PSR talk final

8/7/2019 PSR talk final

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UPDATE ONUPDATE ON

OSTEOPOROSISOSTEOPOROSIS

DR. SALIHA ISHAQ, MBBS, MD.DR. SALIHA ISHAQ, MBBS, MD.American Board of Internal Medicine & Rheumatology.American Board of Internal Medicine & Rheumatology.

Assistant ProfessorAssistant Professor

Department of MedicineDepartment of MedicineAga Khan University HospitalAga Khan University Hospital







ImpactImpact

Chronic painChronic pain

Height lossHeight loss

KyphosisKyphosis Decreased self-Decreased self-

esteemesteem

Restrictive lung dxRestrictive lung dx

Constipation,Constipation,

abdominal painabdominal pain

DepressionDepression



Osteoporosis Is a Chronic,Osteoporosis Is a Chronic,

Progressive Disease withProgressive Disease with

Potentially SeriousPotentially Serious

ConsequencesConsequences Women withWomen with

postmenopausalpostmenopausalosteoporosis canosteoporosis can

have fractures withhave fractures withminimal traumaminimal trauma11

– 1 in 2 women > 50 will1 in 2 women > 50 willexperience an osteoporoticexperience an osteoporoticfracture in their remainingfracture in their remaininglifetimelifetime22

– In 2005, incidence of In 2005, incidence of osteoporotic fractures in womenosteoporotic fractures in women≥≥ 50 was more than 1.4 million50 was more than 1.4 million33

– 1 in 5 patients who have a1 in 5 patients who have ahip fracture will die within ahip fracture will die within ayearyear44

Image courtesy of Geoffrey B. Higgs, MD.1. National Osteoporosis Foundation. Clinician’s Guide to Prevention and Treatment of Osteoporosis. 20082. US Department of Health and Human Services. Bone Health and Osteoporosis: A Report of the Surgeon General. 2004.3. Burge R, et al. J Bone Miner Res. 2007;22:465-475.4. Johnell O, et al. Osteoporos Int . 2004;15:38-42.5



4 of 45



Risk Factors forRisk Factors for

OsteoporosisOsteoporosisNon-modifiableNon-modifiable

AgeAge Race (Caucasian, Asian)Race (Caucasian, Asian)

Female genderFemale gender Early menopause (<45Early menopause (<45

y/o)y/o) Slender build (<127 lbs)Slender build (<127 lbs) Positive family historyPositive family history

ModifiableModifiable Low calcium intakeLow calcium intake Low vitamin D intakeLow vitamin D intake Estrogen/androgenEstrogen/androgen

deficiencydeficiency Sedentary lifestyleSedentary lifestyle Cigarette smokingCigarette smoking Alcohol excess (>2Alcohol excess (>2

drinks/day)drinks/day) Caffeine excess (>Caffeine excess (>

cups/day)cups/day) MedicationsMedications

(glucocorticoids,(glucocorticoids,anticonvulsants,excessanticonvulsants,excessthyroxine)thyroxine)



ClassificationClassification PrimaryPrimaryPostmenopausalPostmenopausal

Decreased estrogen results in increased osteoclasticDecreased estrogen results in increased osteoclastic

activity without increased osteoblastic activityactivity without increased osteoblastic activity Bone loss – 2-3% per year of total bone mass (over aBone loss – 2-3% per year of total bone mass (over a

life time a women may loose up to 40% of her peaklife time a women may loose up to 40% of her peakbone mass.)bone mass.)

Most common fx: vertebral, distal forearmMost common fx: vertebral, distal forearm

Age relatedAge related – 3– 3rdrd decade of life starts slowdecade of life starts slowdecline in bone mass at rate of 0.5-1% per yeardecline in bone mass at rate of 0.5-1% per year Most common types of fx: hip and radiusMost common types of fx: hip and radius F>MF>M

8



Menopause

Bone Mass in WomenBone Mass in Women

Over the LifecycleOver the Lifecycle

PercentPe

akBon

eMass

Age (years)10 20 40 50 60 70 8030

Attainment of peak bone mass

0

80

60

40

20

Formation > Resorption

Peak bone mass

100

Resorption > Formation

Bone loss

9



Graphic used with permission from The 2004 Surgeon General’s Report on Bone Health and Osteoporosis: What It Means To You.

