Update on OsteoporosisUpdate on Osteoporosis

Sol Epstein, M.D.Sol Epstein, M.D.Clinical Professor of Medicine and Geriatrics Clinical Professor of Medicine and Geriatrics

Mount Sinai School of MedicineMount Sinai School of MedicineNew York, New YorkNew York, New York

OsteoporosisWRAP SlideCASTOsteoporosisWRAP SlideCAST

Topics to be VisitedTopics to be Visited

► New data on current therapiesNew data on current therapies► New therapiesNew therapies► “ “Hot topics with therapyHot topics with therapy Osteopenia and FRAXOsteopenia and FRAX Drug holidayDrug holiday Waning of fracture effect Waning of fracture effect ONJONJ Atrial FibrillationAtrial Fibrillation Atypical fracturesAtypical fractures Atypical osteoclasts and BP’sAtypical osteoclasts and BP’s Non Skeletal benefits of Vit DNon Skeletal benefits of Vit D

Therapeutic StrategiesTherapeutic Strategies

Bone marrow precursorsBone marrow precursors

OsteoblastsOsteoblastsOsteoclastOsteoclast

Lining cellsLining cells

Stimulators of Stimulators of Bone FormationBone Formation

FluorideFluoridePTH analogsPTH analogs

Sr Ranelate (?)Sr Ranelate (?)

Inhibitors ofInhibitors ofBone Bone ResorptionResorption Estrogen, SERMsEstrogen, SERMs

BisphosphonatesBisphosphonatesCalcitoninCalcitonin

Inhibitors ofRANKL

Cathepsin K

Ibandronate 2.5mg has 62% RRR Ibandronate 2.5mg has 62% RRR in vertebral fractures vs PBOin vertebral fractures vs PBO

(BONE study)(BONE study)

Ibandronate 2.5mg has 62% RRR Ibandronate 2.5mg has 62% RRR in vertebral fractures vs PBOin vertebral fractures vs PBO

(BONE study)(BONE study)

Ibandronate evidence of anti-fracture efficacyIbandronate evidence of anti-fracture efficacyIbandronate evidence of anti-fracture efficacyIbandronate evidence of anti-fracture efficacy

Monthly bandronate150mg has 34 to 38% RRR Monthly bandronate150mg has 34 to 38% RRR in non-vertebral fractures in the pivotal registration trials in non-vertebral fractures in the pivotal registration trials

(Harris; Cranney)(Harris; Cranney)

Monthly bandronate150mg has 34 to 38% RRR Monthly bandronate150mg has 34 to 38% RRR in non-vertebral fractures in the pivotal registration trials in non-vertebral fractures in the pivotal registration trials

(Harris; Cranney)(Harris; Cranney)

Ibrandronate 2.5mg has 69% RRR Ibrandronate 2.5mg has 69% RRR in non-vertebral fractures vs PBOin non-vertebral fractures vs PBO

in higher risk patients in higher risk patients (BONE study)(BONE study)

Ibrandronate 2.5mg has 69% RRR Ibrandronate 2.5mg has 69% RRR in non-vertebral fractures vs PBOin non-vertebral fractures vs PBO

in higher risk patients in higher risk patients (BONE study)(BONE study)

Monthly ibandronate150mg demonstrated statistically greater Monthly ibandronate150mg demonstrated statistically greater reduction in vertebral fractures, and comparable rates ofreduction in vertebral fractures, and comparable rates of non-vertebral / hip fracture vs weekly bisphosphonatesnon-vertebral / hip fracture vs weekly bisphosphonates

in clinical practice settings (VIBE study)in clinical practice settings (VIBE study)

Monthly ibandronate150mg demonstrated statistically greater Monthly ibandronate150mg demonstrated statistically greater reduction in vertebral fractures, and comparable rates ofreduction in vertebral fractures, and comparable rates of non-vertebral / hip fracture vs weekly bisphosphonatesnon-vertebral / hip fracture vs weekly bisphosphonates

in clinical practice settings (VIBE study)in clinical practice settings (VIBE study)

ProspectiveProspectiveTrialsTrials

Meta-analysisMeta-analysisof Trialsof Trials

ObservationalObservationalStudiesStudies

Meta-analysis methodsMeta-analysis methods11

► Meta-analysis of ibandronate registration trials to increase Meta-analysis of ibandronate registration trials to increase sample size and powersample size and power● identical designs: BMD bridging studies for oral identical designs: BMD bridging studies for oral

(MOBILE(MOBILE22) and i.v. (DIVA) and i.v. (DIVA33))● non-vertebral fracture data collected with X-ray non-vertebral fracture data collected with X-ray

confirmationconfirmation

● Primary endpoint: major non-vertebral fractures including Primary endpoint: major non-vertebral fractures including clavicle, humerus, wrist, pelvis, hip and legclavicle, humerus, wrist, pelvis, hip and leg

11Cranney A, Cranney A, et al. Osteoporosis Int. 2008, DOI 10.1007/s00198-008-0653-8et al. Osteoporosis Int. 2008, DOI 10.1007/s00198-008-0653-822Miller PD, et al. J Bone Miner Res 2005;20:1315–22Miller PD, et al. J Bone Miner Res 2005;20:1315–2233Delmas PD, et al. Arthritis Rheum 2006;54:1838–46Delmas PD, et al. Arthritis Rheum 2006;54:1838–46

Meta-analysis ComparesMeta-analysis ComparesHigher vs Lower Dose GroupsHigher vs Lower Dose Groups

Higher dosesHigher doses

Monthly oral†

150mgQuarterly i.v.

