Seminar 08-12-2007 - bisphosphonate mechanism of action

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  • Alendronate significantly decreased both NTx (1 month) and PINP (3 months). The suppression of bone turnover with alendronate was maintained through month 12. Conversely, teriparatide significantly increased both markers of bone remodeling. The increases of the bone formation marker, PINP, were vigorous and rapid (113% above baseline at 1 month), peaking at 6 months of treatment (251% increase above baseline. The increases in the bone resorption marker, NTx, were of far smaller magnitude (58% at peak), reached significance only after 3 months of treatment, and lagged behind those of PINP. Thus, the different effects of the two drugs on bone remodeling were evident after 1 month of treatment, and there were significant differences (P<0.001) between the treatment groups in each marker at each time point (months 1,3,6,12). ___________________ McClung, et al. Differential effects of teriparatide and alendronate on markers of bone remodeling and areal and volumetric bone density in women with osteoporosis. J Bone Miner Res 2003:18(Suppl 2):S40.
  • Key points: After 12 months, the risedronate cohort had a 43% lower incidence of hip fracture than the alendronate cohort. This reduction is based upon an adjusted relative rate reduction. Adjustments were made based on baseline: Hip Age Estrogen use Number of medications History of hospitalizations The percent of cohort with fracture is very similar during the first 3 month (no separation) There is separation of the Kaplan-Meier curves from 3-12 months Background: The time to event plot is crude (unadjusted) fracture incidence, the 43% reduction is adjusted. Patients at risk at each time point (fracture events) BL 3 month 6 month 9 month 12 month Alendronate 21615 (0) 21590 (25) 12993 (54) 8677 (69) 5582 (80) Risedronate 12215 (0) 12202 (13) 6847 (19) 4319 (27) 2584 (29)
  • Key spoken message: “ There are 2 fundamental components of how nitrogen containing bisphosphonates work and exhibit their anti-resorptive effects. These are how they bind to the bone and how they affect the enzyme which is essential for osteoclast activity” I’m going to start talking on the first one – Bone Mineral Affinity Background Terms “potency” and “affinity”: Potency: The amount of drug needed to produce an effect Affinity: A chemical property (ie, force) that causes the drug to associate with a receptor, protein binding pocket, or other surface. Risedronate image used with permission of F.H. Ebetino, P&G Pharmaceuticals FPPS image: Kavanagh, K.L., Guo, K., Oppermann, U. Human farnesyl diphosphate synthase complexed with the clinical inhibitor risedronate To be Published (http://dx.doi.org/10.2210/pdb1yv5/pdb)
  • Key spoken message: “ When comparing the mineral binding, we see differences between the bisphosphonates. However, the correlation between bone mineral binding and the clinical efficacy is not fully clear yet’
  • Key spoken message: “ This shows the amount of bisphosphonate needed to inhibit the enzyme by 50%. We see here heterocyclic bisphosphonates (ie zoledronate and risedronate) have a higher potency for enzyme inhibition than the alkly bisphosphonates (eg alendronate and ibandronate)”
  • 2ef2143t; 13, 15
  • Protocol 054 - PBO patients Left: PBO patient with BV/TV of 22% - plates with holes Right - PBO patient with BV/TV of 8% - mostly rods Resolution 20  m- surface rendered images

