Helmut Petto

Comparative effects of teriparatide and risedronate in glucocorticoid-induced osteoporosis in men: 18-month results of the EuroGIOPs trial.

Data on treatment of glucocorticoid‐induced osteoporosis (GIO) in men are scarce. We performed a randomized, open‐label trial in men who have taken glucocorticoids (GC) for ≥3 months, and had an areal bone mineral density (aBMD) T‐score ≤ –1.5 standard deviations. Subjects received 20 μg/d teriparatide (n = 45) or 35 mg/week risedronate (n = 47) for 18 months. Primary objective was to compare lumbar spine (L1–L3) BMD measured by quantitative computed tomography (QCT). Secondary outcomes included BMD and microstructure measured by high‐resolution QCT (HRQCT) at the 12th thoracic vertebra, biomechanical effects for axial compression, anterior bending, and axial torsion evaluated by finite element (FE) analysis from HRQCT data, aBMD by dual X‐ray absorptiometry, biochemical markers, and safety. Computed tomography scans were performed at 0, 6, and 18 months. A mixed model repeated measures analysis was performed to compare changes from baseline between groups. Mean age was 56.3 years. Median GC dose and duration were 8.8 mg/d and 6.4 years, respectively; 39.1% of subjects had a prevalent fracture, and 32.6% received prior bisphosphonate treatment. At 18 months, trabecular BMD had significantly increased for both treatments, with significantly greater increases with teriparatide (16.3% versus 3.8%; p = 0.004). HRQCT trabecular and cortical variables significantly increased for both treatments with significantly larger improvements for teriparatide for integral and trabecular BMD and bone surface to volume ratio (BS/BV) as a microstructural measure. Vertebral strength increases at 18 months were significant in both groups (teriparatide: 26.0% to 34.0%; risedronate: 4.2% to 6.7%), with significantly higher increases in the teriparatide group for all loading modes (0.005 < p < 0.015). Adverse events were similar between groups. None of the patients on teriparatide but five (10.6%) on risedronate developed new clinical fractures (p = 0.056). In conclusion, in this 18‐month trial in men with GIO, teriparatide showed larger improvements in spinal BMD, microstructure, and FE‐derived strength than risedronate.

High resolution quantitative computed tomography-based assessment of trabecular microstructure and strength estimates by finite-element analysis of the spine, but not DXA, reflects vertebral fracture status in men with glucocorticoid-induced osteoporosis

High-resolution quantitative computed tomography (HRQCT)-based analysis of spinal bone density and microstructure, finite element analysis (FEA), and DXA were used to investigate the vertebral bone status of men with glucocorticoid-induced osteoporosis (GIO). DXA of L1-L3 and total hip, QCT of L1-L3, and HRQCT of T12 were available for 73 men (54.6±14.0years) with GIO. Prevalent vertebral fracture status was evaluated on radiographs using a semi-quantitative (SQ) score (normal=0 to severe fracture=3), and the spinal deformity index (SDI) score (sum of SQ scores of T4 to L4 vertebrae). Thirty-one (42.4%) subjects had prevalent vertebral fractures. Cortical BMD (Ct.BMD) and thickness (Ct.Th), trabecular BMD (Tb.BMD), apparent trabecular bone volume fraction (app.BV/TV), and apparent trabecular separation (app.Tb.Sp) were analyzed by HRQCT. Stiffness and strength of T12 were computed by HRQCT-based nonlinear FEA for axial compression, anterior bending and axial torsion. In logistic regressions adjusted for age, glucocorticoid dose and osteoporosis treatment, Tb.BMD was most closely associated with vertebral fracture status (standardized odds ratio [sOR]: Tb.BMD T12: 4.05 [95% CI: 1.8-9.0], Tb.BMD L1-L3: 3.95 [1.8-8.9]). Strength divided by cross-sectional area for axial compression showed the most significant association with spine fracture status among FEA variables (2.56 [1.29-5.07]). SDI was best predicted by a microstructural model using Ct.Th and app.Tb.Sp (r(2)=0.57, p<0.001). Spinal or hip DXA measurements did not show significant associations with fracture status or severity. In this cross-sectional study of males with GIO, QCT, HRQCT-based measurements and FEA variables were superior to DXA in discriminating between patients of differing prevalent vertebral fracture status. A microstructural model combining aspects of cortical and trabecular bone reflected fracture severity most accurately.