Bone Growth Overtime



Secondary OsteoporosisSecondary Osteoporosis

Disease statesDisease states

AcromegalyAcromegaly Addison’s diseaseAddison’s disease AmyloidosisAmyloidosis AnorexiaAnorexia COPDCOPD HemochromatosisHemochromatosis HyperparathyroidismHyperparathyroidism Lymphoma andLymphoma and

leukemialeukemia Malabsorption statesMalabsorption states

(Celiac sprue)(Celiac sprue)

Multiple myelomaMultiple myeloma

Multiple sclerosisMultiple sclerosis

RheumatoidRheumatoidarthritisarthritis

SarcoidosisSarcoidosis

Severe liver dz,Severe liver dz,

esp. PBCesp. PBC ThalessemiaThalessemia

ThyrotoxicosisThyrotoxicosis

11



yOsteoporosisOsteoporosis

DrugsDrugs AluminumAluminum

AnticonvulsantsAnticonvulsants

Excessive alcohol)Excessive alcohol)

(more than 3 units a(more than 3 units a

day)day)

Excessive thyroxineExcessive thyroxine

Depo ProveraDepo Provera

(decreased bone mass(decreased bone massreversible afterreversible after

stopping medication)stopping medication)

GlucocorticoidsGlucocorticoids

GnRH agonistsGnRH agonists

HeparinHeparin LithiumLithium

12



World Health OrganizationWorld Health Organization

(WHO) Definition(WHO) Definition

Based on BMD testingBased on BMD testing

Normal: T score above –1Normal: T score above –1

Osteopenia: T score between –1 and –2.5Osteopenia: T score between –1 and –2.5

Osteoporosis: T score at or below –2.5Osteoporosis: T score at or below –2.5

Severe osteoporosisSevere osteoporosis:: T score –2.5 orT score –2.5 orlower in the presence of 1 or morelower in the presence of 1 or morefracturesfractures

13



Types of BMD testingTypes of BMD testing

Dual –energy x-ray absorptiometryDual –energy x-ray absorptiometry (DXA or DEXA).(DXA or DEXA).

Gold StandardGold Standard

Measures BMD in spine, hip, or wristMeasures BMD in spine, hip, or wrist

Completed in a few minutesCompleted in a few minutes

Radiation exposure less than 1/10 of standard x-rayRadiation exposure less than 1/10 of standard x-ray Ultrasound densitometryUltrasound densitometry No radiatiation exposureNo radiatiation exposure

Measures BMD in heel, patellaMeasures BMD in heel, patella

Cost-effectiveCost-effective

Poor correlation between US and DXAPoor correlation between US and DXA

Inconsistent young normal reference populations may contributeInconsistent young normal reference populations may contribute

Single-energy x-ray absorptiometry and peripheral dual x-raySingle-energy x-ray absorptiometry and peripheral dual x-ray Quantitative computed tomography (QCT)Quantitative computed tomography (QCT) Radiographic absorptiometryRadiographic absorptiometry

14



testtest

National OsteoporosisNational Osteoporosis

Foundation (NOF) GuidelinesFoundation (NOF) Guidelines

All postmenopausal women under age 65 whoAll postmenopausal women under age 65 whohave one or more additional risk factors forhave one or more additional risk factors for

osteoporotic fx (besides menopause)osteoporotic fx (besides menopause)

All woman aged 65 and older regardless of All woman aged 65 and older regardless of additional risk factorsadditional risk factors

Postmenopausal women who present withPostmenopausal women who present withfracturesfractures

All men above the age of 70All men above the age of 70

15



PTH analog

Available Medications forAvailable Medications for

PostmenopausalPostmenopausal

OsteoporosisOsteoporosis

Oral bisphosphonates are the most commonly usedpharmacologic agents for osteoporosis management2

Oral and IVBisphosphonates

Anabolic Agent1

EstrogenAgonist/Antagonist

Estrogen*

Calcitonin

*Indicated for prevention only; PTH = parathyroid hormone1. National Osteoporosis Foundation. Clinician’s Guide to Prevention and Treatment of Osteoporosis. 2008.2. IMS Health NSP Data. Analysis of PMO product basket. January 2009.

