1 / 43

New Dimensions and Landmark Advances in Osteoporosis Management

Universal Management Measures. Risk factor reductionBone massMedications- stop or reduce dose if possibleSmoking cessation programsFall Prevention MedicationsEnvironmentBalance trainingPhysical Activity/ ExerciseOptimal NutritionCalciumVitamin DBMD Testing When Appropriate. FDA Approv

reya
Download Presentation

New Dimensions and Landmark Advances in Osteoporosis Management

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

    1. New Dimensions and Landmark Advances in Osteoporosis Management Felicia Cosman, MD Professor of Clinical Medicine Columbia University New York, NY Osteoporosis Specialist/Endocrinologist Helen Hayes Hospital, West Haverstraw, NY Clinical Director National Osteoporosis Foundation Washington, DC

    2. Universal Management Measures Risk factor reduction Bone mass Medications- stop or reduce dose if possible Smoking cessation programs Fall Prevention Medications Environment Balance training Physical Activity/ Exercise Optimal Nutrition Calcium Vitamin D BMD Testing When Appropriate

    3. FDA Approved Osteoporosis Treatments Antiresorptive Agents Bisphosphonates Alendronate (Fosamax®) Risedronate (Actonel®) Ibandronate (Boniva®: Oral and IV) Zoledronic Acid (Reclast® IV) Estrogen Agonist/Antagonists Raloxifene (Evista®) Estrogen/Estrogen-Progestin Combinations Calcitonins (Miacalcin, Fortical) Anabolic Therapies Teriparatide (Forteo)

    4. Treating Patients Across the Lifespan Try to take advantage of greatest potential benefits of specific medications and avoid risks: Age is a key determinant HT greatest benefit and least risk early after menopause and for <5 years ET alone: Perhaps can use for longer Raloxifene during 50s to mid to late 60s Bisphosphonates: 60s and beyond Teriparatide can be used at any point along this continuum for more severe patients, but needs to be followed by an antiresorptive treatment to maximize and maintain gains

    5. Major Problem with all Current Osteoporosis Therapies: Adherence and Persistence Fewer than 50% of people remain on any of these therapies beyond one year Patients who are not adherent and persistent do not have fracture benefits Once yearly zoledronic acid has the potential to dramatically improve adherence and persistence to therapy and thus translate clinical trial benefits into real clinical benefits for patients Denosumab (twice yearly subcutaneously) offers potential improvement in persistence and real clinical benefits

    6. Objectives of Presentation Review Zoledronic Acid Pivotal Trials Initial study: Pivotal Fracture Trial (PFT) Most recent study: Recurrent Fracture Trial (RFT) Denosumab Overview

    7. HORIZON Pivotal Fracture Trial (PFT) Overview Objective: To evaluate the potential of once yearly zoledronic acid 5 mg to decrease fracture risk in postmenopausal women with osteoporosis 3-year, randomized, double-blind, placebo-controlled clinical trial 7736 women from 240 clinical centers in 27 countries Treatment Annual infusion of either zoledronic acid 5 mg or placebo Calcium 1000–1500 mg/d; vitamin D 400–1200 IU/d Follow-up visits at 6, 12, 24 and 36 months Telephone interviews every 3 months HORIZON Pivotal Fracture Trial (PFT): Overview Zoledronic acid is a third-generation nitrogen-containing bisphosphonate currently being developed for the treatment of postmenopausal osteoporosis. In the HORIZON Pivotal Fracture Trial (PFT), a randomized, double-blind, placebo-controlled trial carried out at 240 centers in 27 countries, 5 mg zoledronic acid (ZOL) was assessed for efficacy and safety parameters with the goal of decreasing fracture risk in postmenopausal women with osteoporosis. The trial population of 7736 women 65 to 89 years of age were randomly assigned to once yearly treatment with a 15-minute infusion of ZOL 5 mg or placebo. Reference Black DM, Boonen S, Cauley J, et al. Effect of once-yearly infusion of zoledronic acid 5 mg on spine and hip fracture reduction in postmenopausal women with osteoporosis: the HORIZON Pivotal Fracture Trial. Presented at: 28th Annual Meeting of the American Society for Bone and Mineral Research; September 15-19, 2006; Philadelphia, Pa. Abstract 1054. HORIZON Pivotal Fracture Trial (PFT): Overview Zoledronic acid is a third-generation nitrogen-containing bisphosphonate currently being developed for the treatment of postmenopausal osteoporosis. In the HORIZON Pivotal Fracture Trial (PFT), a randomized, double-blind, placebo-controlled trial carried out at 240 centers in 27 countries, 5 mg zoledronic acid (ZOL) was assessed for efficacy and safety parameters with the goal of decreasing fracture risk in postmenopausal women with osteoporosis. The trial population of 7736 women 65 to 89 years of age were randomly assigned to once yearly treatment with a 15-minute infusion of ZOL 5 mg or placebo. Reference Black DM, Boonen S, Cauley J, et al. Effect of once-yearly infusion of zoledronic acid 5 mg on spine and hip fracture reduction in postmenopausal women with osteoporosis: the HORIZON Pivotal Fracture Trial. Presented at: 28th Annual Meeting of the American Society for Bone and Mineral Research; September 15-19, 2006; Philadelphia, Pa. Abstract 1054.

    8. Study Population: HORIZON Inclusion Women 65 to 89 years of age Femoral neck T-score =–2.5 or =–1.5 with two mild or one moderate prevalent vertebral fracture Exclusion Current use of bisphosphonates, PTH, or strontium ranelate Failure to meet specified washout periods for previous BP use Two strata Stratum I: No current osteoporosis therapy (80% of total population) Stratum II: SERMs, calcitonin, HT/ET, or tibolone at baseline (20% of total population) Study Population Women were eligible for the trial if they had osteoporosis documented by either a femoral neck T-score =–2.5 or femoral neck T-score =–1.5 with 2 mild or 1 moderate prevalent vertebral fracture. Patients were excluded from the trial if they failed to meet a prespecified washout schedule for prior bisphosphonate use: Oral BP for 48 weeks or more: 2 years Oral BP for between 8 and 48 weeks: 1 year Oral BP for between 2 and 8 weeks: 6 months Oral BP for =2 weeks: 2 months Any IV BP: 2 years Creatinine clearance was assessed at Visit 1 and Visit 2. Patients with a creatinine clearance of less than 30 mL/min on either occasion were excluded. Patients were assigned to 1 of 2 treatment strata based on their current or planned osteoporosis treatment: Stratum I: no current osteoporosis medication and meets washout criteria for prior medication (HRT, SERMs, calcitonin, tibolone) Use for 26 weeks or more:1 year Use for 12 or more weeks, but less than 26 weeks: 6 months Use for 4 or more weeks, but less than 12 weeks: 3 months Use for less than 4 weeks: 1 month Stratum II: concomitant hormone therapy/estrogen therapy, selective estrogen receptor modulators (SERM), calcitonin, or tibolone All patients were instructed to take calcium and vitamin D throughout the study. Reference Black DM, Boonen S, Cauley J, et al. Effect of once-yearly infusion of zoledronic acid 5 mg on spine and hip fracture reduction in postmenopausal women with osteoporosis: the HORIZON Pivotal Fracture Trial. Presented at: 28th Annual Meeting of the American Society for Bone and Mineral Research; September 15-19, 2006; Philadelphia, Pa. Abstract 1054.Study Population Women were eligible for the trial if they had osteoporosis documented by either a femoral neck T-score =–2.5 or femoral neck T-score =–1.5 with 2 mild or 1 moderate prevalent vertebral fracture. Patients were excluded from the trial if they failed to meet a prespecified washout schedule for prior bisphosphonate use: Oral BP for 48 weeks or more: 2 years Oral BP for between 8 and 48 weeks: 1 year Oral BP for between 2 and 8 weeks: 6 months Oral BP for =2 weeks: 2 months Any IV BP: 2 years Creatinine clearance was assessed at Visit 1 and Visit 2. Patients with a creatinine clearance of less than 30 mL/min on either occasion were excluded. Patients were assigned to 1 of 2 treatment strata based on their current or planned osteoporosis treatment: Stratum I: no current osteoporosis medication and meets washout criteria for prior medication (HRT, SERMs, calcitonin, tibolone) Use for 26 weeks or more:1 year Use for 12 or more weeks, but less than 26 weeks: 6 months Use for 4 or more weeks, but less than 12 weeks: 3 months Use for less than 4 weeks: 1 month Stratum II: concomitant hormone therapy/estrogen therapy, selective estrogen receptor modulators (SERM), calcitonin, or tibolone All patients were instructed to take calcium and vitamin D throughout the study. Reference Black DM, Boonen S, Cauley J, et al. Effect of once-yearly infusion of zoledronic acid 5 mg on spine and hip fracture reduction in postmenopausal women with osteoporosis: the HORIZON Pivotal Fracture Trial. Presented at: 28th Annual Meeting of the American Society for Bone and Mineral Research; September 15-19, 2006; Philadelphia, Pa. Abstract 1054.

