior-posterior, and inferior-anterior quadrants. Cortical thickness was measured at the femoral neck for all 4 quadrants QCT quadrant analysis was performed using 3 thresholds: 350 mg/cm3, 375 mg/cm3, and 400 mg/cm3

-1.29 (1.18)

0.10 (1.34)

-1.11 (0.77)

-0.21 (0.87)

-0.95 (0.74)

-0.13 (0.83)

Week 52 to week 76, Mean (SE) P-value

-0.09 (0.06)

Increased in all quadrants for all 3 Week 52 to thresholds, except in the superior-anterior week 76c quadrant, where a decrease or no change (n=30) was observed for all 3 thresholds From week 52 to week 76

0.94 (0.98)

-0.01 (1.20)

0.73 (0.75)

-0.58 (0.91)

0.41 (0.73)

-0.64 (0.88)

400 mg/cm 3
Baseline to week 52, Mean (SE) P-value Week 52 to week 76, Mean (SE) P-value

400 mg/cm 3
Baseline to week 52, Mean (SE) P-value Week 52 to week 76, Mean (SE) P-value

MET (n=30-34) -0.01 (0.06)

Superior-Anterior Femoral Neck Quadrant Cortical vBMD (cm3)

Decreased in all quadrants for all BL to 3 thresholds, except in the inferior-anterior week 52 quadrant at the 350 mg/cm3 threshold, (n=34)b where there was a minimal increase Impact of Rethresholding on QCT Results Overall, directionality and findings were generally consistent across the quadrants and the 3 thresholds In most cases where discrepancies exist, the 375 mg/cm3 and 400 mg/cm3 thresholds were comparable and the data from the 350 mg/cm3 threshold deviated from those results vBMD results demonstrated a decrease in standard deviation (SD) with increasing mg/cm3 threshold Cortical thickness results did not show a change in SD with increasing threshold Definition of the boundary from trabecular to cortical bone improved with higher thresholds, and less partial volume effect was observed. The decrease in SD for vBMD values is likely a reflection of the improved definition Week 52 to week 76c (n=30)

-0.09 (0.06)

-0.98 (1.00)

0.58 (1.12)

-0.93 (0.79)

0.49 (0.88)

-0.86 (0.78)

0.53 (0.86)

References
0.83 (1.04) -1.67 (1.24) 0.69 (0.87) -2.43 (1.03)d 0.65 (0.87) -2.55 (1.03)d 1. Adams JE. Quantitative computed tomography. Eur J Radiol. 2009; 71: 415-424. 2. Bilezikian JP, Kravitz BG, Lewiecki EM, et al. Effects of rosiglitazone on bone: assessing QCT parameters in a mechanistic study of postmenopausal women with type 2 diabetes mellitus. Presented at the 2010 Annual Meeting of the American Society for Bone and Mineral Research, Toronto, Canada; October 15-19, 2010. Poster SA0035. 3. Home PD, Pocock SJ, Beck-Nielsen H, et al. Rosiglitazone evaluated for cardiovascular outcomes in oral agent combination therapy for type 2 diabetes (RECORD): a multicentre, randomized, open-label trial. Lancet. 2009; 373: 2125-2135. 4. Kahn SE, Zinman R, Lachin J, et al, for the A Diabetes Outcome Progression Trial (ADOPT) Study Group. Rosiglitazone-associated fractures in type 2 diabetes: an analysis from A Diabetes Outcomes Progression Trial (ADOPT). Diabetes Care. 2008; 31: 845-851.