Transcript

  • 1. Werkingsmechanismen vanWerkingsmechanismen van bestaande anti-osteoporosebestaande anti-osteoporose medicatiesmedicaties Zijn ze van belang in de keuze voor de individuele patiënt? Wat kunnen we in de nabije toekomst verwachten? azMaastricht UHasselt
  • 2. Veranderingen in botombouw met medicaties Maanden Resorptie Formatie Teriparatide (PTH) Bisfosfonaten Oestrogenen SERMs % Verandering vs. baseline Strontium Ranelaat -100 -50 0 50 100 150 200 250 0 1 3 6 12 azMaastricht UHasselt
  • 3. Mechanisms of action of drugs to prevent fractures Markers of Bone resorption Bone formation Architecture Mineralization Antiresorptives   c  Strontium ranelate * * * c Teriparatide, Preotact     *demonstrated in animal studies c: unchanged azMaastricht UHasselt
  • 4. Routes and frequency of drug administration and duration of studies Drug Route Regimen Duration of studies (years) Alendronate po d,w 4.2/10 Risedronate po d,w 5/7 Ibandronate po m 3 IV shot 3m Zoledronate IV 15’ y 3 Calcitonin nasal d 3 Strontium ranelate po d 5 Teriparatide SC d 1.5 Preotact SC d 1.5 Po: oral intake; IV: intravenous administration; SC: subcutaneous administration; nasal: nasal spray; D: daily ; W: weekly; Y: yearlyazMaastricht UHasselt
  • 5. Anti-Fracture Effects of Drugs in primary analysis of RCT’s Fractures prevented: Spine Non-spine Hip Alendronate x x x Risedronate x x x Ibandronate x Zoledronate x x x Raloxifene x Calcitonin x Strontium ranelate x x rhPTH 1-34 x x 1-84 x azMaastricht UHasselt
  • 6. Anti-Fracture Effects of Drugs in primary analysis of RCT’s and post-hoc analyses (*) Fractures prevented: Spine Non-spine Hip Alendronate x x x Risedronate x x x Ibandronate x x* Zoledronate x x x Raloxifene x x* Calcitonin x Strontium ranelate x x x* rhPTH 1-34 x x 1-84 x azMaastricht UHasselt
  • 7. Reduction of non-vertebral fractures in analyses atReduction of non-vertebral fractures in analyses at the end of main anti-fracture studiesthe end of main anti-fracture studies azMaastricht UHasselt
  • 8. Risico voor nieuwe fractuur binnen het jaar na een wervelfractuur 0 5 10 15 20 25 30 Percent(%)ofPatients 25% nieuwe fractuur: Niet-wervel: 5% Wervel: 20% Lindsay R, Geusens P et al, JAMA, 2001, 320azMaastricht UHasselt
  • 9. 0,0 4,0 8,0 12,0 16,0 20,0 24,0 maanden 0,00 0,03 0,06 0,09 0,12 0,15 % > 80 50-59 60-69 70-79 n= 537 n= 554 n= 475 n= 591 Refracture incidence in 50+ women and men (all causes, all locations) Van Helden, Osteoporosis Int, 2006, 348 Van Geel, BMC Medicine, 2007 Center, JAMA, 2007 azMaastricht UHasselt YEARS OF FOLLOW-UP 302520151050 FRACTURE-FREEPROBABILITY 1,0 0,8 0,6 0,4 0,2 0,0 10% subsequent fracture 50% of subsequent fracture within 2 years within 5 years after initial fracture
  • 10. Anti-Fracture Effects of Drugs Published data on speed of action (in months) Fractures prevented: Spine Alendronate 12 Risedronate 6 Ibandronate 12 Zoledronate 12 Raloxifene 12 Calcitonin 36 Strontium ranelate 12 rhPTH 1-34 18 1-84 18 azMaastricht UHasselt
  • 11. Anti-Fracture Effects of DrugsAnti-Fracture Effects of Drugs Published data on speed of effect (in months)Published data on speed of effect (in months) Fractures prevented: references Spine Non-spine Alendronate 12 12 Pols, Ost Int, 1999, 461 Risedronate 6 6 Roux, CMROpin, 2004, 433 Ibandronate 12 36* Zoledronate 12 36 Raloxifene 12 Calcitonin 36 Strontium ranelate 12 12 if >80 yrs Seeman, JBMR, 2006, 1113 rhPTH 1-34 18 18 1-84 18 * Cranney, Adachi, EULAR, 2007, Abstract azMaastricht UHasselt
