Bisphosphonates in Treating Osteoporosis

1. Bisphosphonates Ranuccio Nuti Department of Medicine, Surgery and NeurosciencesUniversity of Siena, Italy

2. Agenda Mechanism of action and microarchitecture Long-term clinical results and drug holiday Potential harms

3. O P OH HO CH3 HO C CH2 CH2 N (CH2)4 CH3 HO P OH O IBANDRONATE PAMIDRONATE O P OH HO HO C CH2 CH2 OH HO P O 12 BISPHOSPHONATES O P OH HO O CH2 C OH N OH HO P OH HO P N N OH CH3 C O RISEDRONATE OH HO P NH2 O O ZOLEDRONATE P OH HO Pyrophosphate C S H Cl ALENDRONATE HO P OH O O P OH HO TILUDRONATE HO C CH2 CH2 CH2 NH2 HO P OH O CLODRONATE O P OH HO ETIDRONATE O C Cl Cl P HO OH Bisphosphonate HO P OH C OH CH3 O HO OH P The physicochemical effects of bisphosphonates are very similar to those of pyrophosphate. They bind avidly to calcium phosphate crystals and inhibit their growth, aggregation, and dissolution. The affinity for bone mineral is the basis for their use as skeletal markers and as inhibitors of ectopic calcification and of bone resorption. O Department of Medicine, Surgery and Neurological Sciences, University of Siena

4. BP BP BP BP BP BP BP Bone BP BP BP BP Bone 12 Bisphosphonates Are Internalised by Osteoclasts During Bone Resorption Bind to bone mineral BP BP BP BP Bone Concentrate at sites of bone resorption Release and intracellular uptake during resorption Loss of resorptive function Weiss HM, et al. Drug Metab Dispos 2008;36:2043-9 Department of Medicine, Surgery and Neurological Sciences, University of Siena

5. 12 Bisphosphonates mevalonate Dimethylallyl diphosphate Isopentenyl diphosphate (IPP) Apppl FPP synthase Geranylgeranyl diphosphate (GGPP) Farnesyl diphosphate (FPP) Cholesterol Farnesyl proteins Geranylgeranylated proteins Prenylated proteins required for osteoclast function and survival ATP-BP metabolites induce osteoclast apoptosis “Simpler” non-N Bisphosphonates Nitrogen-containing Bisphosphonates BP BP BP BP BP BP BP BP BP BP BONE Department of Medicine, Surgery and Neurological Sciences, University of Siena

6. 12 BISPHOSPHONATES • Clodronato (im) • Pamidronato (iv) • Neridronato (im) • Alendronato (os) • Risedronato (os) • Ibandronato (os/iv) • Zoledronato (iv) Department of Medicine, Surgery and Neurological Sciences, University of Siena

7. 14 12 BISPHOSPHONATE POTENCY Hydroxyapatite Binding FPPS Activity 1.5 4 3 1.0 FPP synthase activity IC50, J774 cells (μM) Adsorption Affinity Constant (KL L/mol x 106) 2 0.5 1 0.0 ALN IBA RIS ZOL PAM 0 CLO ETD RIS IBA ALN ZOL [Nancollas GH, et al. J Bone Miner Res. 2002;17(suppl 1):S368] [Dunford JE, et al. J Pharmacol Exp Ther. 2001;296:235-242]] Department of Medicine, Surgery and Neurological Sciences, University of Siena

8. Bisphosphonates prevent osteoblast and osteocyte apoptosis and inhibit osteoclast activity via different mechanisms Hemichannel opening leads to activation of the kinases Src and extracellular signal-regulated kinases (ERKs), followed by phosphorylation of the ERK cytoplasmic target p90RSK kinase and its substrates BAD and C/EBPβ, resulting in inhibition of apoptosis. Bellido T. et al. al. 2010

9. Effect of four bisphosphonates at different doses on osteoblast proliferation in MG-63 cell line after 24 h of incubation High doses of nitrogen-containing or non-nitrogen-containing bisphosphonates can reduce the proliferation of MG-63 osteoblast-like cells by arresting the cell cycle and inducing apoptosis/ necrosis. Manzano-Moreno J. Et al. 2015

