Malang pain update yearly bisphosphonate
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Malang pain update yearly bisphosphonate

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Malang pain update yearly bisphosphonate Malang pain update yearly bisphosphonate Presentation Transcript

  • Osteoporosis management Efficacy and safety of yearly bisphosphonate
  • Osteoporosis Increase morbidity and mortality
  • Who to treat ? Prior h/o hip/vertebral # or T Score < -2.5 or T Score -1 to -2.5 & 10 yr risk (FRAX) : HIP # > 3 % or major osteoporotic # > 20 % Postmenopausal women /men > 50 yrs with
  • Bone marrow precursors Osteoblasts Osteoclast Lining cells Stimulators of Bone Formation Fluoride PTH analogs Sr Ranelate (?) Inhibitors of Bone Resorption Estrogen, SERMs Bisphosphonates Calcitonin Inhibitors of RANKL Cathepsin K Therapeutic strategies
  • Treatments & Efficacy Vertebral Fx Non-vertebral Fx Other Fx Hip Fx Oral HRT Yes Yes Yes Etidronate* Yes Alendronate* Yes Yes Yes Risedronate* Yes Yes Yes Ibandronate* Yes [Yes] Raloxifene* Yes Calcitriol* Yes Strontium Ranelate* Yes Yes [Yes]
  • Vertebral Fx Non-vertebral Fx Other Fx Hip Fx Subcutaneous Teriparatide* Yes Yes 1-84 PTH* Yes Denosumab* Yes Yes Yes Intravenous Pamidronate Ibandronate* Zoledronate* Yes Yes Yes Intranasal or Subcutaneous Calcitonin* Yes
  • Vertebral Fx Nonvertebral Fx Other Fx Hip Fx Alendronate* Yes Yes Yes Risedronate* Yes Yes Yes Zoledronic acid* Yes Yes Yes PTH* Yes Yes ??? Strontium ranelate* Yes Yes ??? Denosumab* Yes Yes Yes Appropriate use of appropriate treatments can halve the incidence of fractures * plus calcium + vitaminD
  • Mainstay of treatment : Bisphosphonates Approval in US for osteoporosis • Alendronate : 1995 • Risedronate : 2000 • Ibandronate : 2005 • Zoledronate : 2007.
  • Contraindications
  • Duration of treatment
  • Hot topics
  • HIP FRACTURE – Female Age 75 and over Give single oral dose 100,000 IU vitaminD @ as soon as feasible post hip fracture & start 1000mg CaCO3+800IU vitaminD asap, (if on this already – continue) Already on a BP(bisphosphonate)? No Yes Good prognosis & eGFR 30 or over Duration of treatment?Yes No 1. Patient or resident carer understand concepts of osteoporosis, fracture risk reduction & protocol for ingesting oral BP AND 2. No contraindications to oral BPs [dysphagia / oesophageal stricture / achalasia /hypocalcaemia]. Yes Oral ALN 70mg / wk No Patient suitable for IV BP & eGFR 35 or over Yes No Arrange IV zoledronic acid 5mg infusion (over at least 15min), 4-6/52 after hip fracture Consider oral BP or, if at risk equivalent to that of fracture plus T-score -2.4 or less, consider strontium ranelate. Continue b.d. calcium + vitaminD Continue b.d. oral calcium + vitaminD More than 2yr 2yr or less Optimal compliance with / adherence to BP & BP well tolerated YesNo Continue oral BP IF eGFR is 30 or more Otherwise continue b.d. calcium + vitaminD GREATER GLASGOW & CLYDE PROTOCOL FOR FRACTURE SECONDARY PREVENTION AFTER HIP FRACTURE IN WOMEN AGE 75+
  • Zoledronic acid 5 mg IV once a year
  • Once Yearly Zoledronic Acid Reduces Fractures  HORIZON Pivotal Fracture Trial  Multi-national, multi-center, RCT  7,736 women age 65-89 with T-score < -2.5 or fracture plus T-score < -1.5  Calcium 1000-1500 mg/day vit D (400- 1200 IU/day)  Zoledronic acid IV infusion 5 mg Black et al. NEJM 356:1809-1822, 2007
  • ZOL reduces hip fracture *Relative risk reduction (95% confidence interval) vs placebo Black et al. NEJM 356:1809-1822, 2007 P = .0024 1 2 3 0 Placebo (n = 3861) ZOL 5 mg (n = 3875) CumulativeIncidence(%) Time to First Hip Fracture (months) 0 3 6 9 12 15 18 21 24 27 30 33 36 41%* (17%, 58%)