3mg

Lower doseLower dose

Daily oral 2.5mg

Bimonthly i.v. 2mgNOT LICENSED

*ACE = annual cumulative exposure = dose x doses/year x absorption (e.g. 2.5 x 365 x 0.6% = 5.5mg ACE)*ACE = annual cumulative exposure = dose x doses/year x absorption (e.g. 2.5 x 365 x 0.6% = 5.5mg ACE)††Absorption for oral ibandronate = 0.6%Absorption for oral ibandronate = 0.6%11

11Barrett J, et al. J Clin Pharmacol 2004;44:951–65Barrett J, et al. J Clin Pharmacol 2004;44:951–65

(ACE* ~11mg) (ACE* 5.5mg)

compared with

Time to non-vertebral fracture is Time to non-vertebral fracture is extended with ibandronate ACE extended with ibandronate ACE 10.8mg10.8mg

*For time to fracture with ibandronate versus daily dose*For time to fracture with ibandronate versus daily dose††Cox regression analyses for difference in RR of fracture with ibandronate versus daily doseCox regression analyses for difference in RR of fracture with ibandronate versus daily doseCranney A, et al. Osteoporosis Int. 2008, DOI 10.1007/s00198-008-0653-8Cranney A, et al. Osteoporosis Int. 2008, DOI 10.1007/s00198-008-0653-8

p=0.036 (log-rank)*p=0.036 (log-rank)*

Est

imat

ed f

ract

ure

rate

(%

)E

stim

ated

fra

ctur

e ra

te (

%)

66

55

44

33

22

11

00

Higher doses (ACE Higher doses (ACE 10.8mg)10.8mg)

Daily dose (ACE 5.5mg)Daily dose (ACE 5.5mg)

00 100100 200200 300300 400400 500500 600600 700700

38% RRR38% RRR††

p=0.0375p=0.0375

Time (days)Time (days)

Higher dose ibandronate reduced non-Higher dose ibandronate reduced non-vertebral fracture risk at 2 yearsvertebral fracture risk at 2 years

*Includes marketed 150mg monthly oral (ACE 10.8mg) and 3mg i.v. quarterly (ACE 12mg), plus the unlicensed 2mg every 2 *Includes marketed 150mg monthly oral (ACE 10.8mg) and 3mg i.v. quarterly (ACE 12mg), plus the unlicensed 2mg every 2 months i.v. dose (ACE 12mg)months i.v. dose (ACE 12mg)

Fracture rate from Kaplan-Meier analysis; RRR from Cox regression adjusted for baseline characteristicsFracture rate from Kaplan-Meier analysis; RRR from Cox regression adjusted for baseline characteristicsCranney A, et al. Osteoporosis Int. 2008, DOI 10.1007/s00198-008-0653-8Cranney A, et al. Osteoporosis Int. 2008, DOI 10.1007/s00198-008-0653-8

Higher doses

38% RRRp=0.0375

No

n-v

erte

bra

l fr

actu

rera

te a

t 2

year

s (%

)

4.8 3.1

6

4

2

0

Daily dose(ACE 5.5 mg) (ACE ≥10.8 mg)*

LimitationsLimitations

► Trials not primarily designed to Trials not primarily designed to study fracture efficacy study fracture efficacy

► Baseline patient characteristics Baseline patient characteristics controlled for, were limited to controlled for, were limited to those collected in study those collected in study protocolprotocol

► P values not adjusted for P values not adjusted for multiple comparisonsmultiple comparisons

► Greater power and sample size to Greater power and sample size to detect differences in fracture rates detect differences in fracture rates

► Evidence from meta-analysis of two Evidence from meta-analysis of two large phase III randomised large phase III randomised controlled clinical trialscontrolled clinical trials

► Consistent nonvertebral fracture Consistent nonvertebral fracture data collection, confirmed by x-raydata collection, confirmed by x-ray

► Validity of analysis increased by Validity of analysis increased by maintaining randomisationmaintaining randomisation

► Study conducted externally by Study conducted externally by experts in meta-analysis and experts in meta-analysis and osteoporosisosteoporosis

StrengthsStrengths

Cranney A, et al. Osteoporosis Int. 2008, DOI 10.1007/s00198-008-0653-8Cranney A, et al. Osteoporosis Int. 2008, DOI 10.1007/s00198-008-0653-8

Primary analysis: monthly ibandronatePrimary analysis: monthly ibandronatevs weekly bisphosphonates at 12 monthsvs weekly bisphosphonates at 12 months

RR = adjusted RR (hazard ratio) using Cox regression controlling for potentialRR = adjusted RR (hazard ratio) using Cox regression controlling for potentialconfounding variables; Persistent patient cohort with no refill gap >45 daysconfounding variables; Persistent patient cohort with no refill gap >45 days(monthly) or 30 days (weekly); (monthly) or 30 days (weekly); Fx = absolute number of fracturesFx = absolute number of fractures