10. Preservation of spine microarchitecture by alendronate: Comparison of the cancellous structure of T12 baboon vertebra in controls, OVX, and different doses of alendronate. Reduced vertebral fracture risk with alendronate may be due to a combination of factors including the increased bone volume, reduced turnover and greater mineralization Hordon LD. et al 2006

11. 3D Synchrotron images provide changes in low-mineralized bone fractions (green areas) as an indicator of the remodeling at trabecular surfaces at baseline and after 5 yrs of risedronate treatment. Conventional micro-CT analysis demonstrated that risedronate provided sustained benefits on mineralization and architecture, two key determinants of bone strength, over 5 years lending support for its long-term efficacy in fracture risk reduction. Borah B. et al 2006

12. Cortical and Trabecular Microarchitectural Deterioration in Postmenopausal Women at different stages Bala Y. Et al 2014

13. Percent change in Tot.vBMD, Ct.vBMD, Tb.vBMD, and cortical porosity at the distal tibia (HR-pQCT) Risedronate slows microstructural deterioration in younger and partly reverses it in older postmenopausal women, features likely to contribute to antifracture efficacy Bala Y. Et al 2014

14. 12 Antifracture Benefits of Bisphosphonates for the Treatment of Postmenopausal Osteoporosis Alendronate, risedronate, and zoledronic acid decreased fracture risk at the spine, nonvertebral sites, and the hip alone, whereas ibandronate reduced vertebral but not nonvertebral fractures. McClung M et al. Am J Med. 2013 Jan;126(1):13-20 Department of Medicine, Surgery and Neurological Sciences, University of Siena

15. Cross-design synthesis evaluating the effects of bisphosphonates on single clinical fracture types in randomized trials and database studies. Compliant/persistent patients in the “realworld” setting benefit from bisphosphonate treatment to a similar extent as patients in randomized trials. Wilkes M. et al. 2010

16. 12 HORIZON-Recurrent Fracture Trial (Zoledronate 5 mg i.v .) Male and female pts who had undergone surgical repair of a low-trauma hip fracture within the previous 90 days (mean age, 74.5 years) Lyles KW, et al. N Engl J Med. 2007; 357: 1-11 Lyles KW, et al. N Engl J Med. 2007; 357: 1-11 Department of Medicine, Surgery and Neurological Sciences, University of Siena

17. 12 Zoledronic Acid 5 mg Reduced Risk of All-Cause Mortality Lyles KW, et al. N Engl J Med. 2007; 357: 1-11 Department of Medicine, Surgery and Neurological Sciences, University of Siena

18. Trends in antiosteoporosis drug prescribing after hip fracture Although the prescribing of anti-osteoporosis drugs after hip fracture has increased substantially since 2000 in the UK, the overall rate remained inadequate with the continuing increase in the absolute number of hip fractures, Klop C. . et al. 2015

19. Effects of Continuing or Stopping Alendronate After 5 Years of Treatment (FLEX study) Women who discontinued alendronate after 5 years showed a moderate decline in BMD and a gradual rise in biochemical markers but no higher fracture risk other than for clinical vertebral fractures compared with those who continued alendronate. Black D. et al. 2006

20. The Effect of 6 Versus 9 Years of Zoledronic Acid Treatment in Osteoporosis: A Randomized Second Extension to the HORIZON-Pivotal Fracture Trial (PFT) The results suggest almost all patients who have received six annual ZOL infusions can stop medication for up to 3 years with apparent maintenance of benefits Black D. et al. 2014

21. 12 Recommendations for Drug Holiday from Bisphosphonates McClung M et al. Am J Med. 2013 Jan;126(1):13-20 Department of Medicine, Surgery and Neurological Sciences, University of Siena

22. 12 The Impact of Adherence to Osteoporosis Treatment Persistence (taking the drug for the recommended time) Adherence to drug prescription + Compliance (taking the drug as prescribed) Poor adherence to OP therapy negatively affects therapeutic outcomes Department of Medicine, Surgery and Neurological Sciences, University of Siena

23. 12 Adherence with bisphosphonate therapy and BMD change in clinical practice Weycker D et al. Osteoporos Int 2012 Department of Medicine, Surgery and Neurological Sciences, University of Siena

24. Association between compliance and risk of fractures. A significant association between high compliance and reduced fracture risk is observed, which becomes augmented with longer treatment duration (B) Association between persistence and risk of fractures. A decrease in the odds ratio is observed with longer treatment duration, corresponding to a risk reduction range between 13% and 54%. (C) Sampalis J. et al 2012