    9. Baseline Characteristics Baseline Characteristics Mean baseline demographic and disease characteristics were balanced between treatment groups. The mean age was 73 years. Geographic distribution was similar, with approximately half of the population in each group from Western and Eastern Europe. Femoral neck T-scores were <–2.5 in about 72% of patients in both groups and approximately 63% had at least one prevalent baseline vertebral fracture Most patients (85%) were naive to prior bisphosphonate use. Reference Black DM, Boonen S, Cauley J, et al. Effect of once-yearly infusion of zoledronic acid 5 mg on spine and hip fracture reduction in postmenopausal women with osteoporosis: the HORIZON Pivotal Fracture Trial. Presented at: 28th Annual Meeting of the American Society for Bone and Mineral Research; September 15-19, 2006; Philadelphia, Pa. Abstract 1054. Baseline Characteristics Mean baseline demographic and disease characteristics were balanced between treatment groups. The mean age was 73 years. Geographic distribution was similar, with approximately half of the population in each group from Western and Eastern Europe. Femoral neck T-scores were <–2.5 in about 72% of patients in both groups and approximately 63% had at least one prevalent baseline vertebral fracture Most patients (85%) were naive to prior bisphosphonate use. Reference Black DM, Boonen S, Cauley J, et al. Effect of once-yearly infusion of zoledronic acid 5 mg on spine and hip fracture reduction in postmenopausal women with osteoporosis: the HORIZON Pivotal Fracture Trial. Presented at: 28th Annual Meeting of the American Society for Bone and Mineral Research; September 15-19, 2006; Philadelphia, Pa. Abstract 1054.

    10. Morphometric Vertebral Fracture Results (Stratum I) Morphometric Vertebral Fracture Results (Stratum I) Incident morphometric vertebral fracture (height reduction from baseline of =20% and 4 mm) was evaluated in patients without concomitant osteoporosis therapy (Stratum I). Among Stratum I patients, ZOL 5 mg reduced the risk of new vertebral fractures by 60% compared with placebo in the first year of the trial, by 71% in year 2, and by 70% in year 3 (P < .0001 for each time point). At 3 years, 3.3% of zoledronic acid patients exhibited new fractures as compared with 10.9% of placebo patients in Stratum I. This reflects a highly statistically significant relative risk reduction of 70% (P < .0001) versus placebo. Reference Black DM, Boonen S, Cauley J, et al. Effect of once-yearly infusion of zoledronic acid 5 mg on spine and hip fracture reduction in postmenopausal women with osteoporosis: the HORIZON Pivotal Fracture Trial. Presented at: 28th Annual Meeting of the American Society for Bone and Mineral Research; September 15-19, 2006; Philadelphia, Pa. Abstract 1054. Morphometric Vertebral Fracture Results (Stratum I) Incident morphometric vertebral fracture (height reduction from baseline of =20% and 4 mm) was evaluated in patients without concomitant osteoporosis therapy (Stratum I). Among Stratum I patients, ZOL 5 mg reduced the risk of new vertebral fractures by 60% compared with placebo in the first year of the trial, by 71% in year 2, and by 70% in year 3 (P < .0001 for each time point). At 3 years, 3.3% of zoledronic acid patients exhibited new fractures as compared with 10.9% of placebo patients in Stratum I. This reflects a highly statistically significant relative risk reduction of 70% (P < .0001) versus placebo. Reference Black DM, Boonen S, Cauley J, et al. Effect of once-yearly infusion of zoledronic acid 5 mg on spine and hip fracture reduction in postmenopausal women with osteoporosis: the HORIZON Pivotal Fracture Trial. Presented at: 28th Annual Meeting of the American Society for Bone and Mineral Research; September 15-19, 2006; Philadelphia, Pa. Abstract 1054.

    11. Cumulative Risk of Hip Fracture (Strata I + II) Cumulative Risk of Hip Fracture (Strata I & II) ZOL 5 mg reduced the relative risk of incurring a hip fracture over time by 41% compared with placebo (hazard ratio=0.59; P = .0024). Reference Black DM, Boonen S, Cauley J, et al. Effect of once-yearly infusion of zoledronic acid 5 mg on spine and hip fracture reduction in postmenopausal women with osteoporosis: the HORIZON Pivotal Fracture Trial. Presented at: 28th Annual Meeting of the American Society for Bone and Mineral Research; September 15-19, 2006; Philadelphia, Pa. Abstract 1054. Cumulative Risk of Hip Fracture (Strata I & II) ZOL 5 mg reduced the relative risk of incurring a hip fracture over time by 41% compared with placebo (hazard ratio=0.59; P = .0024). Reference Black DM, Boonen S, Cauley J, et al. Effect of once-yearly infusion of zoledronic acid 5 mg on spine and hip fracture reduction in postmenopausal women with osteoporosis: the HORIZON Pivotal Fracture Trial. Presented at: 28th Annual Meeting of the American Society for Bone and Mineral Research; September 15-19, 2006; Philadelphia, Pa. Abstract 1054.

    12. Cumulative Risk of Clinical Vertebral Fracture (Strata I & II) Cumulative Risk of Clinical Vertebral Fracture (Strata I & II) Assessment of number of clinical fractures (painful fractures that led to an office evaluation) occurring over 3 years revealed that a single annual infusion of ZOL 5 mg reduced the risk of clinical vertebral fractures by 77% compared with placebo over 3 years (P < .0001). Reference Black DM, Boonen S, Cauley J, et al. Effect of once-yearly infusion of zoledronic acid 5 mg on spine and hip fracture reduction in postmenopausal women with osteoporosis: the HORIZON Pivotal Fracture Trial. Presented at: 28th Annual Meeting of the American Society for Bone and Mineral Research; September 15-19, 2006; Philadelphia, Pa. Abstract 1054. Cumulative Risk of Clinical Vertebral Fracture (Strata I & II) Assessment of number of clinical fractures (painful fractures that led to an office evaluation) occurring over 3 years revealed that a single annual infusion of ZOL 5 mg reduced the risk of clinical vertebral fractures by 77% compared with placebo over 3 years (P < .0001). Reference Black DM, Boonen S, Cauley J, et al. Effect of once-yearly infusion of zoledronic acid 5 mg on spine and hip fracture reduction in postmenopausal women with osteoporosis: the HORIZON Pivotal Fracture Trial. Presented at: 28th Annual Meeting of the American Society for Bone and Mineral Research; September 15-19, 2006; Philadelphia, Pa. Abstract 1054.

    13. Cumulative Risk of Clinical Non-vertebral Fracture (Strata I & II) Cumulative Risk of Clinical Non-vertebral Fracture (Strata I & II) Incidence of clinical non-vertebral fractures was significantly reduced (approximately 25%) over 3 years with ZOL 5 mg treatment compared with placebo (P = .0002; estimated hazard ratio of 0.75). The most frequent fracture locations were wrist, hip, arm, and rib. Reference Black DM, Boonen S, Cauley J, et al. Effect of once-yearly infusion of zoledronic acid 5 mg on spine and hip fracture reduction in postmenopausal women with osteoporosis: the HORIZON Pivotal Fracture Trial. Presented at: 28th Annual Meeting of the American Society for Bone and Mineral Research; September 15-19, 2006; Philadelphia, Pa. Abstract 1054. Cumulative Risk of Clinical Non-vertebral Fracture (Strata I & II) Incidence of clinical non-vertebral fractures was significantly reduced (approximately 25%) over 3 years with ZOL 5 mg treatment compared with placebo (P = .0002; estimated hazard ratio of 0.75). The most frequent fracture locations were wrist, hip, arm, and rib. Reference Black DM, Boonen S, Cauley J, et al. Effect of once-yearly infusion of zoledronic acid 5 mg on spine and hip fracture reduction in postmenopausal women with osteoporosis: the HORIZON Pivotal Fracture Trial. Presented at: 28th Annual Meeting of the American Society for Bone and Mineral Research; September 15-19, 2006; Philadelphia, Pa. Abstract 1054.

    14. Zoledronic Acid Produced Significant Increases in BMD Over 3 Years Reclast Produced Significant Increases in BMD Over 3 Years Treatment with Reclast produced significant increases in BMD over 3 years at total hip, femoral neck, and lumbar spine Total hip BMD was measured in all study participants. Reclast produced a significantly greater change from baseline in total hip BMD over time compared with placebo: At 3 years, the mean difference was 6.02 (4.15 vs –1.87; P < .0001). Femoral neck BMD was measured in all study participants. Reclast produced a significantly greater change from baseline in femoral neck BMD over time compared with placebo: At 3 years, the mean difference was 5.06 (3.92 vs –1.13; P < .0001). In a subset of study participants, Reclast produced a significantly greater percentage change from baseline in lumbar spine BMD over time compared with placebo: At 3 years, the mean difference was 6.71 (6.95 vs 0.51; P < .0001). Reference Black DM, Delmas PD, Eastell R, et al, for the HORIZON Pivotal Fracture Trial. Once-yearly zoledronic acid for treatment of postmenopausal osteoporosis. N Engl J Med. 2007;356:1809-1822. Reclast Produced Significant Increases in BMD Over 3 Years Treatment with Reclast produced significant increases in BMD over 3 years at total hip, femoral neck, and lumbar spine Total hip BMD was measured in all study participants. Reclast produced a significantly greater change from baseline in total hip BMD over time compared with placebo: At 3 years, the mean difference was 6.02 (4.15 vs –1.87; P < .0001). Femoral neck BMD was measured in all study participants. Reclast produced a significantly greater change from baseline in femoral neck BMD over time compared with placebo: At 3 years, the mean difference was 5.06 (3.92 vs –1.13; P < .0001). In a subset of study participants, Reclast produced a significantly greater percentage change from baseline in lumbar spine BMD over time compared with placebo: At 3 years, the mean difference was 6.71 (6.95 vs 0.51; P < .0001). Reference Black DM, Delmas PD, Eastell R, et al, for the HORIZON Pivotal Fracture Trial. Once-yearly zoledronic acid for treatment of postmenopausal osteoporosis. N Engl J Med. 2007;356:1809-1822.