  • P < .0001 CumulativeIncidence(%) Time to First Clinical Vertebral Fracture (months) 0 3 6 9 12 15 18 21 24 27 30 33 36 77% (63%, 86%) Placebo (n = 3861) ZOL 5 mg (n = 3875) 1 2 3 0 ZOL reduces vertebral fx *Relative risk reduction (95% confidence interval) vs placebo Black et al. NEJM 356:1809-1822, 2007
  • P = .0002 Time to First Clinical Non-vertebral Fracture (months) 2 4 6 8 10 12 0 3 6 9 12 15 18 21 24 27 30 33 36 25% (13%, 36%) Placebo (n = 3861) ZOL 5 mg (n = 3875) 0 CumulativeIncidence(%) ZOL reduces non-vertebral fx *Relative risk reduction (95% confidence interval) vs placebo Black et al. NEJM 356:1809-1822, 2007
  • Zoledronic Acid will Improve Patient Compliance as Once- Yearly IV Therapy is Preferred Data from Lindsay R, et al. Poster presented at ECCEO6; March 15-18, 2006; Vienna, Austria. 16.4 18.9 Both Are Equal Once-Yearly IV Once-Weekly Pill More convenient More willing to take long term Overall preference N = 122 66.4 59.8 0 20 40 60 80 100 68.0 66.4 15.6 18.0 20.5 15.6 19.7 13.9 % of Patients More satisfying
  • 24 J Bone Miner Res. 2012;27:240–242 HORIZON-PFT 3-years data: Black DM, et al. N Engl J Med. 2007;356:1809-1822 (HORIZON: Health Outcomes and Reduced Incidence with Zoledronic acid ONce Yearly) HORIZON-Pivotal Fracture Trial Extention
  • 25 • 3-year, randomized, double-blind, placebo-controlled extension trial • 2456 postmenopausal women • Primary endpoint: Percentage change in FN BMD at Year 6 vs. Year 3 • Secondary endpoints: BMD at other sites, BTMs, fracture incidence, safety HORIZON-PFT Extension: Study Overview Black DM, et al. J Bone Miner Res. 2012;27:240–242
  • 26 Primary Endpoint: % Change of ZOL 5 mg Treatment in Femoral Neck BMD at Years 6 VS Years 3 *P < 0.0001, P value computed from 3-way ANOVA with treatment, stratum and region as explanatory variables **P value computed from 2-way ANOVA with treatment and region as explanatory variables. MITT = modified intention to treat 1Black DM, et al. N Engl J Med. 2007;356:1809-1822 2Black DM, et al. J Bone Miner Res. 2012;27:240–242 Z6 n= 589 609 608 600 524 450 Z3P3 n= 599 613 606 602 540 467 Z3 n= 3851 PBO n= 3845
  • 27 ZOL n= 268 262 236 228 PBO n= 265 258 226 212 Z6 n= 101 100 Z3P3 n= 102 84 ZOL n= 268 262 236 228 PBO n= 265 258 226 212 Z6 n= 101 100 Z3P3 n= 102 84 *P = 0.1910 **P < 0.0001 1Black DM, et al. N Engl J Med. 2007;356:1809-1822 2Black DM, et al. J Bone Miner Res. 2012;27:240–242 Secondary Endpoint: % Change of ZOL 5 mg Treatment in Lumbar Spine BMD at Years 6 VS Years 3
  • 28 Secondary Endpoint: 6 years of annual ZOL 5 mg infusions provides continued fracture protection Discontinuation of ZOL 5 mg treatment after 3 years still giving residual effect on prevention nonvertebral fractures Continuation of ZOL 5 mg treatment for 6 years significantly reduced New Morphometric Vertebral Fractures Core study:†P < 0.001 relative risk reduction vs placebo (PBO); n = the number of patients in the analysis population with X-rays at Year 3 and Year 6; ITT = intention to treat , Z3P3 = ZOL for 3 years and placebo for 3 years, Z6 = ZOL for 6 years. †The event rate is from Kaplan-Meier estimate at Month 36 in the extension study 1Black DM, et al. N Engl J Med. 2007;356:1809-1822 2Black DM, et al. J Bone Miner Res. 2012;27:240–242 *P = 0.0348 *P < 0.001