RR=0.36p<0.01

RR=1.06p=0.84

RR=0.88p=0.26

RR=0.82p=0.052

Fx=15

0.20

Fractures

Monthly oral ibandronate(n=7,345)

Weekly oral BPs(n=56,837)

Fx=103

Non-vertebral Hip Vertebral Any

Fra

ctu

re in

cid

ence

(%

) 1.30

Fx=858Fx=8Fx=135Fx=106Fx=95Fx=738

1.29

0.190.24

0.11

1.511.40

1.6

1.2

0.8

0.4

0

Reginster JY et al. Ann Rheum Dis 2008;67,Suppl. II; 539, Abstr. SAT0338 and SAT0339 Reginster JY et al. Ann Rheum Dis 2008;67,Suppl. II; 539, Abstr. SAT0338 and SAT0339

High Affinity BPs may diffuse less well in bone and remain nearer accessible surfacesHigh Affinity BPs may diffuse less well in bone and remain nearer accessible surfaces

BP BPBP

BP

High re-attachment High re-attachment through recyclingthrough recycling

BP

Low desorptionLow desorption

BP

Avid uptakeAvid uptake

G Russell 2005

BPs can be detected in BPs can be detected in body fluids many body fluids many

months after injectionmonths after injection

Zoledronic Acid has high affinity for Zoledronic Acid has high affinity for bone mineral leading to:bone mineral leading to:

HONN

O

O

=

=

P

P

OHOH

OHOH

ZOL has long duration of action

Proposed Mechanism of Local Recycling Proposed Mechanism of Local Recycling of Zoledronic Acid in Boneof Zoledronic Acid in Bone

HORIZON Recurrent Fracture Trial:HORIZON Recurrent Fracture Trial:Overview and Study DesignOverview and Study Design

► Objective: Demonstrate potential of once yearly Objective: Demonstrate potential of once yearly zoledronic acid to reduce number of clinical fractures zoledronic acid to reduce number of clinical fractures after surgical repair of recent low-trauma hip fractureafter surgical repair of recent low-trauma hip fracture

► Multicenter, event-driven, randomized, double-blind, Multicenter, event-driven, randomized, double-blind, placebo-controlled, parallel-group clinical trialplacebo-controlled, parallel-group clinical trial

► 2127 men and women from 148 clinical centers in 23 2127 men and women from 148 clinical centers in 23 countriescountries

Patients enrolled and maintained until prespecified Patients enrolled and maintained until prespecified number of clinical fracture events occurred, or when number of clinical fracture events occurred, or when patient reached 36 monthspatient reached 36 months

*All patients received calcium 1000–1500 mg/d and vitamin D 800–1200 IU/d and follow-up telephone calls every 3 months starting at Month 9.1. Lyles KW, et al. N Engl J Med. 2007;357:1799-18092. Lyles KW, et al. Presented at: 29th ASBMR; September 16-19, 2007; Honolulu, Hawaii. Abstract 1055.

HORIZON Recurrent Fracture Trial:HORIZON Recurrent Fracture Trial:Study PopulationStudy Population

► InclusionInclusion11

● Male or female patients ≥ 50 years of age Male or female patients ≥ 50 years of age ● Randomized up to 90 days following surgical procedure for a Randomized up to 90 days following surgical procedure for a

low-trauma hip fracturelow-trauma hip fracture● Ambulatory prior to hip fractureAmbulatory prior to hip fracture● Normal serum calciumNormal serum calcium

► ExclusionExclusion1,21,2

● Use of oral bisphosphonates within prespecified washout periodUse of oral bisphosphonates within prespecified washout period● Use of IV bisphosphonates within 2 yearsUse of IV bisphosphonates within 2 years● Calculated creatinine clearance <30 mL/minCalculated creatinine clearance <30 mL/min

1. Lyles KW, et al. N Engl J Med. 2007;357:1799-1809.2. Lyles KW, et al. Presented at: 29th ASBMR; September 16-19, 2007; Honolulu, Hawaii. Abstract 1055.

0 4 8 12 16 20 24 28 32 36

Month

0

2

4

6

8

10

12

14

16

18

20C

um

ula

tive I

ncid

en

ce (

%) P = .001Zoledronic acid (n = 1065)

Placebo (n = 1062)

HORIZON Recurrent Fracture Trial: HORIZON Recurrent Fracture Trial: Zoledronic Acid Reduced Zoledronic Acid Reduced Cumulative 3-Year Risk of Fractures by 35% Over TimeCumulative 3-Year Risk of Fractures by 35% Over Time

35%*

Clinical fracture defined as any fracture that came to the attention of the clinician during the course of the study, typically owing to symptoms such as pain, and including vertebral, hip, and non-vertebral fractures (excluding facial and digital fractures and fractures in abnormal bone (eg bone containing metastases).*Relative risk reduction vs placeboLyles KW, et al. N Engl J Med. 2007;357:1799-1809.

