1. The Therapeutic Use of Reclast® (zoledronic acid) in Pagets Disease of the Bone Stephanie Piemontese PharmD Candidate 2010 University of Pittsburgh School of Pharmacy

2. Objectives

3. Normal Bone Physiology Bone has both structural and metabolic properties – Structural: locomotion, respiration, and protection – Metabolic: storage of Ca++, Phos, and carbonate; H ion buffering, bind toxins and heavy metals Bone is made up of collagen and mineral components – Collagen gives flexibility and energy-absorbing capability – Mineral component gives stiffness and strength

4. Two types of bone: cortical and trabecullar – Cortical bones major function strength/protection – Trabecular bone is more metabolically active fjfj

5. Pagets Disease of the Bone Non malignant disease involving accelerated bone resorption followed by deposition of dense, chaotic, and ineffectively mineralized bone Differs from osteoporosis by the involvement of discrete sections of bone remodeling Schneider, Dipiro

6. Aside from osteoporosis Pagets is the most common bone disorder Equally prevalent in men and women Increased incidence in persons > 50 yo 3% US population affected Schneider

7. Clinical Features Schneid, Dum Can affect any area Most commonly involves axial skeleto – Usually affects at least 2 bones Can be symptomatic of asymptomatic Most common symptom is pain the affected bone

8. schn Complications include: Neurologic, hearing, vision, cardiac, and oncologic

9. Occurs in 3 phases (Schneider) 1.Intense osteoclastic activity and bone resorption 2.Osteoblastic phase producing woven bone, with ineffective mineralization 3.Dense cortical and trabecullar bone deposition

10. Etiology schle, dum Viral and hereditary causes Particles contained in osteoclasts of Pagetic bone appear to be paramyxovirus nucleocapsids

11. Summary

12. Reclast® (zoledronic acid) Approved by the FDA in 2001 A bisphosphonate approved for: – Treatment of osteoporosis in postmenopausal women – Prevention of osteoporosis in postmenopausal women – Treatment to increase bone mass in men with osteoporosis – Treatment and prevention of glucocorticoid-induced osteoporosis in patients expected to be on glucocorticoids for at least 12 months

13. Indication for Pagets Disease Indicated for treatment of Pagets disease in both men and women Indicated in patients with elevations in serum alkaline phosphatatse of > 2 times higher than upper limit of age-specific normal ranges OR Those who are symptomatic OR Those at risk for complications from their disease

14. Dosage and Administration A single 5mg infusion given IV over no less than 15 minutes 1500mg elemental calcium and 800 IU vitamin D daily Administer through a separate vented infusion line Avoid contact with any calcium or divalent cation- containing solutions Patients must be appropriately hydrated prior to administration Acetaminophen administration following Reclast administration may reduce incidenc of acute-phase reaction symptoms

15. Retreatment of Pagets Disease After a single treatment with Reclast and extended remission period is observed Specific re-treatment data are not available However, can be considered in patients who have relapsed based on serum alkaline phosphatase OR In those patients who failed to achieve normalization of their serum alkaline phosphatase level OR In symptomatic patients as dictated by medical practice

16. Mechanism of Action Class: bisphosphonate Acts primarily on the bone Inhibitor of osteoclast-mediated bone resorption High affinity for mineralized bone

17. Contraindications Hypcalcemia Hypersensitivity to any component

18. Warnings and Precautions Reclast® Zometa® Hypocalcemia and Mineral Metabolism Renal Impairment Osteonecrosis of the Jaw (ONJ) Pregnancy Musculoskeletal Pain Patients with Asthma

19. Adverse Reactions Most common ADR (>10%) were pyrexia, myalgia, headache, arthralgia, pain in extermities Other clincially important ADR were flu-like illness, nausea, vomiting, diarrhea, eye inflammation, hypocalcemia, hypophosphatemia, ONJ, acute renal impairment, allergic reactions

20. Drug Interactions Aminoglycosides Loop diuretics Nephrotoxic drugs Drugs primarily excreted by the kidney

21. Use in Specific Populations Pregnant and nursing mothers – should not receive Reclast Pediatric use – not indicated Geriatric use – monitor renal function Renal Impairment – should not be used <35mL/min Hepatic Impairment – no data

22. Pharmacodynamics Treatment with a 5mg annual dose of Reclast reduces bone turnover markers to the pre- menopausal range with an approxiamte 55% reduction Serum beta-C-telopeptides = bone resorption Bone specific alkaline phosphatase & serum N- terminal propeptide of type I collagen = bone formation Progressive reduction of bone turnover with repeated annual dosing

23. Pharmacokinetics Distribution – Triphasic process – t/2α=0.24hrs, t1/2β=1.87hrs, t1/2γ=146hrs – Protein binding ranges from 28% to 53% Metabolism – Does not inhibit P450 enzymes in vitro Elimination

24. Clinical Trial Reid IR, Miller P, Lyles K, et al. Comparison of a Single Infusion of Zoledronic Acid with Risedronate for Pagets Disease. NEJM. 2005; 353:898-908.

