Trabecular Bone Score in Patients With Chronic Glucocorticoid Therapy Induced Osteoporosis Treated With Alendronate or Teriparatide

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1 ARTHRITIS & RHEUMATOLOGY Vol. 68, No. 9, September 2016, pp DOI /art VC 2016, American College of Rheumatology Trabecular Bone Score in Patients With Chronic Glucocorticoid Therapy Induced Osteoporosis Treated With Alendronate or Teriparatide Kenneth G. Saag, 1 Donato Agnusdei, 2 Didier Hans, 3 Lynn A. Kohlmeier, 4 Kelly D. Krohn, 2 Edward S. Leib, 5 Edmund J. MacLaughlin, 6 Jahangir Alam, 2 Christine Simonelli, 7 Kathleen A. Taylor, 2 and Robert Marcus 8 Objective. To determine the effect of alendronate (ALN) and teriparatide on trabecular bone score (TBS) in patients with glucocorticoid-induced osteoporosis. Methods. Patients with chronic glucocorticoid therapy induced osteoporosis (median 7.5 mg/day prednisone equivalent for 90 days) were randomized to receive oral ALN 10 mg/day (n 5 214) or subcutaneous teriparatide 20 mg/day (n 5 214) for 36 months; 118 patients in the ALN group and 123 patients in the teriparatide group completed treatment. Dual x-ray absorptiometry (DXA) results for 53 patients receiving ALN and 56 patients receiving teriparatide who had DXA scans with adequate resolution to perform TBS analysis and completed 36 months of therapy were blindly analyzed for TBS at baseline and 3, 6, 12, 18, 24, and 36 months. Results. In teriparatide-treated patients, TBS was significantly increased at 18 months compared to baseline, and by 36 months had increased 3.7% (P < 0.05). In ALN-treated patients, there was not a ClinicalTrials.gov identifier: NCT Supported by Eli Lilly and Company and/or one of its wholly owned subsidiaries (Lilly). 1 Kenneth G. Saag, MD, MSc: University of Alabama at Birmingham; 2 Donato Agnusdei, MD, Kelly D. Krohn, MD, Jahangir Alam, MS, Kathleen A. Taylor, PhD: Eli Lilly and Company, Indianapolis, Indiana; 3 Didier Hans, PhD: Lausanne University Hospital, Lausanne, Switzerland; 4 Lynn A. Kohlmeier, MD: Spokane Osteoporosis Center, Spokane, Washington; 5 Edward S. Leib, MD: University of Vermont College of Medicine, Burlington; 6 Edmund J. MacLaughlin, MD: Cambridge, Maryland; 7 Christine Simonelli, MD: HealthEast Osteoporosis Care, St. Paul, Minnesota; 8 Robert Marcus, MD: Stanford University, Stanford, California. Dr. Saag has received consulting fees, speaking fees, and/or honoraria from Amgen, Eli Lilly and Company, and Merck (less than $10,000 each). Dr. Agnusdei is a former employee of Eli Lilly and Company, owns stock in Eli Lilly and Company, and has received consulting fees, speaking fees, and/or honoraria from Eli Lilly and Company (more than $10,000). Dr. Hans is on the Board of Directors of Medimaps Group, is co-owner of the Trabecular Bone Score patent, significant change in TBS compared to baseline at any time point. Changes in lumbar spine bone mineral density (BMD) measured by DXA in the subgroup with TBS data were similar to BMD results in the overall study population. At 36 months, increases in lumbar spine BMD were 5.5% and 10.3% in patients treated with ALN and teriparatide, respectively. Conclusion. In patients with glucocorticoidinduced osteoporosis, both ALN and teriparatide increased lumbar spine BMD. However, trabecular bone score significantly increased with teriparatide but did not significantly change with ALN. The pathogenesis of glucocorticoid-induced osteoporosis is predominantly reduced bone formation. TBS may represent a sensitive measure to discriminate treatment effects of an anabolic versus an antiresorptive drug in glucocorticoid-induced osteoporosis. Glucocorticoid therapy is the cause of the most common form of secondary osteoporosis, glucocorticoidinduced osteoporosis. Apoptosis of osteoblasts and osteocytes is the major pathogenetic mechanism, resulting in reduced bone formation and increased risk of fracture (1). Glucocorticoids are beneficial for treating chronic inflammatory conditions, but bone loss and and is part owner of Medimaps Group. Dr. Kohlmeier has received consulting fees, speaking fees, and/or honoraria from Eli Lilly and Company, AbbVie, Pfizer, and Alexion Pharmaceuticals (less than $10,000 each) and from Shire (more than $10,000). Drs. Krohn and Taylor and Mr. Alam own stock in Eli Lilly and Company. Dr. Simonelli has received consulting fees, speaking fees, and/or honoraria from Eli Lilly and Company (less than $10,000) and Amgen (more than $10,000). Dr. Marcus is a former employee of Eli Lilly & Company. Address correspondence to Kenneth G. Saag, MD, MSc, University of Alabama at Birmingham, FOT 820, 1530 Third Avenue South, Birmingham, AL ksaag@uab.edu. Submitted for publication November 5, 2015; accepted in revised form April 14,