25. The main potential harms of bisphosphonates Possible hypersensitivity reaction of the GI mucosa due to the prolonged exposure to the BP Gastrointestinal side effects Possible inflammation of arterial wall or increase of blood calcium levels Atrial fibrillation Extraskeletal Possible pill-esophagitis, cell dysplasia or Barrets’ esophagus Cancer of esophagus Atypical femur fractures Longterm decreased bone resorption Skeletal Possible participation of suppression of bone turnover Osteonecrosis of the jaw Reyes C, 2015

26. Meta-Analysis of Total Adverse Cardiovascular Events Associated with Use of Bisphosphonates. Bisphosphonates do not have beneficial or harmful effects on atherosclerotic CV events Kim D. et al. 2014

27. Meta-Analysis of Atrial Fibrillation Associated with Use of Bisphosphonates. Zoledronic acid may modestly increase the risk of atrial fibrillation. Given the large reduction in fractures with bisphosphonates, changes in osteoporosis treatment decision due to CV risk are not justified. Kim D. et al. 2014

28. 12 Exposure to oral bisphosphonates and esophageal cancer risk: A UK General Practice Research Database cohort study Adjusted HR 0.96 [95% CIs 0.74-1.25] Adjusted HR 1.07 [95% Cis 0.77-1.49] This large study does not provide evidence for an increased risk of esophageal (or gastric) cancer in persons using oral bisphosphonates. Cardwell CR et al. JAMA 2010; 304(6):657-63 Department of Medicine, Surgery and Neurological Sciences, University of Siena

29. Risk of bisphosphonates on oesophageal and gastric cancer in women (above) and men (below) The results support a small but significant increased risk of oesophageal cancer in women prescribed bisphosphonates and is based on the largest number of exposed cases to date in the UK. Wright E. et al 2012,

30. What this study adds This series of nested case-control studies was conducted with two large general population primary care databases and found no overall association between use of bisphosphonates and risk of oesophageal, gastric, or colorectal cancers An increased risk of gastric cancer associated with use of alendronate was found in one database, but with no evidence of a duration response

31. 12 Risk Factors for Bisphosphonate associated ONJ • Intravenous bisphosphonates • Cancer and anti-cancer therapy • Dental extraction, oral bone manipulating surgery, poor fitting dental appliances, interiorly trauma • Duration of exposure to bisphosphonates treatment • Glucocorticoids • Co-morbid conditions (i.e. malignancy) • Alcohol and/or tobacco abuse • Pre-existing dental or periodontal disease Woo SB et al., Ann Intern Med. 2006 The absolute risk of bisphosphonate-associated osteonecrosis of the jaw is approximately 1 case per 100 000 person-years when bisphosphonates are administered for osteoporosis treatment Brown J. et al. 2014 J Bone Mineral Res, September 2007 Department of Medicine, Surgery and Neurological Sciences, University of Siena

32. 12 Pathogenetic mechanisms and Incidence of Atypical Femoral Fractures (AFF) • Alterations to the normal pattern of collagen cross-linking • - Changes to maturity of cross-links formed by enzymaticprocesses • - Advanced glycationend-productaccumulation • Microdamageaccumulation • Increasedmineralization • Reducedheterogeneityofmineralization • Variations in rates of bone turnover • Reduced vascularity and antiangiogenic • effects Incidence of AFF according to duration of bisphosphonate exposure (unadjusted and age-adjusted) The absolute risk of bisphosphonate-associated atypical subtrochanteric and diaphyseal femur fracture is between 2 and 78 cases per 100 000 person-yrs Brown J. Et al 2014 Shane E et al J Bone Miner Res 2014. Atypical subtrochanteric and diaphyseal femoral fractures: second report of ASBMR task force Dell RM et al. J Bone Miner Res 2012 Department of Medicine, Surgery and Neurological Sciences, University of Siena

33. At this time, the evidence suggests that AFFs are stress fractures. There is generalized suppression of remodeling as the result of BP treatment,; when BPs are stopped, the risk of an AFF may decline. It is possible, and indirectly supported by the reported difference in risk between ethnic groups, that lower limb geometry contributes to the risk for developing an AFF.