the therapeutic use of reclast® (zoledronic acid) in pagets disease of the bone stephanie...
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The Therapeutic Use of Reclast® (zoledronic acid) in Paget’s Disease
of the BoneStephanie Piemontese
PharmD Candidate 2010University of Pittsburgh School of
Pharmacy
Objectives
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
• Two types of bone: cortical and trabecullar– Cortical bone’s major function
strength/protection– Trabecular bone is more metabolically active
• fjfj
Paget’s 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
• Aside from osteoporosis Paget’s is the most common bone disorder
• Equally prevalent in men and women• Increased incidence in persons > 50 yo• 3% US population affected• Schneider
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
schn
• Complications include: Neurologic, hearing, vision, cardiac, and oncologic
• Occurs in 3 phases (Schneider)1. Intense osteoclastic activity and bone resorption2. Osteoblastic phase producing woven bone, with
ineffective mineralization3. Dense cortical and trabecullar bone deposition
Etiology schle, dum
• Viral and hereditary causes• Particles contained in osteoclasts of Pagetic
bone appear to be paramyxovirus nucleocapsids
Summary
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
Indication for Paget’s Disease
• Indicated for treatment of Paget’s 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 rangesOR
• Those who are symptomatic OR
• Those at risk for complications from their disease
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
Retreatment of Paget’s 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 phosphataseOR
• In those patients who failed to achieve normalization of their serum alkaline phosphatase levelOR
• In symptomatic patients as dictated by medical practice
Mechanism of Action
• Class: bisphosphonate• Acts primarily on the bone• Inhibitor of osteoclast-mediated bone
resorption• High affinity for mineralized bone
Contraindications
• Hypcalcemia• Hypersensitivity to any component
Warnings and Precautions
• Reclast® ≠ Zometa®• Hypocalcemia and Mineral Metabolism• Renal Impairment• Osteonecrosis of the Jaw (ONJ)• Pregnancy• Musculoskeletal Pain• Patients with Asthma
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
Drug Interactions
• Aminoglycosides• Loop diuretics• Nephrotoxic drugs• Drugs primarily excreted by the kidney
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
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
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
Clinical Trial
• Reid IR, Miller P, Lyles K, et al. Comparison of a Single Infusion of Zoledronic Acid with Risedronate for Paget’s Disease. NEJM. 2005; 353:898-908.
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
Patient Selection
Inclusion Criteria• Men and women > 30yo• Radiologically confirmed
Paget’s 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
Paget’s disease in the preceding 180 days
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 daysOR
• 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
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
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
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)
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
Serum Alkaline Phosphatase
Serum N-terminal propeptide of type I collagen
Serum βC-telopeptide of type I collagen
Urinary αC-telopeptide of type I collage to creatine ratio
QoL Assessment
Component of SF-36 % patients -Zoledronic Acid % patients -Risedronate
Physical Functioning 43 34
Physical Role 28 26
Bodily Pain 50 37
General Health 39 31
Vitality 49 40
Social Functioning 28 28
Emotional Role 23 16
Mental Health 28 27
Percent of Patients with at least 5-point change at 6 months
Mean changes from baseline in the 8 domains assessed by the SF-36
Bone Biopsy
• Performed in 22 patients– 12 zoledronic acid patients, 10 risedronate
patients
• 2 specimens (1 from each group) came from sites of Paget’s disease
• Both were otherwise normal– Increased mineralization in the risedronate
specimen
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)
ADE Days 1-3Variable # patients in
Zoledronic Acid (%)N=177
# patients in Risedronate (%)N=172
P value
Influenza-like illness 17 (9.6) 7 (4.1) 0.06
Myalgia 13 (7.3) 6 (3.5) 0.16
Pyrexia 13(7.3) 1 (0.6) <0.01
Fatigue 12 (6.8) 4 (2.3) 0.07
Headache 12 (6.8) 7 (4.1) 0.35
Rigors 12 (6.8) 1 (0.6) <0.01
Nausea 11 (6.2) 3 (1.7) 0.05
Bone pain 9 (5.1) 2 (1.2) 0.06
• 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
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
Weaknesses
• Raw values for many statistics not reported
Reclast’s place in Paget’s Disease Therapy
Questions