  • 12. Comparisons between anti-osteoporosis drugs  Anti-fracture studies differed in  patient selection and characteristics  fracture endpoints [clinical, vertebral (clinical, morphometric), non-vertebral (various definitions) or hip)  doses of drugs  statistical approaches (intention-to-treat or per-protocol)  concomitant use of calcium and vitamin D  trial duration  proportion of patients lost to follow-up azMaastricht UHasselt
  • 13. Comparisons between anti-osteoporosis drugs  Head-to-head RCTs with anti-fracture effects as primary endpoint unlikely to become available  need enormous numbers of patients  would prove extremely costly to conduct  No head-to-head RCTs with fracture prevention as primary endpoint  Thus, rates of fracture reduction and speed of onset of anti- fracture effect compared to placebo should not be compared directly and no inferences should be made regarding superiority of one efficacious treatment over another azMaastricht UHasselt
  • 14. Meta-analyses  Highest level of evidence  But results depend on patient selection  RR non-vertebral fractures: Boonen, 2006 Cranney, 2002  Alendronate 0.86 (CI: 0.76-0.97) 0.51 (CI: 0.43-0.65) (including non-OP) (including only ≥10 mg/d)  Risedronate 0.81 (CI: 0.71-0.92) 0.73 (CI: 0.61-0.87) (including 3 studies) (including 7 trials)
  • 15. Bone resorption markers –100 –80 –60 –40 –20 0 Baseline Month 6 Month 12 Mean%change Urine NTx Serum CTx p<0.001 p<0.001 –40% –53% –55% –74% p<0.001 p<0.001 Month 3 p<0.001 Treatment difference 13% p<0.001 Treatment difference 19% Alendronate n = 442 429 414 365 449 443 423 382 Risedronate n = 457 449 426 375 459 455 433 387 Alendronate 70 mg OW Risedronate 35 mg OW –100 –80 –60 –40 –20 0 Baseline Month 6 Month 12Month 3 azMaastricht UHasselt
  • 16. Hip Trochanter BMD 0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5 5.0 Baseline Month 6 Month 12 p≤0.001 3.4% 2.1% Mean%change p≤0.001 Treatment difference=1.4 %, p<0.001. Alendronate (n=464) Risedronate (n=481) azMaastricht UHasselt
  • 17. Gastro-intestinal side effectsGastro-intestinal side effects No significant differences between treatment groups Number (%) of patients Alendronate 70 mg OW (n=515) Risedronate 35 mg OW (n=527) ≥1 upper-GI adverse experience 116 (22.5) 106 (20.1) Discontinued due to upper-GI adverse experience 13 (2.5) 16 (3.0) Discontinued due to serious upper-GI adverse experience 0 (0.0) 1 (0.2) azMaastricht UHasselt
  • 18. Cumulative Hip Fracture Incidence ↓43% * at Month 12 *Adjusted Relative Rate Reduction, p = 0.01, 95% CI: 13% - 63% Baseline Month 6 Month 12 %ofcohortwithahipfracture 0.00 0.10 0.20 0.30 0.40 0.50 0.58 alendronate risedronate Silverman et al. Osteoporos Int. January 2007 azMaastricht UHasselt
  • 19. Extra-skeletal benefits  Raloxifene  reduced the risk of invasive breast cancer in the CORE study by 66% over 8 years  recently been approved by the FDA for the prevention of ER positive breast cancer in women at high risk  Estrogens  attenuate severe climacteric symptoms  No first-line treatment of osteoporosis alone, because of side effects (breast cancer, thromboembolisms, cardiovascular thrombotic events)  Zoledronate, given yearly within 90 days of a hip fracture  all-cause mortality -28% over 3 years when  reason for the reduced mortality in this study is not clear azMaastricht UHasselt Geusens et al. Nature Osteoporosis Clin Pract, 2008, in press