0

2

4

6

8

10

12

14

16

18

20

All ClinicalAll ClinicalFracturesFractures

ClinicalClinicalVertebralVertebralFracturesFractures

8.6%8.6%(92/1065)(92/1065)

13.9%13.9%(139/1062)(139/1062)

3.8%3.8%(39/1062)(39/1062)

1.7%1.7%(21/1065)(21/1065)

35%*35%*(16%, 50%)(16%, 50%)

46%†46%†(8%, 68%)(8%, 68%)

*P = .0012; †P = .0210, relative risk reduction vs placebo. Values above bars are cumulative event rates based on Kaplan-Meier estimates at Month 24.

Even

t R

ate

(%

)

Zoledronic acid Placebo

HORIZON Recurrent Fracture Trial: HORIZON Recurrent Fracture Trial: Zoledronic Acid Zoledronic Acid Reduced Subsequent Fracture Risk Over TimeReduced Subsequent Fracture Risk Over Time

Lyles KW, et al. N Engl J Med. 2007;357:1799-1809.

HORIZON Recurrent Fracture Trial: Zoledronic HORIZON Recurrent Fracture Trial: Zoledronic Acid Significantly Increased BMD Over 3 YearsAcid Significantly Increased BMD Over 3 Years

Values are least-squares mean difference, Zoledronic acid vs placebo.*P < .0001; †P = .0003; P-value computed from 2-way ANOVA with treatment and region in the model.1. Lyles KW, et al. N Engl J Med. 2007;357:1799-1809. 2. Data on file. Study CZOL446L2310. Novartis Pharmaceuticals Corporation. 3. Lyles KW, et al. Presented at: 29th ASBMR; September 16-19, 2007; Honolulu, Hawaii. Abstract 1055.

-3-2-1012345678

Total HipTotal Hip Femoral NeckFemoral Neck

Mean %

Change

Mean %

Change

From

Base

line

From

Base

line

6.4%*6.4%*

4.4%4.4%††

Zoledronic AcidPlacebo

HORIZON Fracture Trials:HORIZON Fracture Trials:Efficacy ConclusionsEfficacy Conclusions

► In women with In women with postmenopausal postmenopausal osteoporosis, once-yearly osteoporosis, once-yearly infusion of zoledronic acid infusion of zoledronic acid over 3 years significantly over 3 years significantly reduced:reduced:

― Vertebral fractures Vertebral fractures (morphometric 70%)(morphometric 70%)

― Hip fractures (41%)Hip fractures (41%)― Nonvertebral Nonvertebral

fractures(25%)fractures(25%)

1. Black DM, et al. N Engl J Med. 2007;356:1809-1822. 2. Lyles KW, et al. N Engl J Med. 2007;357:1799-1809.

Proven to reduce fractures in 2 large clinical trials

HORIZONHORIZONPivotal Fracture TrialPivotal Fracture Trial11

HORIZONHORIZONRecurrent Fracture TrialRecurrent Fracture Trial22

In patients, once-yearly infusion of In patients, once-yearly infusion of zoledronic acid within 90 days zoledronic acid within 90 days after a surgical procedure for low-after a surgical procedure for low-trauma hip fracture significantly trauma hip fracture significantly reduced:reduced:

— Overall clinical fractures by Overall clinical fractures by 35%35%

— Clinical vertebral fractures Clinical vertebral fractures by 46%by 46%

— (MORTALITY decreased)(MORTALITY decreased)

Other Indications for Zoledronic AcidOther Indications for Zoledronic Acid

► GIOPGIOP

► Male Osteoporosis (approved)Male Osteoporosis (approved)

► Adjuvant therapy for breast cancerAdjuvant therapy for breast cancer

RANK Ligand Is an Essential Mediator of RANK Ligand Is an Essential Mediator of Osteoclast Formation, Function, and SurvivalOsteoclast Formation, Function, and Survival

OsteoblastsActivated Osteoclast

MultinucleatedOsteoclast

Bone Formation

Bone ResorptionAdapted from: Boyle WJ, et al. Nature. 2003;423:337-342.

Provided as an educational resource. Do not copy or distribute.© 2007 Amgen. All rights reserved.

Hormones Growth Factors Cytokines

RANKL

RANK

CFU-M Pre-fusionOsteoclast

RANK Ligand Plays a Key Role in Osteoporosis and RANK Ligand Plays a Key Role in Osteoporosis and Other Conditions of Bone Loss and DestructionOther Conditions of Bone Loss and Destruction

Hofbauer LC, Schoppet M. JAMA. 2004;292:490-495.

Eghbali-Fatourechi G, et al. J Clin Invest. 2003;111:1221-1230.

Hofbauer LC, et al. Endocrinology. 1999;140:4382-4389.

Theriault RL. Oncology. 2004;18(suppl 3):11-15.

Gravallese EM, et al. Arthritis Rheum. 2000;43:250-258.

Roodman GD. N Engl J Med. 2004;350:1655-1664.

Kong Y-Y, et al. Nature. 1999;402:304-309.

Kitazawa S, et al. J Pathol. 2002;198:228-236.