    15. Mean Serum CTX Over Time Mean Serum ß-CTX Over Time Serum ? C-telopeptide (?-CTX ) and bone-specific alkaline phosphatase (BSAP) were measured every 6 months in a subset of patients. Additional measurements at 9-11 days, 1 month and 3 months were taken after the 24-month infusion to evaluate the short-term changes in these markers (see slide 15). The bone resorption marker ?-CTX significantly decreased from baseline at 6 months among patients receiving ZOL 5 mg and remained within the low end of the premenopausal range (0.04 to 0.18 ng/mL) throughout the course of the trial. In placebo patients, ?-CTX did not decrease over the course of the 3-year study period. Reductions in ?-CTX were significant compared with placebo at all time points (P < .0001). Reference Black DM, Boonen S, Cauley J, et al. Effect of once-yearly infusion of zoledronic acid 5 mg on spine and hip fracture reduction in postmenopausal women with osteoporosis: the HORIZON Pivotal Fracture Trial. Presented at: 28th Annual Meeting of the American Society for Bone and Mineral Research; September 15-19, 2006; Philadelphia, Pa. Abstract 1054. Mean Serum ß-CTX Over Time Serum ? C-telopeptide (?-CTX ) and bone-specific alkaline phosphatase (BSAP) were measured every 6 months in a subset of patients. Additional measurements at 9-11 days, 1 month and 3 months were taken after the 24-month infusion to evaluate the short-term changes in these markers (see slide 15). The bone resorption marker ?-CTX significantly decreased from baseline at 6 months among patients receiving ZOL 5 mg and remained within the low end of the premenopausal range (0.04 to 0.18 ng/mL) throughout the course of the trial. In placebo patients, ?-CTX did not decrease over the course of the 3-year study period. Reductions in ?-CTX were significant compared with placebo at all time points (P < .0001). Reference Black DM, Boonen S, Cauley J, et al. Effect of once-yearly infusion of zoledronic acid 5 mg on spine and hip fracture reduction in postmenopausal women with osteoporosis: the HORIZON Pivotal Fracture Trial. Presented at: 28th Annual Meeting of the American Society for Bone and Mineral Research; September 15-19, 2006; Philadelphia, Pa. Abstract 1054.

    16. Mean Serum BSAP Over Time Mean Serum BSAP Over Time In a similar fashion, mean levels of the bone formation marker BSAP decreased during ZOL 5 mg treatment and remained relatively constant within the premenopausal reference range throughout the treatment trial. Among placebo-treated patients, BSAP remained consistently above premenopausal levels through the duration of the trial. The reductions versus placebo were statistically significant at all time points (P<.0001). Reference Black DM, Boonen S, Cauley J, et al. Effect of once-yearly infusion of zoledronic acid 5 mg on spine and hip fracture reduction in postmenopausal women with osteoporosis: the HORIZON Pivotal Fracture Trial. Presented at: 28th Annual Meeting of the American Society for Bone and Mineral Research; September 15-19, 2006; Philadelphia, Pa. Abstract 1054. Mean Serum BSAP Over Time In a similar fashion, mean levels of the bone formation marker BSAP decreased during ZOL 5 mg treatment and remained relatively constant within the premenopausal reference range throughout the treatment trial. Among placebo-treated patients, BSAP remained consistently above premenopausal levels through the duration of the trial. The reductions versus placebo were statistically significant at all time points (P<.0001). Reference Black DM, Boonen S, Cauley J, et al. Effect of once-yearly infusion of zoledronic acid 5 mg on spine and hip fracture reduction in postmenopausal women with osteoporosis: the HORIZON Pivotal Fracture Trial. Presented at: 28th Annual Meeting of the American Society for Bone and Mineral Research; September 15-19, 2006; Philadelphia, Pa. Abstract 1054.

    17. Other Secondary End Points Disability: Significant reductions in limited activity days due to: Back pain (61 days zoledronic acid vs 72 days placebo, P =.0076) Fracture (6 days zoledronic acid vs 10 days placebo, P < .001) Height loss Significantly reduced in zoledronic acid 5 mg group –4 mm zoledronic acid vs 7 mm placebo (P < .0001) Other Secondary End Points At 3 years, ZOL 5 mg was associated with significantly fewer days of activity limited due to fracture and to back pain vs placebo. ZOL 5 mg patients noted a mean of 61 days of limited activity due to back pain compared with 72 days noted among placebo-treated patients (P = .0076). ZOL 5 mg patients experienced a mean of 6 days of limited activity due to fracture compared to 10 days among placebo treated patients (P < .001). One of the secondary efficacy variables to be analyzed was change from baseline in stadiometer height. Reference Black DM, Boonen S, Cauley J, et al. Effect of once-yearly infusion of zoledronic acid 5 mg on spine and hip fracture reduction in postmenopausal women with osteoporosis: the HORIZON Pivotal Fracture Trial. Presented at: 28th Annual Meeting of the American Society for Bone and Mineral Research; September 15-19, 2006; Philadelphia, Pa. Abstract 1054. Other Secondary End Points At 3 years, ZOL 5 mg was associated with significantly fewer days of activity limited due to fracture and to back pain vs placebo. ZOL 5 mg patients noted a mean of 61 days of limited activity due to back pain compared with 72 days noted among placebo-treated patients(P = .0076). ZOL 5 mg patients experienced a mean of 6 days of limited activity due to fracture compared to 10 days among placebo treated patients (P < .001). One of the secondary efficacy variables to be analyzed was change from baseline in stadiometer height. Reference Black DM, Boonen S, Cauley J, et al. Effect of once-yearly infusion of zoledronic acid 5 mg on spine and hip fracture reduction in postmenopausal women with osteoporosis: the HORIZON Pivotal Fracture Trial. Presented at: 28th Annual Meeting of the American Society for Bone and Mineral Research; September 15-19, 2006; Philadelphia, Pa. Abstract 1054.

    18. Common (=5% in ZOL) Post-Dose Symptoms Occurring Within 3 Days After Infusion Common (=5%) Post-Dose Symptoms Occurring Within 3 Days After Infusion The early-onset post-dose adverse events were predominantly transitory, resolving within 3 days of onset. 77% to 86% of all post-dose events resolved by 7 days after onset. As shown here, the incidence of common post-dose adverse events decreased with each sequential dosing: Pyrexia, which occurred in 15% of first doses, decreased to 2% with the second dose and 1% with the third dose of ZOL 5 mg. Myalgia was reported following 8% of first doses but only 2% of second doses and 1% of third doses of ZOL 5 mg. Flu-like illness was associated with 7% of first doses, 2% of second doses and 1% of third doses. Headache rates were 6%, 2%, and 1% in successive doses. Arthralgia occurred in 5%, 2%, and 1% of first, second, and third dosings, respectively. By the third infusion, rates of post-dose symptoms were similar between ZOL 5 mg and placebo. Reference Black DM, Boonen S, Cauley J, et al. Effect of once-yearly infusion of zoledronic acid 5 mg on spine and hip fracture reduction in postmenopausal women with osteoporosis: the HORIZON Pivotal Fracture Trial. Presented at: 28th Annual Meeting of the American Society for Bone and Mineral Research; September 15-19, 2006; Philadelphia, Pa. Abstract 1054. Common (=5%) Post-Dose Symptoms Occurring Within 3 Days After Infusion The early-onset post-dose adverse events were predominantly transitory, resolving within 3 days of onset. 77% to 86% of all post-dose events resolved by 7 days after onset. As shown here, the incidence of common post-dose adverse events decreased with each sequential dosing: Pyrexia, which occurred in 15% of first doses, decreased to 2% with the second dose and 1% with the third dose of ZOL 5 mg. Myalgia was reported following 8% of first doses but only 2% of second doses and 1% of third doses of ZOL 5 mg. Flu-like illness was associated with 7% of first doses, 2% of second doses and 1% of third doses. Headache rates were 6%, 2%, and 1% in successive doses. Arthralgia occurred in 5%, 2%, and 1% of first, second, and third dosings, respectively. By the third infusion, rates of post-dose symptoms were similar between ZOL 5 mg and placebo. Reference Black DM, Boonen S, Cauley J, et al. Effect of once-yearly infusion of zoledronic acid 5 mg on spine and hip fracture reduction in postmenopausal women with osteoporosis: the HORIZON Pivotal Fracture Trial. Presented at: 28th Annual Meeting of the American Society for Bone and Mineral Research; September 15-19, 2006; Philadelphia, Pa. Abstract 1054.