  • 20. Safety issues  BP  GI: adequate intake  Osteonecrosis of the jaw: <1/10 000 to 100 000 in osteoporosis  Atrial fibrillation: zoledronate in 1 of 3 studies, not with alendronare and risedronate  Flu-like symptoms at start (+/- 30% with zoledronate)  Raloxifen  Venous thrombosis  Strontium ranelate  Diarrhea; venous thrombosis; DRESS (<1/10 000)  Teriparatide  Cramps, dizziness azMaastricht UHasselt
  • 21. Oplosbaarheid van alendronaat enOplosbaarheid van alendronaat en generiekengenerieken Epstein, J Appl Res, 2005, 1 azMaastricht UHasselt
  • 22. Therapietrouw  Bisfosfonaten, na 1 jaar therapie:  40% met dagelijkse inname  50% met wekelijkse inname  60% met maandelijkse inname  70% met wekelijkse dosis in fractuurpoli met osteoporose verpleegkundige  Barrières bij artsen en patiënten azMaastricht UHasselt
  • 23. Fundamental Components ofFundamental Components of N-Bisphosphonate Anti-resorptive ActivityN-Bisphosphonate Anti-resorptive Activity Availability, Distribution,Availability, Distribution, Offset of ActionOffset of Action Bone Mineral Affinity Bone Uptake and Release PotencyPotency FPPS Enzyme Inhibition Osteoclast Function Ebetino FH, et al. J Bone Miner Res 2005;20(Suppl 1):S259 Kavanagh KL, et al. http://www.rcsb.org/pdb/explore.do?structureId=1YV5; Accessed 5-Dec-06 azMaastricht UHasselt
  • 24. Differential Binding toDifferential Binding to Bone MineralBone Mineral HAP Adsorption Affinity Constants at pH 7.4 0 1 2 3 4 KL/106 Lmol-1 ZOLALNIBNRIS Adapted from Nancollas GH, et al. Bone 2006;38:617–627 azMaastricht UHasselt
  • 25. FPPS Enzyme Inhibition Potency (ICFPPS Enzyme Inhibition Potency (IC5050)) Amount of N-BP needed to inhibit 50% of max. enzyme activityAmount of N-BP needed to inhibit 50% of max. enzyme activity 1 Kavanagh KL, et al. PNAS 2006;103:7829-7834. 2 Dunford JE, et al. Unpublished data (2006) FPP-S FPP-S IC50Final (nM) 0 5 10 15 20 25 30 100 200 300 400 ALN IBN RIS ZOL ALN RIS azMaastricht UHasselt
  • 26. Pharmacokinetics of bisphosphonates azMaastricht UHasselt Russell, Bone, 2006
  • 27. QCT 12-Month Percent Changes from BLQCT 12-Month Percent Changes from BL Completer Population: Spine BMDCompleter Population: Spine BMD r=0.3133 r=0.46703 (Average of L1 and L2 for entire vertebra excluding transverse process, g/cm3 ) (Average of L1 and L2 for vertebral trabecular BMD, g/cm3 ) P=0.0131 P=0.0194 0 5 10 15 20 25 30 I nt egral Spine Trabecular Spine PercentChangefromBL Prior RI S (n= 112) Prior ALN (n= 119) azMaastricht UHasselt
  • 28. PercentchangeinBMD No OP drug use (n=144) (+6 months) (+18 months) (+30 months) Antiresorptive starting before 6 months and continued for at least 24 months (n = 65) Antiresorptive starting after 6 months and continued for at least 18 months (n = 34) Endpoint Visit 1 Visit 2 Visit 3 Lindsay et al. Program & Abstracts, Endocrine Society 84th Ann Mtg June 19-22, 2002; #OR35-6 Lumbar Spine BMD TPTD20 Followed with Antiresorptive Treatment Fracture Prevention Trial Baseline through Follow-up Study azMaastricht UHasselt
  • 29. Strategie na 5 jaar behandeling metStrategie na 5 jaar behandeling met bisfosfonatenbisfosfonaten Start Fractuur T-score AR* Strategie tijdens 5 jr F.U. na 5 jr Geen fractuur T<-2.5 neen T<-2.5 hoog continuren neen T>-2.0 laag stop + opvolging Fractuur Wervel neen any hoog continueren ja any hoog switch naar PTH Niet-wervel neen T<-2.5 hoog continueren T>-2.0 intermediair stop /continueren? ja any hoog switch naar PTH AR*: absoluut risico voor fracturenazMaastricht UHasselt