Cancer-Related Bone Destruction

Postmenopausal Osteoporosis Treatment-Induced Bone Loss

Bone Erosion of RA

Denosumab and Denosumab and Cancer Induced Bone LossCancer Induced Bone Loss

► Denosumab and AI in non metastatic breast cancer. Denosumab and AI in non metastatic breast cancer. Increased BMD vs Placebo at all sitesIncreased BMD vs Placebo at all sites

► Denosumab and breast cancer mets. Decreased BTM Denosumab and breast cancer mets. Decreased BTM and skeletal related events comparable to IV ZOLand skeletal related events comparable to IV ZOL

► Denosumab and treatment of prostate cancer and bone Denosumab and treatment of prostate cancer and bone mets. Decreased BTMS compared to IV (ZOL).mets. Decreased BTMS compared to IV (ZOL).

Denosumab in OsteoporosisDenosumab in Osteoporosis

► Denosumab fracture trial.( FREEDOM ).Denosumab fracture trial.( FREEDOM ).Study characteristics. Primary outcome is reduction of new vertebral Study characteristics. Primary outcome is reduction of new vertebral fractures. Secondary endpoints include risk of non vertebral fractures fractures. Secondary endpoints include risk of non vertebral fractures and hip fractures. and hip fractures.

► 7686 patients enrolled. Age between 60-90 yrs, Mean age =72yrs. 7686 patients enrolled. Age between 60-90 yrs, Mean age =72yrs. Mean T score at lumbar spine or total hip = -2.8 and total hip -2.2 . 23 Mean T score at lumbar spine or total hip = -2.8 and total hip -2.2 . 23 % had prevalent fractures at baseline. 80 % completed the trial..% had prevalent fractures at baseline. 80 % completed the trial..

► Fracture reduction showed a reduction of vertebral fractures of 61 % Fracture reduction showed a reduction of vertebral fractures of 61 % at 1year.78% year 2 and 65 % year 3. Non vert fracture reduction was at 1year.78% year 2 and 65 % year 3. Non vert fracture reduction was 20%. Hip Fracture reduction was 40%.20%. Hip Fracture reduction was 40%.

► A/Es showed no differences particular with regard to malignancy, A/Es showed no differences particular with regard to malignancy, infection. No cases of ONJ reported. No delayed fracture healing infection. No cases of ONJ reported. No delayed fracture healing seen.seen.

► Data not shown included changes in PTH , serum calcium bone Data not shown included changes in PTH , serum calcium bone biopsies, and worsening of fractures biopsies, and worsening of fractures

ASBMR Sep 2008ASBMR Sep 2008

FRAX®: Gauging 10-Year Fracture ProbabilityFRAX®: Gauging 10-Year Fracture Probability

NOF Guidelines: When to Treat NOF Guidelines: When to Treat

Debated TopicsDebated Topics

► Osteonecrosis of the Jaw (ONJ)Osteonecrosis of the Jaw (ONJ)

► Atrial Fibrillation and BP’sAtrial Fibrillation and BP’s

► Atypical Fractures and BP’sAtypical Fractures and BP’s

► Drug Holiday Drug Holiday

► Combination/ sequential therapy eg BP followed by Combination/ sequential therapy eg BP followed by anabolic .anabolic .

► Giant Osteoclasts with BP’sGiant Osteoclasts with BP’s

26

Observations Regarding Osteonecrosis of the JawObservations Regarding Osteonecrosis of the Jaw

27

Osteonecrosis of the JawOsteonecrosis of the Jaw

► Although there is no universally accepted definition of osteonecrosis of Although there is no universally accepted definition of osteonecrosis of the jaw (ONJ), several authors have observed that ONJ is an oral cavity the jaw (ONJ), several authors have observed that ONJ is an oral cavity lesion characterized by 1 or more spots of bare alveolar or hard palate lesion characterized by 1 or more spots of bare alveolar or hard palate bone, in the absence of local malignancy or radiation therapy to the head bone, in the absence of local malignancy or radiation therapy to the head or neck.or neck.11––6 6

► Persisting for 6-8weeks.Persisting for 6-8weeks.► Known risk factors for ONJ include:Known risk factors for ONJ include:► IV bisphosphonatesIV bisphosphonates► Duration of treatmentDuration of treatment► Dental extractionDental extraction

● Diagnosis of cancerDiagnosis of cancer● Concomitant therapies (eg, chemotherapy, radiotherapy, and corticosteroids)Concomitant therapies (eg, chemotherapy, radiotherapy, and corticosteroids)● Poor oral hygienePoor oral hygiene● Comorbid disorders (eg, pre-existing dental disease, anemia, coagulopathy, Comorbid disorders (eg, pre-existing dental disease, anemia, coagulopathy,

and infection)and infection)

► The mechanism by which ONJ occurs is currently uncertain.The mechanism by which ONJ occurs is currently uncertain.11

28

ONJ: Clinical PresentationONJ: Clinical Presentation

Clinical Features of Suspected ONJClinical Features of Suspected ONJ

► Exposed bone in maxillofacial area Exposed bone in maxillofacial area that occurs in association with dental that occurs in association with dental surgery or occurs spontaneously, with surgery or occurs spontaneously, with no evidence of healing*no evidence of healing*

Working Diagnosis of ONJWorking Diagnosis of ONJ

► No evidence of healing after No evidence of healing after 6 weeks of appropriate evaluation and 6 weeks of appropriate evaluation and dental caredental care

► No evidence of metastatic disease in No evidence of metastatic disease in the jaw or osteoradionecrosisthe jaw or osteoradionecrosis

*Refer for appropriate dental evaluation and care as *Refer for appropriate dental evaluation and care as soon as possible.soon as possible.