    19. Systemic Safety Parameters Renal safety Short term: 9-11 day post-dose monitoring in >4000 patients Transient rises in serum creatinine in 1.8% of patients (vs 0.81% placebo) with resolution and all patients redosed Overall, no cumulative impact on renal function Hypocalcemia (serum calcium < 2.075 mmol/L) 49 cases (2.3%) 9-11 days after 1st ZOL 5 mg infusion, almost none after 2nd (0.1%) or 3rd (0.3%) All asymptomatic and transient Cardiac safety Atrial fibrillation AEs comparable (2.4% ZOL 5 mg, 1.8% placebo) Atrial fibrillation SAEs more common in ZOL n = 50 (1.3%) ZOL 5 mg n = 20 (0.5%) placebo ECG study (n = 559) 9-11 days after 3rd infusion: No differences observed between ZOL 5 mg and placebo Other Safety Parameters Special safety assessments were included in the HORIZON protocol in order to evaluate any potential influence of ZOL 5 mg on renal function, ECG changes, delayed healing and avascular necrosis, maxillofacial complications, and ocular events The investigators conducted a careful monitoring for renal effects with 9-11 day visits after each infusion on a large subset of over half the study patients. Monitoring revealed only small and transient decreases in creatinine clearance with no systematic rises over time. These observations suggest that a annual infusions of ZOL 5 mg, over a 1-minute infusion time, in women with a creatinine clearance of greater than 30 mL/min is well tolerated. Laboratory defined hypocalcemia (serum calcium < 2.07 mmol/L) occurred in 2.3% of women following the first infusion of ZOL mg. No cases were symptomatic. No patients discontinued therapy due to hypocalcemia After second infusion, incidence of asymptomatic hypocalcemia was similar in the ZOL 5 mg and placebo groups. The overall incidence of cardiovascular events was similar in the ZOL and placebo groups. Incidence of atrial fibrillation serious adverse events was 1.24 in ZOL vs 0.44 in placebo. For 45 of 48 cases in the ZOL mg group, these events were reported >30 days post-infusion, long after drug left the circulation. Thus it is considered unlikely their occurrence was related to drug administration or timing of infusion. No known plausible drug-related biological mechanism. To assess cardiac safety, ECGs were collected on 559 patients 9-11 days after the third infusion. No differences were observed in the incidence of arrhythmias. Further evaluation of ongoing studies is planned. Reference Black DM, Boonen S, Cauley J, et al. Effect of once-yearly infusion of zoledronic acid 5 mg on spine and hip fracture reduction in postmenopausal women with osteoporosis: the HORIZON Pivotal Fracture Trial. Presented at: 28th Annual Meeting of the American Society for Bone and Mineral Research; September 15-19, 2006; Philadelphia, Pa. Abstract 1054. Other Safety Parameters Special safety assessments were included in the HORIZON protocol in order to evaluate any potential influence of ZOL 5 mg on renal function, ECG changes, delayed healing and avascular necrosis, maxillofacial complications, and ocular events The investigators conducted a careful monitoring for renal effects with 9-11 day visits after each infusion on a large subset of over half the study patients. Monitoring revealed only small and transient decreases in creatinine clearance with no systematic rises over time. These observations suggest that a annual infusions of ZOL 5 mg, over a 1-minute infusion time, in women with a creatinine clearance of greater than 30 mL/min is well tolerated. Laboratory defined hypocalcemia (serum calcium < 2.07 mmol/L) occurred in 2.3% of women following the first infusion of ZOL mg. No cases were symptomatic. No patients discontinued therapy due to hypocalcemia After second infusion, incidence of asymptomatic hypocalcemia was similar in the ZOL 5 mg and placebo groups. The overall incidence of cardiovascular events was similar in the ZOL and placebo groups. Incidence of atrial fibrillation serious adverse events was 1.24 in ZOL vs 0.44 in placebo. For 45 of 48 cases in the ZOL mg group, these events were reported >30 days post-infusion, long after drug left the circulation. Thus it is considered unlikely their occurrence was related to drug administration or timing of infusion. No known plausible drug-related biological mechanism. To assess cardiac safety, ECGs were collected on 559 patients 9-11 days after the third infusion. No differences were observed in the incidence of arrhythmias. Further evaluation of ongoing studies is planned. Reference Black DM, Boonen S, Cauley J, et al. Effect of once-yearly infusion of zoledronic acid 5 mg on spine and hip fracture reduction in postmenopausal women with osteoporosis: the HORIZON Pivotal Fracture Trial. Presented at: 28th Annual Meeting of the American Society for Bone and Mineral Research; September 15-19, 2006; Philadelphia, Pa. Abstract 1054.

    20. Bone Safety Parameters Histomorphometry evaluable in 93 bone biopsies1,2 Label seen in all specimens Fracture healing2 Non-union: 1 in ZOL 5 mg, 1 in placebo Avascular necrosis (hip or knee)2 4 in ZOL 5 mg, 3 in placebo Osteonecrosis of the jaw2 No spontaneous AE reports AE database search of 50 MedDRA terms, with adjudication Case definition: exposed bone in the mouth > 6 weeks 1 in ZOL 5 mg, 1 in placebo Both cases healed with antibiotic therapy and/or debridement Bone Safety (as of March 31, 2006) Histomorphometry was evaluable for 93 bone biopsies.1,2 Tetracycline label seen in all specimens, indicating ongoing bone remodeling No evidence of delayed fracture healing (non-union):1 in ZOL 5 mg, 1 in placebo2 No evidence of avascular necrosis (hip or knee): 4 in ZOL 5 mg, 3 in placebo2 No difference in the incidence of osteonecrosis of the jaw/osteomyelitis2 No spontaneous reports of osteonecrosis of the jaw The AE database was searched for 50 MedDRA terms and all possible cases were adjudicated by an independent Expert Committee Cases were defined as exposed bone in the mouth > 6 weeks Definition also consistent with symptoms of osteomyelitis Two potential cases were identified on adjudication: 1 in ZOL 5 mg, 1 in placebo Both cases healed with antibiotic therapy and/or debridement Reference 1. Recker RR, Boonen S, Garcia P, et al. The effect of annual treatment with zoledronic acid 5 mg on bone remodeling: bone histomorphometry results from the HORIZON-PFT. Presented at: 28th Annual Meeting of the American Society for Bone and Mineral Research; September 15-19, 2006; Philadelphia, Pa. Abstract SU332. 2. Black DM, Boonen S, Cauley J, et al. Effect of once-yearly infusion of zoledronic acid 5 mg on spine and hip fracture reduction in postmenopausal women with osteoporosis: the HORIZON Pivotal Fracture Trial. Presented at: 28th Annual Meeting of the American Society for Bone and Mineral Research; September 15-19, 2006; Philadelphia, Pa. Abstract 1054. Bone Safety (as of March 31, 2006) Histomorphometry was evaluable for 93 bone biopsies.1,2 Tetracycline label seen in all specimens, indicating ongoing bone remodeling No evidence of delayed fracture healing (non-union):1 in ZOL 5 mg, 1 in placebo2 No evidence of avascular necrosis (hip or knee): 4 in ZOL 5 mg, 3 in placebo2 No difference in the incidence of osteonecrosis of the jaw/osteomyelitis2 No spontaneous reports of osteonecrosis of the jaw The AE database was searched for 50 MedDRA terms and all possible cases were adjudicated by an independent Expert Committee Cases were defined as exposed bone in the mouth > 6 weeks Definition also consistent with symptoms of osteomyelitis Two potential cases were identified on adjudication: 1 in ZOL 5 mg, 1 in placebo Both cases healed with antibiotic therapy and/or debridement Reference 1. Recker RR, Boonen S, Garcia P, et al. The effect of annual treatment with zoledronic acid 5 mg on bone remodeling: bone histomorphometry results from the HORIZON-PFT. Presented at: 28th Annual Meeting of the American Society for Bone and Mineral Research; September 15-19, 2006; Philadelphia, Pa. Abstract SU332. 2. Black DM, Boonen S, Cauley J, et al. Effect of once-yearly infusion of zoledronic acid 5 mg on spine and hip fracture reduction in postmenopausal women with osteoporosis: the HORIZON Pivotal Fracture Trial. Presented at: 28th Annual Meeting of the American Society for Bone and Mineral Research; September 15-19, 2006; Philadelphia, Pa. Abstract 1054.