Teriparatide reduces bone microdamage accumulation in postmenopausal women previously treated with alendronate

Suppression of bone turnover by bisphosphonates is associated with increased bone microdamage accumulation in animal models. Our objective was to study the effects of teriparatide treatment on changes in microdamage accumulation at the iliac crest in previously treatment‐naïve patients or in those switched from alendronate to teriparatide. Sixty‐six postmenopausal women with osteoporosis (mean age, 68.0 yr; and mean BMD T‐score of −2.8 at lumbar spine and −1.7 at total hip; 62% with prevalent fractures) entered this prospective, nonrandomized study and started with 24‐mo 20 μg/d subcutaneous teriparatide treatment in monotherapy: 38 patients stopped previous alendronate treatment (10 mg/d or 70 mg/wk for a mean duration of 63.6 mo) and switched to teriparatide, whereas 28 were previously treatment naïve. Thirty‐one paired biopsies with two intact cortices were collected and analyzed for microstructure and microdamage accumulation at baseline and after 24 mo of teriparatide administration. After 24 mo of teriparatide treatment, crack density (Cr.Dn), crack surface density (Cr.S.Dn), and crack length (Cr.Le) were decreased in previously alendronate‐treated patients, whereas only Cr.Le was reduced in former treatment‐naïve patients. Patients with lower initial femoral neck BMD also showed a higher reduction of microdamage accumulation. Better bone microarchitecture correlated positively, whereas bone turnover markers and age did not correlate with reduced microdamage accumulation on teriparatide. In conclusion, teriparatide reduces microdamage accumulation in the iliac crest of patients previously treated with alendronate. There is insufficient evidence to suggest that age or bone turnover would be associated with this change.

Patient compliance with alendronate, risedronate and raloxifene for the treatment of osteoporosis in postmenopausal women

ABSTRACT Objectives: The aim was to investigate patient compliance with different osteoporosis medications commonly prescribed in clinical practice, to determine risk factors associated with discontinuation and to evaluate quality of life changes. Research design and methods: We conducted a 1-year observational study of patients of age ≥ 60 years in a clinical setting at 917 sites in 10 European countries (Germany, Greece, UK, Sweden, Netherlands, Romania, Norway, Finland, Denmark, Estonia), Lebanon and South Africa. Demographic data, concomitant diseases, the reasons for intervention, educational, socio-economical status and disease knowledge were captured at baseline. Self-reported compliance, discontinuation data and health status were collected. Main outcome measures: Out of 5198 patients, 3490 (67.1%) patients received 60 mg daily raloxifene (RAL), 452 (8.7%) 10 mg daily alendronate (AQD), 769 (14.8%) 70 mg once weekly alendronate (AQW) and 487 (9.4%) 5 mg daily risedronate (RIS). Among patients completing the study (4231, 81%), the percentage of patients with high compliance was 80% (RAL), 79% (AQD), 65% (AQW) and 76% (RIS). The discontinuation due to side effects was highest on AQW (7.0%), followed by AQD (6.4%), RAL (3.8%) and RIS (3.4%). The discontinuation-rate was higher for patients with a history of surgical menopause, increased age, lack of knowledge about medical prevention of osteoporosis and thin frame as a reason for intervention. The EQ-5D weighted index showed the highest improvement for RIS (0.13), followed by RAL (0.11), AQD (0.08) and AQW (0.07). Conclusions: Data from this non-interventional observational study indicate moderate overall compliance and discontinuation rate with the prescribed osteoporosis medications.

Effects of Teriparatide Compared with Risedronate on Recovery After Pertrochanteric Hip Fracture: Results of a Randomized, Active-controlled, Double-blind Clinical Trial at 26 Weeks