Antiresorptive Agents1

16



TreatmentTreatment

Preventive MeasuresPreventive Measures CalciumCalcium Vitamin D (400-800 IU)Vitamin D (400-800 IU) Regular weight bearingRegular weight bearing

exerciseexercise Weight lifting, salsaWeight lifting, salsa

dancing, walking, jogging,dancing, walking, jogging,tennistennis

Smoking cessationSmoking cessation Minimize alcohol intakeMinimize alcohol intake

Fall prevention esp forFall prevention esp forelderlyelderly

17

NATIONAL OSTEOPOROSISNATIONAL OSTEOPOROSIS



NATIONAL OSTEOPOROSISNATIONAL OSTEOPOROSIS

FOUNDATION:FOUNDATION:

UPDATED RECOMMENDATIONSUPDATED RECOMMENDATIONS

Recommended Intake for Adults ≥50 YearsRecommended Intake for Adults ≥50 Years

CalciumCalcium

(mg/day)(mg/day)

Vitamin DVitamin D33

(IU/day)(IU/day)

Previous (2003)Previous (2003) 12001200 400–800400–800

Current updateCurrent update 12001200 800–1000800–1000

“NOF revised its recommendations after careful consideration and review of a growing body of evidence that calcium and vitamin D3 deficiency is widespread throughout the world as well as in

the US, particularly in adults 50 and older.”

NOF Scientific Statement, Revised October 2008

Adapted from National Osteoporosis Foundation. Physician’s Guide to Prevention and Treatment of Osteoporosis. National Osteoporosis Foundation, 2003; National OsteoporosisFoundation. National Osteoporosis Foundation’s updated recommendations for calcium andvitamin D intake. Available at: www.nof.org/prevention/calcium_and_VitaminD.htm. Accessed 26 January 2009.





Number of patientsNumber of patients 12551255 : Most patients had 1–5 Vertebral Fx at baseline (n = 926 of 1: Most patients had 1–5 Vertebral Fx at baseline (n = 926 of 1

378 actually completed the study378 actually completed the study

Mean AgeMean Age 68 (postmenopausal)68 (postmenopausal)

Study DesignStudy Design 5 year, randomized, double-blind, placebo-controlled5 year, randomized, double-blind, placebo-controlled

DrugDrug Placebo (n = 311), 100 IU (n = 316), 200 IUPlacebo (n = 311), 100 IU (n = 316), 200 IU(n = 316, marketed dose) or 400 IU (n = 312) Calcitonin(n = 316, marketed dose) or 400 IU (n = 312) Calcitonin

Calcium/Vitamin DCalcium/Vitamin D 1000 mg/400 IU daily1000 mg/400 IU daily

% with Prevalent VFx% with Prevalent VFx 79%79%

Primary EndpointPrimary Endpoint Spine BMD and new VFX in patients withSpine BMD and new VFX in patients withlow bone mass (T < –2.0) and 1–5 new VFXlow bone mass (T < –2.0) and 1–5 new VFX

CALCITONIN NASAL SPRAY THERAPYCALCITONIN NASAL SPRAY THERAPYPREVENT RECURRENCE OF OSTEOPOROTICPREVENT RECURRENCE OF OSTEOPOROTIC

FRACTURES(PROOF)FRACTURES(PROOF)

Chesnut et al: AJM 2000, Vol 109, 267-276Chesnut et al: AJM 2000, Vol 109, 267-276



PROOFPROOFEFFECT OF NASAL CALCITONIN ON RISK OFEFFECT OF NASAL CALCITONIN ON RISK OF

VERTEBRAL FRACTURESVERTEBRAL FRACTURES

Women withWomen withDecreased Decreased DoseDose new fracturesnew fractures risk risk p<0.05?p<0.05?

PlaceboPlacebo 26%26% --100 IU100 IU 22%22% 15%15% NoNo

200 IU200 IU 18%18% 33%33% YesYes

400 IU400 IU 22%22% 16%16% NoNo

Chesnut et al: AJM 2000, Vol 109, 267-276Chesnut et al: AJM 2000, Vol 109, 267-276

Lost 59% of participants to follow-up!Lost 59% of participants to follow-up!



TreatmentTreatment

Estrogen Replacement TherapyEstrogen Replacement Therapy

(ERT)(ERT)

IndicationIndication: Used to prevent and treat: Used to prevent and treat

osteoporosis (FDA indication is for prevention)osteoporosis (FDA indication is for prevention)

Mechanism:Mechanism: Decreases osteoclast activityDecreases osteoclast activity DoseDose: Estrogen: 0.625mg qd, 0.3mg offers bone: Estrogen: 0.625mg qd, 0.3mg offers bone

protection as well; Progesterone 2.5mg qd (if protection as well; Progesterone 2.5mg qd (if

uterus present)uterus present)



HRTHRT

AdvantagesAdvantages Increases boneIncreases bone

density (1-5%) anddensity (1-5%) anddecreases risk of decreases risk of fracture (25%)fracture (25%)