    21. The Effect of Once Yearly Zoledronic Acid 5 mg on New Fractures and Mortality After Hip Fracture: The HORIZON-Recurrent Fracture Trial Lyles KW, et al. Zoledronic acid and clinical fractures and mortality after hip fracture. N Engl J Med. 2007;357:1799-1809 The Effect of Once Yearly Zoledronic Acid 5 mg on New Fractures and Mortality After Hip Fracture: The HORIZON Recurrent Fracture Trial The information in these slides is intended for peer-to-peer discussion between qualified Novartis medical personnel and external physicians; it is not approved for promotional purposes. Use and dissemination of this information is subject to all local medical, legal, and regulatory restrictions. This information was presented at the American Society for Bone and Mineral Research (ASBMR) 28th Annual Meeting; September 16-19, 2007; Honolulu, Hawaii; and was published as: Lyles KW, Colón-Emeric CS, Magaziner JS, et al. Zoledronic acid and clinical fractures and mortality after hip fracture. N Engl J Med. 2007. [e-publication 10.1056/NEJMoa074941 at www.nejm.org] The Effect of Once Yearly Zoledronic Acid 5 mg on New Fractures and Mortality After Hip Fracture: The HORIZON Recurrent Fracture Trial The information in these slides is intended for peer-to-peer discussion between qualified Novartis medical personnel and external physicians; it is not approved for promotional purposes. Use and dissemination of this information is subject to all local medical, legal, and regulatory restrictions. This information was presented at the American Society for Bone and Mineral Research (ASBMR) 28th Annual Meeting; September 16-19, 2007; Honolulu, Hawaii; and was published as: Lyles KW, Colón-Emeric CS, Magaziner JS, et al. Zoledronic acid and clinical fractures and mortality after hip fracture. N Engl J Med. 2007. [e-publication 10.1056/NEJMoa074941 at www.nejm.org]

    22. HORIZON-Recurrent Fracture Trial (RFT) Primary and Secondary Efficacy End Points Primary Objective Reduce the rate of new clinical fractures after surgical procedure for low-trauma hip fracture Secondary Objectives Reduce the risk of clinical vertebral, hip, and non-vertebral fractures Increase BMD at the total hip and femoral neck of the non-fractured hip at months 12 and 24 HORIZON-Recurrent Fracture Trial: Primary and Secondary Efficacy End Points The primary objective of HORIZON-RFT was to demonstrate that zoledronic acid 5 mg administered annually as a single 15-minute infusion to men and women after surgical repair of low-trauma hip fracture significantly reduces the rate of clinical fractures (defined as all subsequent osteoporotic fractures) compared with placebo. The secondary efficacy objectives were to show the treatment benefits of zoledronic acid 5 mg versus placebo in: reducing the risk of clinical vertebral fracture, hip fracture, and non-vertebral clinical fracture increasing BMD at the total hip and femoral neck of the non-fracture hip at 12 and 24 months reducing the likelihood of being hospitalized In applicable countries, exploratory objectives were to estimate and compare measures of resource utilization (such as hospital, ER, and clinic visits) among patients treated with zoledronic acid 5 mg versus placebo, and to demonstrate improved quality of life measures using the EQ-5D health questionnaire. Reference Lyles KW, Colón-Emeric CS, Magaziner JS, et al. Zoledronic acid and clinical fractures and mortality after hip fracture. N Engl J Med. 2007. [e-publication 10.1056/NEJMoa074941 at www.nejm.org] HORIZON-Recurrent Fracture Trial: Primary and Secondary Efficacy End Points The primary objective of HORIZON-RFT was to demonstrate that zoledronic acid 5 mg administered annually as a single 15-minute infusion to men and women after surgical repair of low-trauma hip fracture significantly reduces the rate of clinical fractures (defined as all subsequent osteoporotic fractures) compared with placebo. The secondary efficacy objectives were to show the treatment benefits of zoledronic acid 5 mg versus placebo in: reducing the risk of clinical vertebral fracture, hip fracture, and non-vertebral clinical fracture increasing BMD at the total hip and femoral neck of the non-fracture hip at 12 and 24 months reducing the likelihood of being hospitalized In applicable countries, exploratory objectives were to estimate and compare measures of resource utilization (such as hospital, ER, and clinic visits) among patients treated with zoledronic acid 5 mg versus placebo, and to demonstrate improved quality of life measures using the EQ-5D health questionnaire. Reference Lyles KW, Colón-Emeric CS, Magaziner JS, et al. Zoledronic acid and clinical fractures and mortality after hip fracture. N Engl J Med. 2007. [e-publication 10.1056/NEJMoa074941 at www.nejm.org]

    23. HORIZON-Recurrent Fracture Trial Overview Double-blind, placebo-controlled RCT 2127 men and women, 148 clinical centers, 23 countries Treatment Annual infusion of either zoledronic acid 5 mg or placebo Loading dose of vitamin D 50,000–125,000 IU Calcium 1000–1500 mg/d; vitamin D 800–1200 IU/d Follow-up visits at 6, 12, 24, and 36 months Telephone interviews every 3 months starting at month 9 HORIZON-Recurrent Fracture Trial: Overview Zoledronic acid is a third-generation nitrogen-containing bisphosphonate currently being developed for the treatment of postmenopausal women with osteoporosis. The HORIZON Recurrent Fracture Trial (RFT) was a multicenter, event-driven, randomized, double-blind, placebo-controlled, parallel-group trial in men and women who had recent surgical repair of a low-trauma hip fracture. The trial population included 2127 men and women from 148 clinical centers in 23 countries. Patients received a loading dose of 75,000–125,000 units of vitamin D2 or 50,000–75,000 units of vitamin D3 IM or orally, and then began a maintenance dose of 800–1200 IU of vitamin D PO daily and elemental calcium (1000–1500 mg PO daily in a divided dose). Patients continued maintenance doses for at least 14 days prior to receiving study drug (zoledronic acid 5 mg IV infusion over 15 minutes or placebo). Patients received their study drug infusion at any time between day 14 following vitamin D2 or D3 administration and 90 days after surgical repair of their low trauma hip fracture. An IV formulation of study medication was administered every 12 months before the end-of-study visit. Follow-up visits were conducted at months 6, 12, 24, and 36, and telephone interviews were conducted every 3 months starting at month 9. Reference Lyles KW, Colón-Emeric CS, Magaziner JS, et al. Zoledronic acid and clinical fractures and mortality after hip fracture. N Engl J Med. 2007. [e-publication 10.1056/NEJMoa074941 at www.nejm.org]HORIZON-Recurrent Fracture Trial: Overview Zoledronic acid is a third-generation nitrogen-containing bisphosphonate currently being developed for the treatment of postmenopausal women with osteoporosis. The HORIZON Recurrent Fracture Trial (RFT) was a multicenter, event-driven, randomized, double-blind, placebo-controlled, parallel-group trial in men and women who had recent surgical repair of a low-trauma hip fracture. The trial population included 2127 men and women from 148 clinical centers in 23 countries. Patients received a loading dose of 75,000–125,000 units of vitamin D2 or 50,000–75,000 units of vitamin D3 IM or orally, and then began a maintenance dose of 800–1200 IU of vitamin D PO daily and elemental calcium (1000–1500 mg PO daily in a divided dose). Patients continued maintenance doses for at least 14 days prior to receiving study drug (zoledronic acid 5 mg IV infusion over 15 minutes or placebo). Patients received their study drug infusion at any time between day 14 following vitamin D2 or D3 administration and 90 days after surgical repair of their low trauma hip fracture. An IV formulation of study medication was administered every 12 months before the end-of-study visit. Follow-up visits were conducted at months 6, 12, 24, and 36, and telephone interviews were conducted every 3 months starting at month 9. Reference Lyles KW, Colón-Emeric CS, Magaziner JS, et al. Zoledronic acid and clinical fractures and mortality after hip fracture. N Engl J Med. 2007. [e-publication 10.1056/NEJMoa074941 at www.nejm.org]

    24. HORIZON-Recurrent Fracture Trial Study Population Inclusion Male or female patients aged 50 years and older Randomized up to 90 days following surgical procedure for a low-trauma hip fracture Ambulatory prior to hip fracture Unwilling or unable to take oral bisphosphonates Exclusion Use of oral bisphosphonates (or any use of IV within 2 years) Calculated creatinine clearance <30 mL/min Hypercalcemia or hypocalcemia Other metabolic bone diseases Any prior use of parathyroid hormone or its analogs for >1 week, any use of fluoride or strontium HORIZON-Recurrent Fracture Trial: Study Population Inclusion criteria for HORIZON-RFT included male or female patients 50 years of age or older. Patients could be randomized up to 90 days following surgical repair of a low-trauma hip fracture, and all patients were required to ambulatory with or without an assistive device prior to the hip fracture. Exclusion criteria included: use of oral bisphosphonates; calculated creatinine clearance <30.0 mL/min; serum calcium >2.75 mmoL/L; hypocalcemia (serum corrected calcium <2.0 mmol/L at screening and/or randomization); primary hyperparathyroidism, hypoparathyroidism, osteogenesis imperfecta, Paget’s disease, or any other metabolic bone disease, except osteoporosis; any prior use of IV bisphosphonate within 2 years; and any prior use of parathyroid hormone and analogs for >1 week. Reference Lyles KW, Colón-Emeric CS, Magaziner JS, et al. Zoledronic acid and clinical fractures and mortality after hip fracture. N Engl J Med. 2007. [e-publication 10.1056/NEJMoa074941 at www.nejm.org] HORIZON-Recurrent Fracture Trial: Study Population Inclusion criteria for HORIZON-RFT included male or female patients 50 years of age or older. Patients could be randomized up to 90 days following surgical repair of a low-trauma hip fracture, and all patients were required to ambulatory with or without an assistive device prior to the hip fracture. Exclusion criteria included: use of oral bisphosphonates; calculated creatinine clearance <30.0 mL/min; serum calcium >2.75 mmoL/L; hypocalcemia (serum corrected calcium <2.0 mmol/L at screening and/or randomization); primary hyperparathyroidism, hypoparathyroidism, osteogenesis imperfecta, Paget’s disease, or any other metabolic bone disease, except osteoporosis; any prior use of IV bisphosphonate within 2 years; and any prior use of parathyroid hormone and analogs for >1 week. Reference Lyles KW, Colón-Emeric CS, Magaziner JS, et al. Zoledronic acid and clinical fractures and mortality after hip fracture. N Engl J Med. 2007. [e-publication 10.1056/NEJMoa074941 at www.nejm.org]