  • 29 A single infusion of ZOL 5 mg reduced bone resorption marker rapidly than weekly oral ALN 70 mg (Urine NTX) (Serum β-CTX ) * P<0.0001; †P<0.05, for relative change from baseline, ZOL vs ALN; NTX: urine N-telopeptide; β-CTX: Serum β-C-telopeptide of type I collagen Saag, et al. Bone 2007;40:1238-1243
  • 30 Safety: Overall No Increase in Risk of AEs or SAEs With Long-term (6-Year) ZOL 5 mg Treatment Compared with 3 Years of Treatment Category Z6 (N=613) n (%) Z3P3 (N=616) n (%) P-value Total no. of patients with an AE 552 (90) 552 (89) 0.85 Serious AEs 191 (31) 168 (27) 0.15 Deaths 26 (4) 18 (3) 0.22 Cardiovascular AE Atrial fibrillation AEs 21 (3.4%) 13 (2.1%) 0.17 Atrial fibrillation SAEs* 11 (1.8%) 6 (1.0%) 0.23 Stroke related AEs 26 (4.2%) 19 (3.1%) 0.29 Stroke SAEs 19 (3.1%) 9 (1.5%) 0.06 Stroke deaths* 1 (0.2%) 0 (0%) 0.50 New hypertension AEs† 48 (7.8%) 94 (15.2%) <0.001 *P = 0.1910 **P < 0.0001 1Black DM, et al. N Engl J Med. 2007;356:1809-1822 2Black DM, et al. J Bone Miner Res. 2012;27:240–242
  • 31 Safety: Five most common Post-Dose Symptoms (≤ 3 Days After Infusion) and declined markedly with subsequent infusions 0 2 4 6 8 10 12 14 16 Annual Infusion Pyrexia Myalgia Flu-like illness Headache Arthralgia 1 2 3 1 2 3 1 2 3 1 2 3 1 2 3 Incidence(%) 15% 2% 1% 1% 2% 1% 2% 1% 2% 1% 8% 7% 6% 5% Placebo values cross-hatched 1% Treatment with antipyretic analgesics appeared to mitigate these symptoms2 Acetaminophen four times/day for 3 days significantly reduced the incidence and severity of post-dose symptoms following ZOL infusion3 1Black DM, et al. N Engl J Med. 2007;356:1809-1822
  • 32 ZOL= 3595 3574 3284 2989 PBO= 3624 3615 3338 3031 Z6= 613 572 517 459 Z3P3= 616 584 537 475 Renal Safety: 6 Years of ZOL Therapy Has No Cumulative Impact on Creatinine Clearance 1Black DM, et al. N Engl J Med. 2007;356:1809-1822 2Black DM, et al. J Bone Miner Res. 2012;27:240–242
  • HORIZON-PFT Extension Study: Summary • Long-term efficacy - 6 years of ZOL therapy led to: – Significantly greater increases from baseline in FN, TH and trochanter BMD than stopping treatment at 3 years – Significant risk reduction in vertebral morphometric fracture risk vs stopping treatment at 3 years – Maintenance of bone turnover markers within reference range – Losses in BMD and BTMs in discontinuation group were modest 33 Black DM, et al. J Bone Miner Res. 2012;27:240–242
  • Long-term safety •No new safety concerns identified in women with PMO •No statistical difference in AF SAEs vs discontinuation of ZOL •No long-term effect on renal function vs discontinuation of ZOL •No increase in risk for ONJ events vs discontinuation of ZOL •No cases of atypical fractures
  • Summary • Reduce frequent dosing with bisphosphonates may improve compliance as an important thing for the success of osteoporosis treatment. • Six years of annual ZOL 5 mg infusion preserves bone mass and discontinuation after 3 years still provided residual benefit of fracture protection. • It may be beneficial for some women, particularly those at high vertebral fracture risk, to continue ZOL for an additional 3 years 351Black DM, et al. N Engl J Med. 2007;356:1809-1822 2Black DM, et al. J Bone Miner Res. 2012;27:240–242
  • Summary • A single infusion of zoledronic acid 5 mg compared to weekly oral alendronate produced More rapid effect on tone turn over marker • In both HORIZON-PFT ZOL 5 mg and extension were generally safe and well tolerated • Clinical experience with more than 1 million infusions worldwide • Once-yearly IV zoledronic acid 5 mg may be the answer of unmet need of current osteoporosis treatments
  • Thank you Keep your bone healthy