2 TRABECULAR BONE SCORE IN GLUCOCORTICOID-INDUCED OSTEOPOROSIS 2123 fracture risk are increased with their use (1 8). Patients who are taking glucocorticoids have an increased risk of fracture at a higher level of bone mineral density (BMD) compared to patients who are not taking glucocorticoids (8). This increased fracture risk may be due to changes in bone quality that may not be detected by dual x-ray absorptiometry (DXA) (8). Currently recommended therapies for the prevention and treatment of glucocorticoidinduced osteoporosis include antiresorptive drugs such as the bisphosphonates alendronate (ALN), risedronate, and zoledronic acid, together with supplemental calcium and vitamin D. In higher-risk patients, it may be reasonable to consider anabolic therapy with teriparatide (2). A large multicenter randomized controlled trial compared teriparatide to ALN in glucocorticoid-treated patients and showed that teriparatide had a preferential effect on BMD compared to ALN (2). Defining osteoporosis on the sole basis of BMD projected by DXA has limitations (9). The multifactorial nature of this disease encourages that the current definition of osteoporosis evolve toward a complex risk model based on clinical risk factors and BMD (10). Considering clinical risk factors along with BMD in the assessment of fracture risk increases the sensitivity of screening without sacrificing specificity (10). However, while some of the limitations of the current use of DXA are addressed via the concomitant use of clinical risk factors, this only partially takes into account information on bone microarchitecture. As such, any additional information on microarchitecture helps to reduce the significant overlap that exists between those with and those without a truly increased risk of fracture and thus helps to clarify treatment options for a given patient (9). The trabecular bone score (TBS) is a novel graylevel texture measurement based on the use of experimental variograms of 2-dimensional projection images, which can differentiate between two 3-dimensional microarchitectures that exhibit the same BMD but different trabecular characteristics (9,11,12). The TBS measures the mean rate of local variations in gray levels in 2-dimensional projection images (9). It is obtained via reanalysis of DXA scans and can be compared to BMD because both evaluate the same region of bone. TBS is strongly correlated with the trabecular bone volume/tissue volume and number of trabeculae and their connectivity, and is negatively correlated with the space between trabeculae and with the structure model index, a measure of rods and plates in trabecular bone. It is also correlated with mechanical behavior, e.g., stiffness (9,11 15). A high TBS reflects strong, fracture-resistant microarchitecture, whereas a low TBS reflects weak, fracture-prone microarchitecture (15,16). The added value of the TBS to bone mineral densitometry in fracture risk assessment has been documented in cross-sectional, prospective, and longitudinal studies and endorsed by the European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis (16) and the International Society of Clinical Densitometry (17). Based on these characteristics, TBS is now complementing traditional DXA as an additional tool for the determination of trabecular bone properties. Intervention studies suggest that TBS tends to increase with treatments that also improve BMD but that the magnitude of change is less marked than that of BMD (15,16). In this subpopulation analysis, TBS was determined using the archived DXA scans from the previously published study comparing the effects of ALN and teriparatide on lumbar spine BMD in patients with chronic glucocorticoid therapy induced osteoporosis (2). The DXA scans of 53 patients receiving ALN and 56 patients receiving teriparatide who completed 36 months of therapy and had DXA scans with adequate resolution to calculate the TBS were analyzed in a blinded manner to measure change in TBS with treatment. PATIENTS AND METHODS Study design. The primary study was a randomized, double-blind, double-dummy, active comparator controlled study consisting of an ;1.5-month screening phase, an 18- month primary phase, and an 18-month continuation phase. Investigators and patients were blinded with regard to treatment throughout the 36 months (2). The primary objective of the primary study was to compare the change in lumbar spine BMD from baseline to 18 months in patients who received teriparatide to that in patients who received ALN. Both treatment groups included men and women who had taken glucocorticoids for $90 days. Secondary outcomemeasuresat36monthsincludedlumbarspineandhip BMD, levels of bone turnover markers, vertebral and nonvertebral fractures, and adverse events (2). Ambulatory men and women ages 21 or older who had low BMD or who presented with at least 1 low-trauma or fragility fracture (vertebral or nonvertebral) that was likely associated with glucocorticoid therapy, and who had received prednisone or equivalent $5 