    25. HORIZON-Recurrent Fracture Trial Baseline Demographics HORIZON-Recurrent Fracture Trial: Baseline Demographics Demographic characteristics of patients from the ITT population were comparable for the zoledronic acid and placebo groups. the majority of patients were Caucasian (91%) and female (76%). more than half of all patients were from Western and Eastern Europe (58%). Not Shown on Slide, but Should Be Spoken Aloud: The median age of patients was 76 years (range: 50 to 98); 27% of patients were between 65 and 74 years old and 56% were more than 75 years of age. The mean BMI of the overall population was 24.8 kg/m2 (range: 12.4 to 46.8 kg/m2). See Backup Slide Reference Lyles KW, Colón-Emeric CS, Magaziner JS, et al. Zoledronic acid and clinical fractures and mortality after hip fracture. N Engl J Med. 2007. [e-publication 10.1056/NEJMoa074941 at www.nejm.org]HORIZON-Recurrent Fracture Trial: Baseline Demographics Demographic characteristics of patients from the ITT population were comparable for the zoledronic acid and placebo groups. the majority of patients were Caucasian (91%) and female (76%). more than half of all patients were from Western and Eastern Europe (58%). Not Shown on Slide, but Should Be Spoken Aloud: The median age of patients was 76 years (range: 50 to 98); 27% of patients were between 65 and 74 years old and 56% were more than 75 years of age. The mean BMI of the overall population was 24.8 kg/m2 (range: 12.4 to 46.8 kg/m2). See Backup Slide Reference Lyles KW, Colón-Emeric CS, Magaziner JS, et al. Zoledronic acid and clinical fractures and mortality after hip fracture. N Engl J Med. 2007. [e-publication 10.1056/NEJMoa074941 at www.nejm.org]

    26. HORIZON-Recurrent Fracture Trial Baseline Demographics (continued) HORIZON Recurrent Fracture Trial: Baseline Demographics (cont’d.) The median age of patients was 76 years (range: 50 to 98); 27% of patients were between 65 and 74 years old and 56% were more than 75 years of age. The mean BMI of the overall population was 24.8 kg/m2 (range: 12.4 to 46.8 kg/m2). Reference Lyles KW, Colón-Emeric CS, Magaziner JS, et al. Zoledronic acid and clinical fractures and mortality after hip fracture. N Engl J Med. 2007. [e-publication 10.1056/NEJMoa074941 at www.nejm.org] HORIZON Recurrent Fracture Trial: Baseline Demographics (cont’d.) The median age of patients was 76 years (range: 50 to 98); 27% of patients were between 65 and 74 years old and 56% were more than 75 years of age. The mean BMI of the overall population was 24.8 kg/m2 (range: 12.4 to 46.8 kg/m2). Reference Lyles KW, Colón-Emeric CS, Magaziner JS, et al. Zoledronic acid and clinical fractures and mortality after hip fracture. N Engl J Med. 2007. [e-publication 10.1056/NEJMoa074941 at www.nejm.org]

    27. Zoledronic Acid 5 mg Reduced Subsequent Fracture Risk Over Time Zoledronic Acid 5 mg Reduced Subsequent Fracture Risk Over Time With respect to the primary efficacy variable (time to first clinical fracture), 231 patients had at least one adjudicated clinical fracture (92 in zoledronic acid and 139 in placebo). For the primary analysis in the ITT population, the hazard ratio of 0.65 (95% CI: 0.50 to 0.84) for the zoledronic acid group versus the placebo group represents a 35% reduction in the risk of clinical fractures over time (P=0.0012). The level of significance for the two-sided log-rank test was adjusted to 0.0351, to account for the three interim analyses performed for the Data Safety Monitoring Board. As the P-value of 0.0012 is less than the required significance level (0.0351), the superiority of zoledronic acid in reducing the incidence of clinical fractures relative to placebo is concluded. The results of the primary analysis were confirmed and consistent in the per-protocol population. Statistically reductions in favor of zoledronic acid vs. placebo were also observed for non-vertebral fractures (-27%) and vertebral fractures (-46%) The zoledronic acid group had a numerically lower risk in hip fractures compared to the placebo group (30% reduction in risk), but this did not achieve statistical significance. It should be noted that the number of new hip fractures was low since surgical repair of the entry hip often involved arthroplasty, implying that any hip fractures that occurred could only have occurred in the other hip of such patients. Reference Lyles KW, Colón-Emeric CS, Magaziner JS, et al. Zoledronic acid and clinical fractures and mortality after hip fracture. N Engl J Med. 2007. [e-publication 10.1056/NEJMoa074941 at www.nejm.org]Zoledronic Acid 5 mg Reduced Subsequent Fracture Risk Over Time With respect to the primary efficacy variable (time to first clinical fracture), 231 patients had at least one adjudicated clinical fracture (92 in zoledronic acid and 139 in placebo). For the primary analysis in the ITT population, the hazard ratio of 0.65 (95% CI: 0.50 to 0.84) for the zoledronic acid group versus the placebo group represents a 35% reduction in the risk of clinical fractures over time (P=0.0012). The level of significance for the two-sided log-rank test was adjusted to 0.0351, to account for the three interim analyses performed for the Data Safety Monitoring Board. As the P-value of 0.0012 is less than the required significance level (0.0351), the superiority of zoledronic acid in reducing the incidence of clinical fractures relative to placebo is concluded. The results of the primary analysis were confirmed and consistent in the per-protocol population. Statistically reductions in favor of zoledronic acid vs. placebo were also observed for non-vertebral fractures (-27%) and vertebral fractures (-46%) The zoledronic acid group had a numerically lower risk in hip fractures compared to the placebo group (30% reduction in risk), but this did not achieve statistical significance. It should be noted that the number of new hip fractures was low since surgical repair of the entry hip often involved arthroplasty, implying that any hip fractures that occurred could only have occurred in the other hip of such patients. Reference Lyles KW, Colón-Emeric CS, Magaziner JS, et al. Zoledronic acid and clinical fractures and mortality after hip fracture. N Engl J Med. 2007. [e-publication 10.1056/NEJMoa074941 at www.nejm.org]

    28. Zoledronic Acid 5 mg Reduced Risk of All-Cause Mortality by 28% Over Time Zoledronic Acid 5 mg Reduced Risk of All-Cause Mortality by 28% Over Time Analysis confirmed a significant 28% decreased risk of death (Hazard ratio 0.72, 95% CI: 0.56 to 0.93, P=0.0117) with zoledronic acid compared to placebo. The cumulative death rate for both treatment groups over time is shown here. There is a separation of the two treatment groups beginning at approximately Month 16. This is approximately 12 months after the earliest separation of the two treatments groups in time to first clinical fracture (approximately Month 4), after which time the curves for clinical fracture and mortality paralleled each other. It should be noted that after Month 36 (Day 1080), the changes in the Kaplan-Meier curves become oversensitive to the occurrence of death due to the small number of patients who were still being followed up in the study after that time point (149 on placebo and 144 on zoledronic acid). As such, every death that occurs has considerable influence on the cumulative incidence of deaths as well as the shape of the Kaplan-Meier curves. Reference Lyles KW, Colón-Emeric CS, Magaziner JS, et al. Zoledronic acid and clinical fractures and mortality after hip fracture. N Engl J Med. 2007. [e-publication 10.1056/NEJMoa074941 at www.nejm.org]Zoledronic Acid 5 mg Reduced Risk of All-Cause Mortality by 28% Over Time Analysis confirmed a significant 28% decreased risk of death (Hazard ratio 0.72, 95% CI: 0.56 to 0.93, P=0.0117) with zoledronic acid compared to placebo. The cumulative death rate for both treatment groups over time is shown here. There is a separation of the two treatment groups beginning at approximately Month 16. This is approximately 12 months after the earliest separation of the two treatments groups in time to first clinical fracture (approximately Month 4), after which time the curves for clinical fracture and mortality paralleled each other. It should be noted that after Month 36 (Day 1080), the changes in the Kaplan-Meier curves become oversensitive to the occurrence of death due to the small number of patients who were still being followed up in the study after that time point (149 on placebo and 144 on zoledronic acid). As such, every death that occurs has considerable influence on the cumulative incidence of deaths as well as the shape of the Kaplan-Meier curves. Reference Lyles KW, Colón-Emeric CS, Magaziner JS, et al. Zoledronic acid and clinical fractures and mortality after hip fracture. N Engl J Med. 2007. [e-publication 10.1056/NEJMoa074941 at www.nejm.org]