BACKGROUND Osteoporosis drugs might affect fracture-healing. We therefore studied the effects of teriparatide in comparison with risedronate on recovery after pertrochanteric hip fractures. METHODS The study was a randomized, multicenter, active-controlled, 78-week trial comparing teriparatide (20 μg/day) with risedronate (35 mg/week) initiated within 2 weeks after fixation of a low-trauma pertrochanteric hip fracture (AO/OTA 31-A1 or 31-A2). The main inclusion criteria were a bone mineral density T-score of ≤-2.0 and 25-OH-vitamin D of ≥9.2 ng/mL. During the first 26 weeks, patients received study medication with oral or injectable placebo plus calcium and vitamin D in a double-blinded fashion. Secondary (Timed Up-and-Go [TUG] test, hip pain, Short Form [SF]-36 health status, and safety) and exploratory (radiographic outcomes and ability to walk) 26-week end points are reported. RESULTS Of the 224 patients who were randomized, 171 (86 teriparatide, 85 risedronate) were included in the analysis. The mean age was 77 ± 8 years, 77% were female, and 26% had a prior history of low-trauma fracture. The teriparatide group completed the TUG test in a shorter time at 6, 12, 18, and 26 weeks (differences of -5.7, -4.4, -3.1, and -3.1 seconds, respectively; p = 0.021 for the overall difference). They also reported less pain on a visual analog scale immediately after the TUG test at 12 and 18 weeks (adjusted absolute differences of 10.6 and 11.9 mm, respectively; p < 0.05). There were no significant between-group differences in the SF-36 score, Charnley hip pain score, ability to walk, or use of walking aids during follow-up. Radiographic healing at 6, 12, and 26 weeks, mechanical failure of the implant (teriparatide, 7; risedronate, 8), loss of reduction (teriparatide, 2; risedronate, 4), and nonunion (0 cases) were not significantly different. Mild hypercalcemia and hyperuricemia were more frequent with teriparatide. CONCLUSIONS Teriparatide was associated with less pain and a shorter time to complete the TUG test between 6 and 26 weeks compared with risedronate. Other fracture-recovery outcomes were similar. The results should be interpreted with caution as these were secondary end points. LEVEL OF EVIDENCE Therapeutic Level II. See Instructions for Authors for a complete description of levels of evidence.

Study description and baseline characteristics of the population enrolled in a multinational observational study of extended teriparatide use (ExFOS)

Abstract Objective: To better characterize patients who are currently being prescribed teriparatide in Europe, this article describes the study design and baseline characteristics of participants of the Extended Forsteo Observational Study (ExFOS). Research design and methods: ExFOS is a noninterventional, multicenter, prospective, observational study in men and women with osteoporosis treated with teriparatide during the course of normal clinical practice for up to 24 months and with a post-treatment follow-up of at least 18 months. Main outcome measures: Baseline characteristics, including history of fracture and back pain, and health-related quality of life (HRQoL, assessed using the EuroQol-5 Dimension [EQ-5D]). Results: Of 1607 patients enrolled, 90.9% were women. At baseline, mean (standard deviation [SD]) age was 70.3 (9.8) years, and 85.8% of patients had a history of fracture (64.7% with ≥2 fragility fractures). Of those with historic fractures, 90.8% had vertebral fractures (67.8% had thoracic fractures). The mean (SD) of reported bone mineral density T-scores were −3.0 (1.2), −2.4 (1.0), and −2.5 (0.9) for lumbar spine, total hip (left), and femoral neck (left), respectively. Overall, 39.3% of patients had experienced ≥1 fall during the 12 months before enrollment. At baseline, 11.4% of patients were osteoporosis-treatment naïve and 15% were currently using glucocorticoids. The mean (SD) visual analog scale score for back pain during the last month was 50.7 (26.9), and 62.1% of patients experienced daily or almost daily back pain. The median EQ-5D health state value at baseline was 0.62 (first and third quartiles: 0.19, 0.74). Conclusions: Baseline characteristics of the ExFOS study cohort indicate that patients prescribed teriparatide in Europe have severe osteoporosis with highly prevalent vertebral fractures, frequent and disabling back pain, and a poor HRQoL, despite previous pharmacotherapy for osteoporosis. Limitations include non-randomization, lack of a comparator group, and patient self-report for data on prior medication and fracture history.