mg/day for $90 days were eligible for enrollment. To be enrolled, patients had to have a total hip, femoral neck, or lumbar spine BMD T score of 22 or less if there was no known prior fracture (or of 21 or less if they had a prior fragility fracture) (2). Patients were randomly assigned to receive subcutaneous teriparatide (20 mg/day) plus oral placebo or oral ALN (10 mg/ day) plus injectable placebo. All patients received supplements of calcium (1,000 mg/day) and vitamin D (800 IU/day) (2). The objective of this TBS subpopulation analysis was to determine the effect of ALN and teriparatide on TBS in patients with glucocorticoid-induced osteoporosis. The primary end points were change in TBS from baseline at 18 and 36 months. TBS methodology. Using standard analysis procedures recommended by the manufacturer, DXA scans from machines

3 2124 SAAG ET AL Figure 1. Disposition of the patients in the primary study and subpopulation analysis. * 5 One subject withdrew before receiving study drug. DXA 5 dual x-ray absorptiometry. with adequate resolution to calculate the TBS were analyzed using TBS insight software, version 2.1 (Medimaps Group). This retrospective calculation was performed in a blinded-totreatment manner at baseline and at 3, 6, 12, 18, 24, and 36 months. L1 L4 TBS was evaluated in the same regions of measurement as those used for the L1 L4 spinal BMD, with TBS calculated as the mean value of the individual measurements for vertebrae L1 L4, excluding any fractured vertebrae, as per the original DXA (2) and in accordance with International Society of Clinical Densitometry rules for individual vertebrae exclusion (17). In the automated calculation process, a grayscale variogram, examining pixel intensity within the image, was produced. TBS was then calculated as the slope at the origin of the log log representation of the gray-scale variogram, to produce a measure of the mean rate of local variations in these gray-scale differences (9,15). This was expressed as a TBS (unitless) (13). Reported precision varies from 1.1% to 2.1%, with an average of 1.4% (15). Statistical analysis. Statistical tests were performed for the overall study population (full analysis set) and the subset of patients who had TBS measurement available. For baseline demographics, data were presented using mean, SD, and proportion; between-treatment group comparisons were done using Student s t-tests and Pearson s chi-square analysis for continuous and categorical variables, respectively. Changes in BMD and TBS from baseline were calculated for each patient as the absolute change divided by the baseline value and were converted into a percentage. Bivariate intergroup comparisons were performed between those treated with ALN and those receiving teriparatide, using Student s t- tests for continuous variables. All statistical analyses were performed using Stata statistical software (release 12). Data were analyzed on an intent-to-treat basis. P values less than 0.05 were considered significant, and all inferential tests were 2 tailed. Percent change from baseline and SEM for DXA and TBS measurements are displayed graphically. RESULTS Patient disposition and baseline characteristics. Patients with chronic glucocorticoid therapy induced osteoporosis (median 7.5 mg/day prednisone for $90 days) were randomized to receive ALN 10 mg/day (n 5 214) or teriparatide 20 mg/day (n 5 214) for 36 months; 118 patients completed treatment with ALN and 123 patients completed treatment with teriparatide in the primary study (2). Of the patients who completed 36 months of therapy, 53 patients who received ALN and 56 patients who received teriparatide had DXA scans from machines with adequate resolution to calculate the TBS, and those patients were included in this subpopulation analysis (Figure 1). Table 1. Baseline characteristics of the patients with glucocorticoid-induced osteoporosis treated with ALN or teriparatide* Primary study TBS subpopulation ALN (n 5 214) Teriparatide (n 5 214) ALN (n 5 53) Teriparatide (n 5 56) Age, mean 6 SD years Race, no. (%) white 148 (69) 153 (71) 39 (74) 43 (77) Sex, no. (%) female 173 (81) 172 (80) 44 (83) 45 (80) Prior bisphosphonate use, no. (%) 20 (9) 20 (9) 2 (4) 4 (7) Prednisone equivalent, median 7.5 (5.0, 10.0) 7.5 (5.0, 10.0) 7.5 (5.0, 10.0) 7.5 (5.0, 10.0) (25th, 75th percentiles) mg/day Duration of glucocorticoid therapy, 2.0 (0.4, 6.5) 2.3 (0.5, 5.8) 1.9 (0.3, 9.0) 1.6 (0.4, 7.0) median (25th, 75th percentiles) years Lumbar spine T score, mean 6 SD Total hip T score, mean 6 SD TBS value, mean 6 SD NA NA Patients with prevalent fracture, no. (%) Radiographic vertebral fracture 53 (25) 63 (30) 8 (15) 12 (21) Nonvertebral fracture 89 (42) 93 (43) 21 (40) 17 (30) * There were no significant between-group differences. ALN 5 alendronate; TBS 5 trabecular bone score; NA 5 not available. Results of the primary study are reported in reference 2.