Inferior-Posterior Femoral Neck Quadrant Cortical vBMD (cm3) BL to week 52 (n=34)b Week 52 to week 76c (n=30)

-1.47 (1.79)

0.49 (2.01)

-1.66 (0.64)

-0.44 (0.71)

-1.40 (0.60)

-0.39 (0.67)

350
P-value

mg/cm 3

RSG (n= 30-32) (n=30-32) -0.13 (0.09) NS 0.08 (0.05) NS RSG (n= 30-32) (n=30-32) -0.15 (0.04)

MET (n=30-33) 0.10 (0.10)

350
P-value

mg/cm 3

RSG (n= 30-32) (n=30-32) -0.16 (0.09) NS 0.11 (0.09) NS RSG (n= 30-32) (n=30-32) -0.16 (0.06)

MET (n=30-33) 0.01 (0.11)

Baseline to week 52, Mean (SE)

Baseline to week 52, Mean (SE)

Week 52 to week 76, Mean (SE)

-0.01 (0.06)

Week 52 to week 76, Mean (SE) P-value

0.03 (0.11)

1.87 (1.63)

1.63 (1.94)

1.48 (0.63)

-0.50 (0.75)e

1.28 (0.60)

-0.43 (0.71)e

P-value

Inferior-Anterior Femoral Neck Quadrant Cortical vBMD (cm3) BL to week 52 (n=34)b Week 52 to week 76c (n=30)

375 mg/cm 3
Baseline to week 52, Mean (SE) P-value

MET (n=30-34) 0.03 (0.05)

375 mg/cm 3
Baseline to week 52, Mean (SE) P-value

MET (n=30-34) 0.05 (0.06)

Figure 1. Study Design*

From baseline to week 52, RSG resulted in a greater reduction than MET at all 3 thresholds

<0.01 0.09 (0.05) NS RSG (n= 30-32) (n=30-32) -0.17 (0.04) <0.01 0.10 (0.05) 0.04 -0.04 (0.06) MET (n=30-34) 0.02 (0.05) -0.04 (0.06)

<0.01 0.11 (0.08) NS RSG (n= 30-32) (n=30-32) -0.17 (0.06) <0.01 0.13 (0.07) NS -0.07 (0.09) MET (n=30-34) 0.05 (0.06) -0.05 (0.09)

-0.53 (1.96)

0.47 (2.21)

-1.22 (0.95)

0.10 (1.07)

-0.97 (0.88)

0.05 (1.00)

Safety From week 52 to week 76, greater increases were observed following discontinuation of Adverse events observed in this study were RSG than in the MET group at all 3 thresholds consistent with those from previous studies3,4

Week 52 to week 76, Mean (SE) P-value

Week 52 to week 76, Mean (SE) P-value

400 mg/cm 3
2.23 (1.75) 0.91 (2.09) 1.94 (1.10) -0.94 (1.33) 1.61 (1.05) -0.68 (1.27)
Baseline to week 52, Mean (SE) P-value Week 52 to week 76, Mean (SE) P-value

400 mg/cm 3
Baseline to week 52, Mean (SE) P-value Week 52 to week 76, Mean (SE) P-value

BL = baseline; QCT = quantitative computated tomography; SE = standard error; vBMD = volumetric bone mineral density.
a b

Adjusted for baseline value, region, and prior therapy. n values ranged from 32 to 34 between treatment groups and thresholds depending on availability of data. Open-label phase. P0.01. P0.05.

Superior-posterior quadrant. Superior-anterior quadrant. Inferior-posterior quadrant. Inferior-anterior quadrant. MET = metformin; NS = not significant; QCT = quantitated computed tomography; RSG = rosiglitazone; SE = standard error.

c d e

Acknowledgment
Sponsored by GlaxoSmithKline. Editorial support was provided by Scientific Therapeutics Information, Inc, Springfield, New Jersey. All re-analyses of the QCT scans were provided and supported by BioClinica, Inc.

*Rosiglitazone was begun at a total daily dose of 4 mg and force-titrated to 8 mg; metformin was begun at 1000 mg and force-titrated to 2000 mg. If glycemic control was not achieved, glyburide could be added, starting at 2.5 mg/d titrated up to 20 mg/d as necessary. All patients received calcium supplements (500-1000 mg elemental calcium daily) and vitamin D (at least 400 IU daily); HbA1c = glycosylated hemoglobin.