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

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