29

Proposed Mechanisms of ONJProposed Mechanisms of ONJ

► Inhibition of angiogenesisInhibition of angiogenesis

► Decreased bone turnover impeding healing and Decreased bone turnover impeding healing and new bone formation.new bone formation.

► Mandible, maxilla and tooth eruption differs Mandible, maxilla and tooth eruption differs developmentally and anatomically from cancellous developmentally and anatomically from cancellous and cortical bone in other sites.and cortical bone in other sites.

► Immune system may play a role in Immune system may play a role in mechanism ????mechanism ????

30

ONJ and BisphosphonatesONJ and Bisphosphonates

► Incidence of ONJ Incidence of ONJ ● Occurs rarelyOccurs rarely● Reported in patients not taking bisphosphonatesReported in patients not taking bisphosphonates11––33

● No ICD9 code available for diagnosisNo ICD9 code available for diagnosis

► Bisphosphonate-associated ONJ has predominantly occurred in Bisphosphonate-associated ONJ has predominantly occurred in cancer patients receiving IV bisphosphonatescancer patients receiving IV bisphosphonates44::

● ONJ has been reported rarely in osteoporosis patients taking alendronate and ONJ has been reported rarely in osteoporosis patients taking alendronate and other oral bisphosphonates (ibandronate and risedronate zolendronate).other oral bisphosphonates (ibandronate and risedronate zolendronate). 55––77

► ONJ was added to the “Precautions” section of the Prescribing ONJ was added to the “Precautions” section of the Prescribing Information for ALL IV and oral bisphosphonates (effective July Information for ALL IV and oral bisphosphonates (effective July 2005 for alendronate).2005 for alendronate).

► Since their market introduction, over 191 million total prescriptions Since their market introduction, over 191 million total prescriptions have been dispensed for alendronate sodium, risedronate, and have been dispensed for alendronate sodium, risedronate, and ibandronate;ibandronate; 77% of these have been dispensed as alendronate.77% of these have been dispensed as alendronate.88

31

Experience with Bisphosphonates in Experience with Bisphosphonates in Clinical TrialsClinical Trials

► In controlled clinical trials involving more than 17,000 patients, In controlled clinical trials involving more than 17,000 patients, contributing as much as 10 years’ data with alendronate,contributing as much as 10 years’ data with alendronate,1,21,2 there there have been no reports of ONJ:have been no reports of ONJ:

● Includes Includes ≈≈3,000 osteoporosis patients taking alendronate for 3 3,000 osteoporosis patients taking alendronate for 3 to 5 yearsto 5 years

● Includes Includes ≈≈800 osteoporosis patients taking alendronate for 8 800 osteoporosis patients taking alendronate for 8 to 10 yearsto 10 years

● Includes 167 patients taking alendronate in a 2-year study of Includes 167 patients taking alendronate in a 2-year study of patients with pre-existing controlled periodontal disease patients with pre-existing controlled periodontal disease (investigational use)(investigational use)

● Zoledronic acid osteoporosis trial (HORIZON PFT) there was Zoledronic acid osteoporosis trial (HORIZON PFT) there was 1 case in the placebo and 1 case in the treated group. Cases 1 case in the placebo and 1 case in the treated group. Cases were marred by underlying disease and oral lesions.were marred by underlying disease and oral lesions.

1.1. Bone HG et al. Bone HG et al. N Engl J Med.N Engl J Med. 2004;350:1189–1199. 2004;350:1189–1199.2.2. Black D et al. Black D et al. J Bone Miner ResJ Bone Miner Res. 2004;suppl 1:S45.. 2004;suppl 1:S45.

Warnings and Precautions:Warnings and Precautions:Osteonecrosis of the Jaw (1/2Osteonecrosis of the Jaw (1/2))

► Osteonecrosis of the jaw (ONJ) has been reported rarely in Osteonecrosis of the jaw (ONJ) has been reported rarely in patients treated with bisphosphonates, including zoledronic patients treated with bisphosphonates, including zoledronic acidacid

● Most cases have been in cancer patients undergoing dental Most cases have been in cancer patients undergoing dental proceduresprocedures

● Some cases have occurred in patients with PMO treated with either Some cases have occurred in patients with PMO treated with either oral or IV bisphosphonatesoral or IV bisphosphonates

► Routine oral exam should be provided by the prescriber prior Routine oral exam should be provided by the prescriber prior to treatmentto treatment

► While on treatment, patients with concomitant risk factors While on treatment, patients with concomitant risk factors should avoid invasive dental procedures if possibleshould avoid invasive dental procedures if possible

● The clinical judgment of the treating physician should guide the The clinical judgment of the treating physician should guide the management plan of each patient based on individual benefit/risk management plan of each patient based on individual benefit/risk assessmentassessment

Further Reading on ONJFurther Reading on ONJ

Consensus practice guidelines on ONJ.Consensus practice guidelines on ONJ.