4 TRABECULAR BONE SCORE IN GLUCOCORTICOID-INDUCED OSTEOPOROSIS 2125 Figure 2. Trabecular bone score (TBS) and bone mineral density (BMD), determined by dual x-ray absorptiometry (DXA) in TBS subpopulation analysis. Values are the mean 6 SEM percent change from baseline. * 5 P, 0.05 versus the same group at baseline; 5 P, 0.05 for lumbar spine (LS) BMD measured by DXA in teriparatide (TPTD) treated patients versus LS BMD measured by DXA in alendronate (ALN) treated patients or for TBS in TPTD-treated patients versus TBS in ALN-treated patients. Baseline characteristics of the patients in the primary study (2) and the TBS subpopulation are shown in Table 1. Baseline demographics were balanced between the 2 treatment groups in both the primary study and the TBS subpopulation analysis. There were no significant differences between treatment groups in either population. In the TBS subpopulation, prevalent vertebral fractures, confirmed by baseline radiography, were present in 8 (15%) of the patients who received ALN and 12 (21%) of the patients who received teriparatide. Changes in BMD. In both treatment groups in the TBS subpopulation, there were significant increases in lumbar spine BMD from baseline at 3 months and through 36 months. The mean increase in lumbar spine BMD from baseline to 36 months was significantly greater in the teriparatide group (10.3%) than in the ALN group (5.5%) (P, 0.001). Changes in lumbar spine BMD measured by DXA in the subgroup of patients with TBS data were similar to the BMD results in the primary study (2) (data not shown). Changes in TBS. The TBS subpopulation analyses were performed at baseline and at 3, 6, 12, 18, 24, and 36 months. In patients treated with teriparatide, TBS was significantly increased from baseline at 18 and 24 months, and had increased 3.7% by 36 months (P, 0.05). In ALNtreated patients, TBS had not significantly changed compared to baseline at any time point (Figure 2). The changes from baseline in TBS were higher in the teriparatide group compared to the ALN group at each time point, and there was a significant difference between treatment groups from 18 months through 36 months (P, 0.05). Adverse events. In the primary study there were no significant differences between treatment groups in the number of patients reporting $1 adverse event or in the incidence of serious adverse events or adverse events determined by investigators to be possibly related to study drug (2). No additional adverse event analysis was performed on the TBS subpopulation. DISCUSSION This subpopulation analysis of a randomized controlled trial is the first analysis, to our knowledge, in patients with glucocorticoid-induced osteoporosis that shows the effects of teriparatide and ALN treatment on TBS. Previous studies have shown greater improvement

5 2126 SAAG ET AL in BMD in patients treated with teriparatide than in those treated with ALN (2,18). In this subpopulation analysis, TBS increased significantly in the teriparatidetreated group and did not change in the ALN-treated group. It is interesting to note that the average value for TBS at baseline in the current subpopulation analysis was ;1.236, which corresponds to the TBS categories partially degraded bone microarchitectural texture (TBS to,1.350) and degraded bone microarchitectural texture (TBS #1.200), and the tertiles for intermediate and high risk as defined in a recent metaanalysis of TBS (15,19,20), which seems to be consistent with microarchitecture status in patients with glucocorticoid-induced osteoporosis (21). At the time of the primary study, TBS information was not available; however, given the pathophysiology of glucocorticoidinduced osteoporosis, it was determined that an assessment of change in TBS in patients treated with ALN versus those treated with teriparatide may be of value. Glucocorticoid-induced osteoporosis is the most common iatrogenic cause of bone loss (1,22,23). A unique feature of glucocorticoid-induced osteoporosis is that the degree of fracture risk in patients receiving glucocorticoids has been shown to be higher than that in postmenopausal women at the same BMD. (8). This suggests that factors affecting bone quality and possibly affecting bone microarchitecture may play a significant role in glucocorticoid-induced osteoporosis (8,23,24). Along with the rapid bone loss seen with glucocorticoidinduced osteoporosis, there is an increase in fracture risk in the first few months of high-dose treatment, which cannot be explained by the degree of bone loss, again suggesting that other factors affect fracture risk that cannot be identified by measuring BMD alone (24,25). Although