25. Methods Two randomized, controlled trials – independent of each other – identical protocols Included patients from N. America, Europe, Australia, S. Africa Pooled results in a joint analysis

26. Patient Selection Inclusion Criteria Men and women > 30yo Radiologically confirmed Pagets disease Alkaline phosphatase level > 2x upper limit of normal Exclusion Criteria Serum 25-hydroxyvitamin D level < 15ng/mL Primary hyperparathyroidism Evidence of hepatic/renal disease History of uveitis, iritis, or upper GI disorders Diabetic nephropathy/retinopathy Use of therapy specific to Pagets disease in the preceding 180 days

27. Randomization and Treatment Double-blind random assignment through an interactive voice-response system to receive: A 5mg infusion of zoledronic acid over 15 minutes followed by placebo tablets for 60 days OR A saline infusion followed by a 30mg of risedronate per day for 60days All patients received 1g calcium and 400-1000 U calciferol per day

28. Primary Study Endpoints Proportion of patients who had a therapeutic response – Normalization of or reduction of at least 75% in alkaline phosphatase excess at 6 months Measurements were made by Covance Central Laboratory Services

29. Secondary Study Endpoints Biochemical markers of bone resorption and bone formation QOL measured by Medical Outcomes Study 36-Item Short-Form General Health Survey (SF-36) Bone histomorphometry Safety assessments

30. Statistical Analyses Each study had a power of 80% to demonstrate noninferiority of zoledronic acid relative to risedronate Assumed a dropout rate of ~10% per study Calculated would need 88 patients in each group (176 total)

31. Results 182 patients enrolled in zoledronic acid group 175 patients in the risedronate group Similar baseline characteristics – favored male gender in the overall study population

32. Serum Alkaline Phosphatase

33. Serum N-terminal propeptide of type I collagen

34. Serum βC-telopeptide of type I collagen

35. Urinary αC-telopeptide of type I collage to creatine ratio

36. QoL Assessment Component of SF-36% patients -Zoledronic Acid% patients -Risedronate Physical Functioning4334 Physical Role2826 Bodily Pain5037 General Health3931 Vitality4940 Social Functioning28 Emotional Role2316 Mental Health2827 Percent of Patients with at least 5-point change at 6 months

37. Mean changes from baseline in the 8 domains assessed by the SF-36

38. Bone Biopsy Performed in 22 patients – 12 zoledronic acid patients, 10 risedronate patients 2 specimens (1 from each group) came from sites of Pagets disease Both were otherwise normal – Increased mineralization in the risedronate specimen

39. Adverse Events No deaths occurred 146 ADE in zoledronic acid group – 9 serious ADE 133 ADE in risedronate group – 11 serious ADE Marked clustering of ADE in first 3 days after IV drug administration – 53.7% zoledronic acid patients vs. 25.0% risedronate patients (p <0.01)

40. ADE Days 1-3 Variable # patients in Zoledronic Acid (%) N=177 # patients in Risedronate (%) N=172 P value Influenza-like illness17 (9.6)7 (4.1)0.06 Myalgia13 (7.3)6 (3.5)0.16 Pyrexia13(7.3)1 (0.6)<0.01 Fatigue12 (6.8)4 (2.3)0.07 Headache12 (6.8)7 (4.1)0.35 Rigors12 (6.8)1 (0.6)<0.01 Nausea11 (6.2)3 (1.7)0.05 Bone pain9 (5.1)2 (1.2)0.06

41. Frequencies of GI and renal or urinary disorders were similar 1 patient in each group with preexisting renal impairment had moderate increases in SCr Mean SCr level decreased slightly but significantly in the zoledronic acid group vs. the risedronate group by day 10 Hypocalcemia – decreases in serum Ca ++ levels in both groups at day 10

42. Trial Extension Patients who met therapeutic response Serum alkaline phosphatase measured at 6- month intervals Median 190 days after end of core study period – 21/82 risedronate patients lost therapeutic response – 1/113 zoledronic acid patients lost therapeutic response

43. Weaknesses Raw values for many statistics not reported

44. Reclasts place in Pagets Disease Therapy

45. Questions