Sambrook P. Nature Clinical Practice RheumatologySambrook P. Nature Clinical Practice Rheumatology. .

Jan 2009Jan 2009

ONJ .Who gets it, and why?ONJ .Who gets it, and why?

Reid I .BONE 44 (2009) 4-10.Reid I .BONE 44 (2009) 4-10.

Atrial FibrillationAtrial Fibrillation

Atrial FibrillationAtrial Fibrillation

► Atrial Fibrillation with zoledronic acid in the HORIZON PFTAtrial Fibrillation with zoledronic acid in the HORIZON PFT

● Adjudicated SAEs of atrial fibrillation occurred in 1.3% of patients (50 Adjudicated SAEs of atrial fibrillation occurred in 1.3% of patients (50 out of 3862) compared to 0.4% (17 out of 3852) in the placebo groupout of 3862) compared to 0.4% (17 out of 3852) in the placebo group

● Overall incidence of atrial fibrillation AEs was 2.5% of zoledronic acid Overall incidence of atrial fibrillation AEs was 2.5% of zoledronic acid patients (96 out of 3862) vs 1.9% (75 out of 3852) in placebo patients (96 out of 3862) vs 1.9% (75 out of 3852) in placebo

● Over 90% of these events in both groups occurred more than a month Over 90% of these events in both groups occurred more than a month after the infusionafter the infusion

● In an ECG sub-studyIn an ECG sub-study• ECG measurements were performed on a subset of 559 patients ECG measurements were performed on a subset of 559 patients

before and 9 to 11 days after treatmentbefore and 9 to 11 days after treatment• There was no difference in the incidence of atrial fibrillation between There was no difference in the incidence of atrial fibrillation between

treatment groups suggesting these events were not related to the treatment groups suggesting these events were not related to the acute infusionsacute infusions

Atrial FibrillationAtrial Fibrillation

► November 12November 12th th 2008, FDA reported that there is 2008, FDA reported that there is no clear association with bisphosphonate use no clear association with bisphosphonate use and atrial fibrillation based on reviews from 4 and atrial fibrillation based on reviews from 4 pharmaceutical sponsor’s placebo controlled pharmaceutical sponsor’s placebo controlled clinical trial’s data. clinical trial’s data.

► This evaluation included19,687bisphosphonate This evaluation included19,687bisphosphonate treated patients and 18,358 placebo treated treated patients and 18,358 placebo treated patients.patients.

FLEX-Lumbar Spine BMD FLEX-Lumbar Spine BMD Changes From FIT Baseline (mITT Changes From FIT Baseline (mITT))

0

2

4

6

8

10

12

14

16

0 12 24 36 48 60 72 84 96 108 120

Mean Percent Change ( SE) in Lumbar Spine BMDFrom Original FIT Baseline

P<0.001 ALN/ALN vs ALN/PBO.

Me

an

Pe

rce

nt

Ch

an

ge

Me

an

Pe

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nt

Ch

an

ge

MonthMonth

= ALN/Placebo= ALN/Placebo

= ALN/ALN (Pooled 5 mg and 10 mg groups)= ALN/ALN (Pooled 5 mg and 10 mg groups)

FLEX-Total Hip BMD FLEX-Total Hip BMD Changes From FIT Baseline (mITT)Changes From FIT Baseline (mITT)

–1

0

1

2

3

4

5

0 12 24 36 48 60 72 84 96 108 120

Me

an

Pe

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nt

Ch

an

ge

Me

an

Pe

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nt

Ch

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MonthMonthPP<0.001 ALN/ALN vs ALN/PBO.<0.001 ALN/ALN vs ALN/PBO.

Mean Percent Change ( SE) in Total Hip BMDFrom Original FIT Baseline

= ALN/Placebo= ALN/Placebo

= ALN/ALN (Pooled 5 mg and 10 mg groups)= ALN/ALN (Pooled 5 mg and 10 mg groups)

Drug Holiday:Fractures (Exploratory) Drug Holiday:Fractures (Exploratory) Cumulative Incidence During FLEXCumulative Incidence During FLEX

N (%)ALN/PBO (N =

437)ALN/ALN (N =

662)

Any clinical (symptomatic)

93 (21.9) 132 (20.6)

Clinical non-vertebral 83 (19.6) 125 (19.5)

Hip 12 (2.9) 20 (3.1)

Forearm 19 (4.5) 31 (4.9)

Clinical vertebral 23 (5.4) 16 (2.5)*

Morphometric vertebral 46 (11.3) 60 (9.8)

*P=0.011 vs ALNPBO. **P=0.006 vs ALN/PBO.

Atypical Fractures in Pts on Long Term Atypical Fractures in Pts on Long Term BisphosphonatesBisphosphonates

► Odvina et al ;Spontaneous non Vert Fractures with severely suppressed Odvina et al ;Spontaneous non Vert Fractures with severely suppressed bone turnover.bone turnover.

► Lane et al Association of long term BP use and “insufficiency” fractures of Lane et al Association of long term BP use and “insufficiency” fractures of the femur Retrospective case control study: X-ray pattern shows transverse the femur Retrospective case control study: X-ray pattern shows transverse fracture sub trochanteric in areas of thickened cortices. OR = 4.4 and Xray fracture sub trochanteric in areas of thickened cortices. OR = 4.4 and Xray association OR =15.3.association OR =15.3.