  • 30. Botombouw na de menopauze www.courses.washington.edu/ bonephys/opalgo.gif azMaastricht UHasselt
  • 31. En de toekomst? azMaastricht UHasselt
  • 32. OB RANKL OPG Osteocyt Resorption Formation Secondary 20 days 100 days mineralisation OC Proteases IGF-1,2 IGF-BPs Activation PTH, PTHrP,1.25(OH)2D3 calcium deficiency Inhibition Oestrogens RANK Mechanic stimuli TGFB Bone turnoverBone turnover LC PG, NO Sclerostin DKK OC = osteoclast OB = osteoblast LC = lining cell Wnt azMaastricht UHasselt
  • 33.  Replication Pre-OB Pre-OC  Bone formation Osteoblasts  Apoptosis  Bone resorption Osteoclasts  Activity  Bone Matrix Synthesis  OPG RANK RANKL Dual Effects of Strontium RanelateDual Effects of Strontium Ranelate  Differentiation CaSR CaSR + Other? Brennan, CTI, 2006 (ECTS 2006)
  • 34. Anti-RANKL: Effect op merker van botresorptie (CTX-I) met SC injectie om de 6 maanden Phase 2: Postmenopausal Women with Low BMD McClung MR, et al. N Engl J Med. 2006;354:821-831 12 NS vs placebo P < 0.001 vs alendronate P < 0.001 vs placebo -100 -80 -60 -40 -20 0 20 0 2 4 6 8 10 Time (Months) MeanPercentChange fromBaseline Placebo, N = 46 Denosumab 14 mg, N = 53 Denosumab 60 mg, N = 47 Denosumab 100 mg, N = 41 Denosumab 210 mg, N = 46 Alendronate 70 mg/wk, N = 46 azMaastricht UHasselt
  • 35. Wnt signalling and osteoblasts Baron, Endocrinology, 2007 azMaastricht UHasselt
  • 36. Disease and Therapy Mediated by theDisease and Therapy Mediated by the Calcium-Sensing ReceptorCalcium-Sensing Receptor azMaastricht UHasselt
  • 37. ConclusionsConclusions  Anti-osteoporosis agents differ in size and speed of anti-fracture effects between agents, but these differences should be interpreted with caution in the absence of head-to-head RCTs  Anti-osteoporosis agents differ in:  mechanisms of action between classes  pharmacokinetics within classes  extra-skeletal benefits  side effects  these differences can be helpful when deciding about treatment  Future:  Prevention of developing high risk  Sequential treatment with anabolics followed by preservation with anti-resorptives azMaastricht UHasselt
  • 38. Contributors to secondary osteoporosis inContributors to secondary osteoporosis in patients with osteoporosispatients with osteoporosis Postmenopausal women, sent to an osteoporosis clinic, with T-score <-2.5, n=664 33% had known contributors to secondary osteoporosis 33% of the other presumably healthy women had newly diagnosed contributors Tannenbuam, JCEM, 2002, 4431
  • 39. FRACTURE-FREE PROBABILITY OF WOMEN WITH ONEFRACTURE-FREE PROBABILITY OF WOMEN WITH ONE FRACTURE (N = 681)FRACTURE (N = 681) AND WOMEN WITH TWO OR MORE FRACTURES (N = 243)AND WOMEN WITH TWO OR MORE FRACTURES (N = 243) YEARS OF FOLLOW-UP 302520151050 FRACTURE-FREEPROBABILITY 1,0 0,8 0,6 0,4 0,2 0,0 Years of follow up 1 fracture2nd fracture 16% 54% azMaastricht UHasselt
  • 40. Overall Initial and Subsequent Fracture RiskOverall Initial and Subsequent Fracture Risk by Gender (Dubbo study, mean follow up 15-by Gender (Dubbo study, mean follow up 15- 16 yrs)16 yrs) Center, JAMA, 2007, 387Center, JAMA, 2007, 387 % of refractures within 5 years 41% 52% azMaastricht UHasselt
  • 41. UHasselt azMaastricht 0,0 4,0 8,0 12,0 16,0 20,0 24,0 maanden 0,00 0,03 0,06 0,09 0,12 0,15 % > 80 50-59 60-69 70-79 n= 537 n= 554 n= 475 n= 591 Refracture incidence according to age >80 (n=537) 70-79 (n=591) 60-69 (n=475) 50-59 (n=554) Months Van Helden, Osteoporosis Int, 2006, 348 azMaastricht UHasselt