glucocorticoid-induced osteoporosis affects the entire skeleton, it appears to have a predilection for areas with a high percentage of trabecular bone, such as the spine (25). A recently published observational study (23) compared TBS and BMD in a population of women ages who were taking glucocorticoids (prednisolone $5 mg or equivalent daily for.90 days; n 5 64); had previously sustained a fracture of the distal forearm (n 5 46), proximal humerus (n 5 37), vertebrae (n 5 30), or proximal femur (n 5 28); or were considered healthy (n 5 279). As expected, women with fractures had lower spine BMD and lower TBS Z scores compared to the healthy population. For women taking glucocorticoids, the lumbar spine BMD did not differ from that of the healthy age- and sex-matched population without fractures. However, in receiver operating characteristic analysis, women taking glucocorticoids had an increased area under the curve for both TBS and TBS plus lumbar spine BMD, but not for lumbar spine BMD alone compared to the healthy group, suggesting that TBS, but not BMD, can identify those taking glucocorticoids. In a recent cross-sectional study (21) of bone status in a large cohort of glucocorticoid-treated men and women ages 40 years and older (n 5 416) compared to 1,104 sex-, age-, and body mass index matched controls, TBS was found to be a sensitive indicator of fractures. Changes in TBS showed that the use of oral glucocorticoids was associated with impairment of the microarchitectural texture at the central skeleton, which was more marked in those with osteoporotic fractures, whereas no effect on real BMD was observed at any site. The histomorphometric changes in bone observed after glucocorticoid treatment are profound and reflect a multifactorial insult. Probablyofgreatestimpactisasignificant increase in osteoblast apoptosis leading to trabecular thinning and cortical porosity (1,26). In addition, there is a mild decrease in osteoclast production but also in osteoclast apoptosis, causing a net gain in osteoclast function leading to early increased bone resorption (27). The net effect of these perturbations is an alteration of the bone histomorphometry with a decrease in cancellous bone volume (26). Although such changes would affect BMD, it is likely that techniques that can measure microarchitectural changes, especially at sites of high trabecular bone volumes such as the spine, would more effectively quantify the changes that occur with glucocorticoid use. Muschitz et al (12) demonstrated that TBS was strongly correlated with transiliac bone biopsy parameters in more than 123 patients (both men and women). They have concluded that TBS is a practical, noninvasive, surrogate technique for the assessment of cancellous bone microarchitecture and should be implemented as an additional tool for the determination of trabecular bone properties (12). Theoretically, since the TBS parameter is influenced by trabecular pattern, it should also be influenced by treatments known to affect bone microarchitecture. Additionally, from a conceptual point of view, the reported precision of TBS is sufficient to monitor such an effect. Reported short-term precision varies from 1.1% to 2.1% for spine TBS depending on the study, which is similar to studies of BMD (14,15,28 32). It is of note that although most of the published studies were relatively small, the various efficacious therapies for osteoporosis differed in the extent to which they influenced TBS, with bisphosphonates exerting very little effect (33) but other drugs, such as teriparatide, generally increasing TBS over the least significant changes (.3.6% increase over the study periods) (33,34). The results of all reported bisphosphonate-related studies suggest a positive maintenance of the bone

6 TRABECULAR BONE SCORE IN GLUCOCORTICOID-INDUCED OSTEOPOROSIS 2127 texture rather than a significant increase (28,29,33,34) (,1.5% increase over the study periods). A major increase in TBS would have been illogical in the context of bisphosphonates, considering the physiologic pathway of reduction in bone resorption and preservation of bone volume. The effect of anabolic drugs on bone microarchitecture is also consistent with the known increases in bone volume and improved microarchitecture seen with teriparatide (35). Senn et al (34) measured BMD at baseline and after 2 years in a population of postmenopausal women with osteoporosis. Participants were randomly assigned to receive quarterly intravenous ibandronate (n 5 122) or daily subcutaneous teriparatide (n 5 65) and were matched for body mass index, baseline lumbar spine BMD, and age. At the end of the 2 years, teriparatide