► Solomon et al : BP use and non union of humeral fractures. ( 91-365 days Solomon et al : BP use and non union of humeral fractures. ( 91-365 days post Fx). OR =2.37.post Fx). OR =2.37.

Cause and effect ??Cause and effect ??

Association??/Association??/

Possible etiologiesPossible etiologies

Identification of those at riskIdentification of those at risk

Practice changePractice change

Bisphosphonates and Multinucleated Bisphosphonates and Multinucleated Osteoclasts (Oc’s)Osteoclasts (Oc’s)

► Retrospective bone biopsy study from 51 Retrospective bone biopsy study from 51 specimens. Patients on 10mg alendronate for specimens. Patients on 10mg alendronate for years.years.

► Giant hypernucleated Oc’s which have Giant hypernucleated Oc’s which have prolonged apoptosis (27%)prolonged apoptosis (27%)

► Osteoclast count Osteoclast count increased increased 2.6x vs placebo. 2.6x vs placebo. ► BMD increased on Rx 3-4%.BMD increased on Rx 3-4%.► Normal Oc’s may be poor bone resorbers.Normal Oc’s may be poor bone resorbers.► Giant Oc’s compensatory response???Giant Oc’s compensatory response???

Weinstein et al. NEJM Jan 2009

► OsteoarthritisOsteoarthritis22

► Falls/neuromuscular functionFalls/neuromuscular function33

► Multiple sclerosisMultiple sclerosis44

► FibromyalgiaFibromyalgia55

► Type I diabetesType I diabetes66

► Cardiovascular diseaseCardiovascular disease66

► Periodontal diseasePeriodontal disease77

► Cancers: Breast prostateCancers: Breast prostate

Other Disease States: Other Disease States:

1.1. Women to women. Available at: www.womentowomen.com. Accessed July 6, 2005. Women to women. Available at: www.womentowomen.com. Accessed July 6, 2005.

22. Lane NE et al. . Lane NE et al. Arthritis RheumArthritis Rheum. 1999;42:854–860.. 1999;42:854–860.

3.3. Bischoff-Ferrari HA et al. Bischoff-Ferrari HA et al. JAMA.JAMA. 2004;291:1999–2006. 2004;291:1999–2006.

4.4. Munger KL et al. Munger KL et al. NeurologyNeurology. 2004;62:60–65. . 2004;62:60–65.

5.5. Plotnikoff GA et al. Plotnikoff GA et al. Mayo Clin ProcMayo Clin Proc. 2003;78:1463–1470.. 2003;78:1463–1470.

6.6. Holick MF. Holick MF. Am J Clin NutrAm J Clin Nutr. 2004;79:362–371.. 2004;79:362–371.

7.7. Dietrich T et al. Dietrich T et al. Am J Clin NutrAm J Clin Nutr . 2004;80:108–113. . 2004;80:108–113.

Role of Vitamin DRole of Vitamin D: :

25Hydroxy Vitamin D and Risk of 25Hydroxy Vitamin D and Risk of Myocardial Infarction in Men Myocardial Infarction in Men

► Men deficient in Vit D < 15ng/ml had a 2.09 Men deficient in Vit D < 15ng/ml had a 2.09 increased relative risk than those >30ng/ml increased relative risk than those >30ng/ml for MI.for MI.

► Men with intermediate levels 22.6 -29.9 ng/ml Men with intermediate levels 22.6 -29.9 ng/ml had an increased relative risk of 1.60 for MI.had an increased relative risk of 1.60 for MI.

► Men with levels of 15.1- 22.5 ng/ml had an Men with levels of 15.1- 22.5 ng/ml had an increased relative risk of 1.43 for MI.increased relative risk of 1.43 for MI.

Giovannucci E et al Arch Intern Med 168,1174-1180 2008Giovannucci E et al Arch Intern Med 168,1174-1180 2008

Independent Association of Low Serum 25 Hydroxy Vitamin Independent Association of Low Serum 25 Hydroxy Vitamin D levels with All-Cause and Cardiovascular MortalityD levels with All-Cause and Cardiovascular Mortality

► 3258 male and female patients scheduled for coronary 3258 male and female patients scheduled for coronary angiography angiography

► 25 OH D, and 1,25 OH 2 D levels measured as quartiles 25 OH D, and 1,25 OH 2 D levels measured as quartiles over a mean of 7.7yrs.over a mean of 7.7yrs.

► All cause mortality at 7.6 and 13.3 ngs/ml = 2-1.6 x All cause mortality at 7.6 and 13.3 ngs/ml = 2-1.6 x higher respectively. Similar for CV mortality. Both higher respectively. Similar for CV mortality. Both compared to mean 28.4ng/ml.compared to mean 28.4ng/ml.

► Similar results occurred with the lowest 1.25OHD 2 Similar results occurred with the lowest 1.25OHD 2 quartile.quartile.

Dobnig et al. Arch Intern Med 168,12: 1340 – 1349 2008Dobnig et al. Arch Intern Med 168,12: 1340 – 1349 2008

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