    29. Adjudicated Results for Targeted Events Adjudication Results for Targeted Events On adjudication by an expert committee, atrial fibrillation serious adverse events occurred in 12 patients in the zoledronic acid group (1.1%) and in 14 patients in the placebo group (1.3%). All cases of ocular events that were sent for expert review were adjudicated as confirmed ocular events (21 [1.99%] patients in the zoledronic acid 5 mg group and 16 [1.51%] patients in the placebo group). Of these, four patients in the zoledronic acid group and one patient in the placebo group had ocular events that were considered possibly or probably related to study drug by expert review. The cases that were adjudicated as confirmed events of delayed union/nonunion were for 3 (0.28%) patients in the zoledronic acid group (2 incident hip and 1 humerus) and 3 (0.28%) patients in the placebo group (1 incident hip, 1 contralateral hip, and 1 shoulder). The percentage of patients with events adjudicated as confirmed delayed hip fracture healing was comparable for the two treatment groups (34 [3.23%] in the zoledronic acid group vs. 29 [2.74%] in the placebo group). As mentioned above, a total of 2 patients in the zoledronic acid group and 1 patient in the placebo had adjudicated confirmed delayed union/nonunion of fracture of the incident hip. These patients are not included in adjudicated cases of possible delayed hip fracture healing. Thus, a total of 36 (3.42%) patients in the zoledronic acid group and 30 (2.84%) patients in the placebo group had adjudicated confirmed delayed hip fracture healing or delayed union/nonunion of the incident hip. A total of 23 (2.18%) patients in the zoledronic acid group and 26 (2.46%) patients in the placebo group had cases of avascular necrosis that were sent to the adjudication committee for review. Of these, 6 (0.57%) patients in the zoledronic acid group and 4 (0.38%) patients in the placebo group had adjudicated confirmed events of avascular necrosis. Overall, there was no evidence of an increased risk with zoledronic acid of nonunion/delayed union of fracture, delayed hip fracture healing, or avascular necrosis. A total of 9 (0.85%) patients in the zoledronic acid 5 mg group and 3 (0.28%) patients in the placebo group had clinical events that met the pre-specified criteria and were sent to the adjudication committee for review. Of these, 3 (0.28%) patients in the zoledronic acid group and no patients in the placebo group had adjudicated confirmed events of hypocalcemia. For two of the three patients in the zoledronic acid group with confirmed events, the events occurred more than 30 days after the first day of treatment, and both were thought to be not related to study medication by the investigator, as well as by the adjudication committee. For the third patient, the event occurred on the day following the first day of treatment, and was thought to be related to study medication by the investigator, as well as by the adjudication committee. A total of 6 (0.57%) patients in the zoledronic acid group and 11 (1.04%) patients in the placebo group had maxillofacial events that were sent to the adjudication committee for review. Using the predefined criteria of “exposed bone of the jaw of at least 6 weeks duration despite appropriate treatment,” the committee adjudicated all but one case not to be a clinically relevant case of ONJ. The one exception was for a patient in the placebo group, whose event was adjudicated as indeterminate. The data provide further evidence of no association between zoledronic acid and ONJ in men and women with osteoporosis. A total of 160 (15.18%) patients in the zoledronic acid group and 146 (13.81%) patients in the placebo group had renal events (renal function AEs and/or pre-determined laboratory abnormalities) that were sent to the adjudication committee for review. Of these, 87 (8.25%) patients in the zoledronic acid group and 90 (8.51%) patients in the placebo group had confirmed clinically significant renal events. Reference Lyles KW, Colón-Emeric CS, Magaziner JS, et al. Efficacy and safety of zoledronic acid 5 mg in preventing fractures in men and women with prevalent hip fracture: the HORIZON-Recurrent Fracture Trial. Presented at: 29th Annual Meeting of the American Society for Bone and Mineral Research; September 16-19, 2007; Honolulu, Hawaii. Abstract 1055.Adjudication Results for Targeted Events On adjudication by an expert committee, atrial fibrillation serious adverse events occurred in 12 patients in the zoledronic acid group (1.1%) and in 14 patients in the placebo group (1.3%). All cases of ocular events that were sent for expert review were adjudicated as confirmed ocular events (21 [1.99%] patients in the zoledronic acid 5 mg group and 16 [1.51%] patients in the placebo group). Of these, four patients in the zoledronic acid group and one patient in the placebo group had ocular events that were considered possibly or probably related to study drug by expert review. The cases that were adjudicated as confirmed events of delayed union/nonunion were for 3 (0.28%) patients in the zoledronic acid group (2 incident hip and 1 humerus) and 3 (0.28%) patients in the placebo group (1 incident hip, 1 contralateral hip, and 1 shoulder). The percentage of patients with events adjudicated as confirmed delayed hip fracture healing was comparable for the two treatment groups (34 [3.23%] in the zoledronic acid group vs. 29 [2.74%] in the placebo group). As mentioned above, a total of 2 patients in the zoledronic acid group and 1 patient in the placebo had adjudicated confirmed delayed union/nonunion of fracture of the incident hip. These patients are not included in adjudicated cases of possible delayed hip fracture healing. Thus, a total of 36 (3.42%) patients in the zoledronic acid group and 30 (2.84%) patients in the placebo group had adjudicated confirmed delayed hip fracture healing or delayed union/nonunion of the incident hip. A total of 23 (2.18%) patients in the zoledronic acid group and 26 (2.46%) patients in the placebo group had cases of avascular necrosis that were sent to the adjudication committee for review. Of these, 6 (0.57%) patients in the zoledronic acid group and 4 (0.38%) patients in the placebo group had adjudicated confirmed events of avascular necrosis. Overall, there was no evidence of an increased risk with zoledronic acid of nonunion/delayed union of fracture, delayed hip fracture healing, or avascular necrosis. A total of 9 (0.85%) patients in the zoledronic acid 5 mg group and 3 (0.28%) patients in the placebo group had clinical events that met the pre-specified criteria and were sent to the adjudication committee for review. Of these, 3 (0.28%) patients in the zoledronic acid group and no patients in the placebo group had adjudicated confirmed events of hypocalcemia. For two of the three patients in the zoledronic acid group with confirmed events, the events occurred more than 30 days after the first day of treatment, and both were thought to be not related to study medication by the investigator, as well as by the adjudication committee. For the third patient, the event occurred on the day following the first day of treatment, and was thought to be related to study medication by the investigator, as well as by the adjudication committee. A total of 6 (0.57%) patients in the zoledronic acid group and 11 (1.04%) patients in the placebo group had maxillofacial events that were sent to the adjudication committee for review. Using the predefined criteria of “exposed bone of the jaw of at least 6 weeks duration despite appropriate treatment,” the committee adjudicated all but one case not to be a clinically relevant case of ONJ. The one exception was for a patient in the placebo group, whose event was adjudicated as indeterminate. The data provide further evidence of no association between zoledronic acid and ONJ in men and women with osteoporosis. A total of 160 (15.18%) patients in the zoledronic acid group and 146 (13.81%) patients in the placebo group had renal events (renal function AEs and/or pre-determined laboratory abnormalities) that were sent to the adjudication committee for review. Of these, 87 (8.25%) patients in the zoledronic acid group and 90 (8.51%) patients in the placebo group had confirmed clinically significant renal events. Reference Lyles KW, Colón-Emeric CS, Magaziner JS, et al. Efficacy and safety of zoledronic acid 5 mg in preventing fractures in men and women with prevalent hip fracture: the HORIZON-Recurrent Fracture Trial. Presented at: 29th Annual Meeting of the American Society for Bone and Mineral Research; September 16-19, 2007; Honolulu, Hawaii. Abstract 1055.

    30. Where does Zoledronic Acid Fit into the Armamentarium Against Osteoporosis First line for all patients with hip fracture Data show dismal diagnostic and treatment rates for these patients right now An easily administered, well tolerated, agent, given only once yearly, has dramatic efficacy in reducing subsequent fracture risk and even reducing mortality Consider as first line treatment for patients in whom a bisphosphonate is the chosen type of therapy Why not offer all patients a choice? Many prefer this option Efficacy is unequalled Certainly offer to all patients who have difficulty taking weekly or monthly bisphosphonates due to upper GI symptoms or difficulty with adherence or persistence to regimen

    31. Once Yearly Therapy Summary and Conclusions      Infusion Therapy  Required: Overcoming barriers and directing patients to IV administration sites - Infusion centers - Rheumatologists - Endocrinologists - Other specialists skilled in infusion therapy

    32. Once Yearly Therapy Summary and Conclusions     Most managed care health systems have designated infusion services Initiating therapy in the hospital following hip or osteoporosis-related fracture is an option