Effect of Teriparatide or Risedronate in Elderly Patients With a Recent Pertrochanteric Hip Fracture: Final Results of a 78‐Week Randomized Clinical Trial

We present final results of a study comparing teriparatide 20 μg every day (QD) with risedronate 35 mg once per week (QW) started within 2 weeks after surgery for a pertrochanteric hip fracture. Patients with BMD T‐score ≤ –2.0 and 25OHD ≥9.2 ng/mL were randomized to receive 26‐week double‐dummy treatment plus calcium and vitamin D, followed by 52‐week open‐label treatment with the same assigned active drug. Primary endpoint was change from baseline in lumbar spine (LS) BMD at 78 weeks. Secondary and exploratory endpoints were change in BMD at the proximal femur, function, hip pain (Charnley score and 100 mm Visual Analog Scale [VAS]), quality of life (Short Form‐36), radiology outcomes, and safety. Data were analyzed with mixed models for repeated measures (MMRM) and logistic regression. Totally, 224 patients were randomized; 171 (teriparatide: 86) contributed to the efficacy analyses (mean ± SD age: 77 ± 7.7 years, 77% females). Mean baseline LS, femoral neck (FN), and total hip (TH) T‐scores were –2.16, –2.63, and –2.51, respectively. At 78 weeks, BMD increased significantly more with teriparatide compared to risedronate at the LS (+11.08% versus +6.45%; p < 0.001) and FN (+1.96% versus –1.19%; p = 0.003), with no significant between‐group difference in TH BMD. Timed up‐and‐go (TUG) test was significantly faster with teriparatide at 6, 12, 18, and 26 weeks (differences: –3.2 to –5.9 s; p = 0.045 for overall difference). Hip pain during TUG test by 100 mm VAS was significantly lower with teriparatide at 18 weeks (adjusted difference: –11.3 mm, p = 0.033; –10.0 and –9.3 mm at 12 and 26 weeks, respectively; p = 0.079 for overall difference). Other secondary and exploratory outcomes were not different. Teriparatide group showed two new hip fractures versus seven with risedronate (p = 0.171) and more frequent hypercalcemia and hyperuricemia. In conclusion, 78‐week treatment with teriparatide showed significantly greater increases in LS and FN BMD, less pain, and a faster TUG test versus risedronate.

A statistical method to convert published response rates into marginal distributions with an example application in psoriasis

Assessment of severity is essential for the management of chronic diseases. Continuous variables like scores obtained from the Hamilton Rating Scale for Depression or the Psoriasis Area and Severity Index (PASI) are standard measures used in clinical trials of depression and psoriasis. In clinical trials of psoriasis, for example, the reduction of PASI from baseline in response to therapy, in particular the proportion of patients achieving at least 75%, 90%, or 100% improvement of disease (PASI 75, PASI 90, or PASI 100), is typically used to evaluate treatment efficacy. However, evaluation of the proportions of patients reaching absolute PASI values (eg, ≤1, ≤2, ≤3, or ≤5) has recently gained greater clinical interest and is increasingly being reported. When relative versus absolute scores are standard, as is the case with the PASI in psoriasis, it is difficult to compare absolute changes using existing published data. Thus, we developed a method to estimate absolute PASI levels from aggregated relative levels. This conversion method is based on a latent 2-dimensional normal distribution for the absolute score at baseline and at a specific endpoint with a truncation to allow for baseline inclusion criterion. The model was fitted to aggregated results from simulations and from 3 phase III studies that had known absolute PASI proportions. The predictions represented the actual results quite precisely. This model might be applied to other conditions, such as depression, to estimate proportions of patients achieving an absolute low level of disease activity, given absolute values at baseline and proportions of patients achieving relative improvements at a subsequent time point.

The Lumley-Method, A Recommended Network Meta-Analysis for Indirect Comparisons, Summarized for Practitioners

METHODS: We give more details than in the article of how the proposed variance function aggregates study-heterogeneities and of how effect-sizes and confidence intervals can be derived from the parameter- and variance-estimates. We discuss why dependencies coming from the network-structure should be incorporated into confidence-interval calculations and of how the model can be extended with an in the article suggested Bayesian approach for modeling the random-effects parameters. RESULTS: We include an example of how the Lumley-method can be applied in practice. We present based on the program- example in the article a corrected R-version and a translation into SAS. For both we show how aggregated study-data should be structured and dummy-coded before running the program. The Lumley-method was applied to simulated data with known model-parameters and we show for different scenarios how close the estimates come. For selected treatment comparisons we present effect-sizes with confidence intervals. We apply also the Bayesian extension and discuss its advantages. CONCLUSIONS: Based on our research we give recommendations of when the Lumley-method should be best applied, and discuss limitations. 1 Lumley T: Network meta-analysis for indirect treatment comparisons. Stat. Med. 2002; 21:2313-2324. ABSTRACT 13 T2-T3 -1.37 0.341 0 1 -1 0 5 14 T2-T3 -1.976 0.31 0 1 -1 0 5 15 T2-T3 -1.804 0.336 0 1 -1 0 5 16 T2-T4 -3.095 0.37 0 1 0 -1 6 17 T2-T4 -1.654 0.401 0 1 0 -1 6 18 T2-T4 -2.324 0.381 0 1 0 -1 6 19 T3-T1 2.249 0.413 -1 0 1 0 7 20 T3-T1 1.622 0.406 -1 0 1 0 7 21 T3-T1 2.631 0.413 -1 0 1 0 7 22 T3-T2 -0.783 0.432 0 -1 1 0 8 23 T3-T2 -0.726 0.459 0 -1 1 0 8 24 T3-T2 -0.506 0.471 0 -1 1 0 8 25 T4-T1 2.813 0.465 -1 0 0 1 9 26 T4-T1 3.48 0.503 -1 0 0 1 9