had produced a greater increase in lumbar spine BMD (7.6% versus 2.9%) and TBS (4.3% versus 0.3%) than ibandronate. The authors concluded that, in postmenopausal women with osteoporosis, 2-year treatment with teriparatide led to an independent increase in lumbar spine BMD and TBS, suggesting that teriparatide has independent positive effects on lumbar spine BMD and microarchitecture. However, all of those studies included patients with primary osteoporosis and not patients with glucocorticoid-induced osteoporosis. In the current subpopulation analysis, patients treated with teriparatide demonstrated a significant increase in TBS compared to baseline as early as 18 months and continued to experience an increase up to 36 months, to reach 3.7% (P, 0.05). Patients treated with ALN did not have a significant change in TBS compared to baseline at any time point. Changes in lumbar spine BMD measured by DXA in the subgroup of patients with TBS data were similar to the BMD results for the overall study population. At 36 months, increases in lumbar spine BMD were 5.5% and 10.3% in patients treated with ALN and teriparatide, respectively. There were only weak correlations between change in BMD and change in TBS from baseline at 36 months, suggesting that BMD and TBS measure different bone entities and that TBS may be an important test in addition to BMD for monitoring patients taking glucocorticoids. TBS may better reflect the differential effects of an anabolic versus an antiresorptive drug in the treatment of glucocorticoidinduced osteoporosis than BMD. Our subpopulation analysis indicated that TBS is responsive to change as a result of teriparatide therapy in patients with glucocorticoid-induced osteoporosis, which was not the case for ALN. Whether this change is predictive of alterations in risk of future fracture is currently not known and needs to be investigated. In the larger primary study, there was a significant difference in the incidence of radiographic spine fractures, with 10 fractures in the ALN group and 1 in the teriparatide group at 18 months (P ) (18). At 36 months, there were 13 fractures in the ALN group and 3 in the teriparatide group (P ) (2). A limitation of the subpopulation analysis was that there were not enough incident fractures to compare treatment groups in the small group of patients with TBS data. Other limitations of this analysis were the inclusion of only ;25% of the original study participants due to dropout or poor resolution of their DXA scans. Original randomization did not take into account whether each investigative site had newer DXA machines capable of TBS analysis. Most of the research with TBS has been both cross-sectional and prospective and has examined fracture risk prediction. At this time, less is known about the clinical significance of a longitudinal increase in TBS while receiving an anabolic drug like teriparatide. Maintenance of TBS compared to that achieved with placebo could translate into fracture reduction compared to placebo. An increase in TBS in patients receiving an anabolic drug could represent improvement in microarchitecture. Larger prospective studies would be necessary to understand the clinical significance of an increase in TBS. In patients with chronic glucocorticoid therapy induced osteoporosis, both ALN and teriparatide increased lumbar spine BMD. TBS also significantly increased with teriparatide, but did not with ALN. TBS is a sensitive measure of bone microarchitecture and fracture risk, independent of BMD. In this subpopulation analysis, TBS appears to better discriminate the treatment effects of an anabolic versus an antiresorptive agent in glucocorticoid-induced osteoporosis, compared to DXA. This ability to potentially detect improvement in microarchitecture may be a valuable tool for the clinical management of osteoporosis and may also help explain the differences between anabolic and antiresorptive treatment. ACKNOWLEDGMENTS The authors wish to thank Lee Castagnaro (INC Research) and Barbara Utterback (Eli Lilly and Company) for their assistance in manuscript preparation and review. AUTHOR CONTRIBUTIONS All authors were involved in drafting the article or revising it critically for important intellectual content, and all authors approved the final version to be published. Dr. Saag had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study conception and design. Saag, Krohn, Leib, Alam, Marcus. Acquisition of data. Saag, Hans, Krohn, Leib, Simonelli, Marcus. Analysis and interpretation of data. Saag, Agnusdei, Hans, Kohlmeier, Krohn, Leib, MacLaughlin, Alam, Taylor.

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