    33. Denosumab: Overview Fully human monoclonal antibody-IgG2 isotype High affinity and specificity for human RANK Ligand Pharmacokinetics (SC): similar to other fully human IgG2 monoclonal antibodies Absorption is rapid and prolonged (Cmax ˜1-4 wks postdose) Long half-life ˜34 days with max dose Distribution ˜ intravascular volume Clearance ˜ reticuloendothelial system No kidney filtration or excretion of intact molecule Phase 3 should be completed by midyear 2008 NDA should be in by end 2008 Denosumab is an investigational, fully human monoclonal antibody with a unique mechanism of action that binds with high affinity to, and inhibits the activity of human RANK (receptor activator of nuclear factor kappa B) ligand, the primary mediator of osteoclast activity. Amgen scientists have confirmed the essential role of RANK Ligand pathway in the formation, activation and survival of osteoclasts, the cells that are associated with bone resorption.1,2 Since RANK Ligand is part of the TNF receptor superfamily, high specificity is demonstrated by the fact that denosumab does not bind to other TNF receptors.1 The pharmacokinetics (SC administration) of denosumab in postmenopausal women were nonlinear with dose. The serum profiles were characterized by three distinct phases: 1) a prolonged absorption phase, which resulted in maximum serum concentrations that increased disproportionately greater (2.6-fold) than the increase in dose and were observed between 5 and 21 days after administration; 2) a prolonged ?-phase, characterized by half-lives that increased with dose to a maximum of 32 days; and 3) a more rapid terminal phase observed at concentrations 1,000 ng/ml with a half-life that increased from 5 to 10 days as dose increased from 0.01 to 3.0 mg/kg. Because of the nonlinear pharmacokinetics, the mean serum residence time increased with dose from 12 to 46 days.1 Bekker PJ, Holloway DL, Rasmussen AS, et al. A single-dose placebo-controlled study of denosumab, a fully human monoclonal antibody to RANKL, in postmenopausal women. J Bone Miner Res. 2004;19:1059-1066. Boyle WJ, Simonet WS, Lacey DL, et al. Osteoclast differentiation and activation. Nature. 2003;423:337-342. Denosumab is an investigational, fully human monoclonal antibody with a unique mechanism of action that binds with high affinity to, and inhibits the activity of human RANK (receptor activator of nuclear factor kappa B) ligand, the primary mediator of osteoclast activity. Amgen scientists have confirmed the essential role of RANK Ligand pathway in the formation, activation and survival of osteoclasts, the cells that are associated with bone resorption.1,2 Since RANK Ligand is part of the TNF receptor superfamily, high specificity is demonstrated by the fact that denosumab does not bind to other TNF receptors.1 The pharmacokinetics (SC administration) of denosumab in postmenopausal women were nonlinear with dose. The serum profiles were characterized by three distinct phases: 1) a prolonged absorption phase, which resulted in maximum serum concentrations that increased disproportionately greater (2.6-fold) than the increase in dose and were observed between 5 and 21 days after administration; 2) a prolonged ?-phase, characterized by half-lives that increased with dose to a maximum of 32 days; and 3) a more rapid terminal phase observed at concentrations 1,000 ng/ml with a half-life that increased from 5 to 10 days as dose increased from 0.01 to 3.0 mg/kg. Because of the nonlinear pharmacokinetics, the mean serum residence time increased with dose from 12 to 46 days.1 Bekker PJ, Holloway DL, Rasmussen AS, et al. A single-dose placebo-controlled study of denosumab, a fully human monoclonal antibody to RANKL, in postmenopausal women. J Bone Miner Res. 2004;19:1059-1066. Boyle WJ, Simonet WS, Lacey DL, et al. Osteoclast differentiation and activation. Nature. 2003;423:337-342.

    34. Mechanism of Action for Denosumab Denosumab is an investigational, fully human monoclonal antibody that binds with high affinity to, and inhibits the activity of human RANK (receptor activator of nuclear factor kappa B) ligand, a key mediator of osteoclast activity1. RANK Ligand is an essential pathway in the formation, activation, and survival of osteoclasts1,2. Denosumab does not bind to other TNF receptors.1 The pharmacokinetics (SC administration) of denosumab in postmenopausal women were nonlinear with dose. The serum profiles were characterized by three distinct phases: 1) a prolonged absorption phase: maximum serum concentrations increased disproportionately greater (2.6-fold) than the increase in dose and were observed between 5 and 21 days after administration; 2) a prolonged ?-phase: half-lives that increased with dose to a maximum of 32 days; and 3) a more rapid terminal phase observed at concentrations <1,000 ng/mL with a half-life that increased from 5 to 10 days as dose increased from 0.01 to 3.0 mg/kg. The mean serum residence time increased with dose from 12 to 46 days.1 1. Bekker PJ, et al. A single-dose placebo-controlled study of AMG-162, a fully human monoclonal antibody to RANKL, in postmenopausal women. J Bone Miner Res. 2004;19:1059-1066. 2. Boyle WJ, et al. Osteoclast differentiation and activation. Nature. 2003;423:337-342. 3. Peterson MC, et al. AMG 162 maintains serum concentrations for up to 9 months following a single subcutaneous dose in healthy postmenopausal women. J. Bone Miner. Res. 2003; 18(Suppl 2):S166. Abstract SA393 and poster. Denosumab is an investigational, fully human monoclonal antibody that binds with high affinity to, and inhibits the activity of human RANK (receptor activator of nuclear factor kappa B) ligand, a key mediator of osteoclast activity1. RANK Ligand is an essential pathway in the formation, activation, and survival of osteoclasts1,2. Denosumab does not bind to other TNF receptors.1 The pharmacokinetics (SC administration) of denosumab in postmenopausal women were nonlinear with dose. The serum profiles were characterized by three distinct phases: 1) a prolonged absorption phase: maximum serum concentrations increased disproportionately greater (2.6-fold) than the increase in dose and were observed between 5 and 21 days after administration; 2) a prolonged ?-phase: half-lives that increased with dose to a maximum of 32 days; and 3) a more rapid terminal phase observed at concentrations <1,000 ng/mL with a half-life that increased from 5 to 10 days as dose increased from 0.01 to 3.0 mg/kg. The mean serum residence time increased with dose from 12 to 46 days.1 1. Bekker PJ, et al. A single-dose placebo-controlled study of AMG-162, a fully human monoclonal antibody to RANKL, in postmenopausal women. J Bone Miner Res. 2004;19:1059-1066. 2. Boyle WJ, et al. Osteoclast differentiation and activation. Nature. 2003;423:337-342. 3. Peterson MC, et al. AMG 162 maintains serum concentrations for up to 9 months following a single subcutaneous dose in healthy postmenopausal women. J. Bone Miner. Res. 2003; 18(Suppl 2):S166. Abstract SA393 and poster.

    35. Denosumab Phase 2 Study 1-year data: N Engl J Med 2006 McClung MR, Lewiecki EM, Cohen SB, Bolognese MA, et al. Denosumab in postmenopausal women with low bone mineral density. N Engl J Med. 2006;354:821-831. 2-year data: J Bone Miner Res 2007 Lewiecki EM, Miller PD, McClung MR, Cohen SB, et al. Two-year treatment with denosumab (AMG 162) in a randomized phase 2 study of postmenopausal women with low bone mineral density. J Bone Miner Res. 2007 Dec;22(12):1832-41. 4-year data: ASBMR Oral Presentation 2007 Miller P, Bolognese M, Lewiecki EM, McClung M, et al. Effect of denosumab on bone mineral density and bone turnover markers: 48-month results. ASBMR 2007. Abstract 1205.

    36. Denosumab Phase 2 Study Randomized, placebo-controlled, dose-ranging study Postmenopausal women (n = 412) with low BMD or OP Spine T-score -1.8 to -4.0, or TH or FN T-score -1.8 to -3.5) Mean Spine T-Score -2.1 Treatment Assignments: 7 denosumab dosing groups (6, 14, 30 mg Q3M; 14, 60, 100, or 210 mg Q6M SQ), 1 open label 70 mg weekly alendronate group Placebo group All subjects received 1000 mg Ca and 400 IU D daily Primary end point: Spine BMD at 12 months Prespecified exploratory analysis: BMD, BTMs, safety at 24 and 48 months

    37. Spine BMD

    38. Total Hip BMD Similar changes were seen at the femoral neck and trochanter (slides in backup).Similar changes were seen at the femoral neck and trochanter (slides in backup).

    39. 1/3 Radius BMD

    40. Serum CTX

    41. Serum BSAP

    42. Medications Under Development Medications Currently Under Development or FDA Review: New Estrogen Agonist/Antagonist Agents Bazedoxifene (Wyeth) and CEE/Bazedoxifene combo Lasofoxifene (Pfizer) Arzoxifene (Lilly) New PTH Compounds: Cyclic 1-31PTH (Zelos) New PTH Delivery Systems (Patch, Oral, Nasal) Cathepsin K Inhibitor (Merck) PTH Receptor Antagonist (GSK) Antisclerostin Antibody (Amgen) Glucagon-Like Peptide

    43. Summary Landmark Advances and Emerging Therapies New therapies are evolving Persistence must be considered All approved bisphosphonates are effective if they are taken Two landmark trials demonstrate zoledronic acid reduces vertebral and non-vertebral (including hip) fracture risk; and one study demonstrates mortality reduction

    44. Summary Landmark Advances and Emerging Therapies Mononclonal antibodies are in late stage III development; initial studies promising New Estrogen Agonist/Antagonist Agents might have greater potency than current one (raloxifene) and might provide additional rationale for use

More Related