SAT0353 Back pain and quality of life: 18- and 24-month final results from the italian study on severe osteoporosis (ISSO)

Background The ISSO was an Italian, 24-month, observational, prospective study that evaluated the effectiveness of anti-osteoporotic treatments available in normal clinical practice for severe multi-fractured osteoporotic patients defined according to reimbursement criteria set out by the Italian Health National Service (Note 79, second part). Objectives The primary objective of the study was to estimate the proportion of patients experiencing one or more new clinical vertebral and non-vertebral fragility fractures in the first 24 months from the initiation of anti-osteoporosis medication. The evaluation of back pain and Health-Related Quality of Life (HRQOL) at 18 and 24 months were important secondary endpoints of the study and results are herein presented. Methods Back pain was evaluated by using a 0-10 visual analogue scale ([VAS]; 0 = no pain, 10 = worst possible pain), whereas the HRQOL was evaluated by using the European Quality of Life 5-Dimensions questionnaire (EQ-5D), which includes 5 dimensions of health (mobility, self-care, usual activities, pain/discomfort, anxiety/depression), and with a 0-100 mm VAS (0 = worst imaginable health state, 100 = best imaginable health state). Results Of the 769 patients (mean age ± SD 72.8±8.8 years; 689 [90.7%] women) enrolled between April 2008 and February 2009, 663 (87.2%) started a therapy and 438 (57.6%) completed the 24 months of observation. Teriparatide (572/663 patients, 86.3%) was the drug most commonly used during the study: 420/663 (63.3%) patients received only teriparatide (OT), 38/663 (5.7%) only bisphosphonates, 19/663 (2.9%) only parathyroid hormone, and 18/663 (2.7%) only strontium ranelate, while 168/663 patients (25.3%) took more than one drug. The rate of patients with back pain decreased from baseline to 18 and 24 months both in the total population (TP) (94.1%, 79.5% and 76.2%, respectively) and in those treated with OT (95.0%, 77.1% and 75.9%). The mean decreases in pain VAS from baseline to 18 and 24 months were -1.93 (95% CI: -2.21 to -1.65) and -2.05 (95% CI: -2.37 to -1.73) in TP, and were -2.31 (95% CI: -2.65 to -1.97) and -2.64 (95% CI: -3.04 to -2.23) in OT, respectively. The mean changes in EQ-5D score from baseline to 18 and 24 months were 0.125 (95% CI: 0.103 to 0.148) and 0.116 (95% CI: 0.093 to 0.138) in TP, and were 0.138 (95% CI: 0.108 to 0.167) and 0.121 (95% CI: 0.093 to 0.149) in OT, respectively. Changes in EQ-5D VAS were consistent with those of score. Conclusions The results at 18 and 24 months of the ISSO study show that the prescribed treatment was associated with improvements in back pain and HRQOL, which were sustained up to the end of the 24-month observational period. Patients treated with teriparatide as monotherapy improved at least as markedly as did the TP. Disclosure of Interest F. Bertoldo: None Declared, O. Di Munno: None Declared, L. Pietrogrande: None Declared, R. Del Fiacco Employee of: Eli Lilly Italy, H. Petto Employee of: Eli Lilly austria, P. Marchi Employee of: Eli Lilly Italy, S. Silvestri Shareholder of: Eli Lilly italy (minority shareholder), Employee of: Eli Lilly Italy