Relief of hot flashes,Relief of hot flashes,vaginal drynessvaginal dryness

Decreases LDL,Decreases LDL,

increases HDLincreases HDL ?Prevention of ?Prevention of

Alzheimer’s diseaseAlzheimer’s disease RelativelyRelatively

inexpensiveinexpensive

DisadvantagesDisadvantages

Accelerated bone loss afterAccelerated bone loss afterstoppingstopping

Increased risk of uterine caIncreased risk of uterine ca(if unopposed)(if unopposed)

Increased risk of Increased risk of thromboembolic eventsthromboembolic events

Possible increased risk of Possible increased risk of breast cancerbreast cancer

Side effects: breastSide effects: breasttenderness, breakthroughtenderness, breakthroughbleedingbleeding

Increased risk of Increased risk of coronary events incoronary events inwomen with known CADwomen with known CADin first year of usein first year of use(HERS trial(HERS trial))



RALOXIFENERALOXIFENE

::



Number of PatientsNumber of Patients 7705 patients (2 subgroups)7705 patients (2 subgroups)

Substudy 1 = 5064 with hip or spine T-scoreSubstudy 1 = 5064 with hip or spine T-score ≤≤ –2.5 Substudy 2 =–2.5 Substudy 2 =2641 with prior VFX2641 with prior VFX

Mean AgeMean Age 67 (postmenopausal)67 (postmenopausal)

Mean FN T-ScoreMean FN T-Score -3.2 SDs-3.2 SDs

Study DesignStudy Design 3 year, randomized, double-blind, placebo-controlled3 year, randomized, double-blind, placebo-controlled

DrugDrug 60 mg (marketed dose) or 120 mg raloxifene60 mg (marketed dose) or 120 mg raloxifene

Calcium/Vitamin DCalcium/Vitamin D 500 mg/400 IU daily500 mg/400 IU daily

Primary EndpointPrimary Endpoint VFX and non-VFX in patients with low bone mass (T-score < –2.5)VFX and non-VFX in patients with low bone mass (T-score < –2.5)or radiographic VFXor radiographic VFX

::RALOXIFENERALOXIFENE

MULTIPLE OUTCOMES OF RALOXIFENE EVALUATIONMULTIPLE OUTCOMES OF RALOXIFENE EVALUATION

((

MORE)MORE)

JAMA, August 18, 1999--Vol 282, No. 7, pp 637-645



Effect of Raloxifene in Women withEffect of Raloxifene in Women with

or Without Pre-Existing Fracturesor Without Pre-Existing Fractures

MORE Trial3 YearsMORE Trial3 Years

%ofWomenw

ith

Inciden

tVertebralF

r actures

Raloxifene 60 mg/d

Placebo

Without Pre-ExistingVertebral Fracture

RR 0.5a

(95% CI = 0.3–0.7)

With Pre-ExistingVertebral Fracture

RR 0.7a

(95% CI = 0.6–0.9)

30%

55%

0

5

10

15

20

25

With permission from Ettinger B, et al. JAMA. 1999;282:637-645.

aWomen who completed the study and had evaluable radiographs at 36 months.



Available Bisphosphonates forAvailable Bisphosphonates for

Osteoporosis FDA ApprovedOsteoporosis FDA Approved

OralOral

– AlendronateAlendronate (daily, weekly)(daily, weekly)– RisedronateRisedronate (daily, weekly, monthly)(daily, weekly, monthly)

– IbandronateIbandronate (daily, monthly)(daily, monthly)

IntravenousIntravenous– IbandronateIbandronate (quarterly)(quarterly)

– Zoledronic acidZoledronic acid (annual)(annual)

Off-labelOff-label– PamidronatePamidronate (IV quarterly)(IV quarterly)



ALENDRONATEALENDRONATE



THE FRACTURE INTERVENTIONTHE FRACTURE INTERVENTION

TRIAL (FIT):TRIAL (FIT):

A LANDMARK STUDY IN OSTEOPOROSISA LANDMARK STUDY IN OSTEOPOROSIS

FirstFirst comprehensive fracture studycomprehensive fracture study in postmenopausal women within postmenopausal women with

bone massbone mass

(T < -1.6): with and without existing vertebral fracture(T < -1.6): with and without existing vertebral fracture

Specifically designed to investigate the effect of alendronate on theSpecifically designed to investigate the effect of alendronate on the

reduction in the risk of fractures:reduction in the risk of fractures:

– vertebral (symptomatic and morphometric)vertebral (symptomatic and morphometric)

– any symptomaticany symptomatic– any non-vertebralany non-vertebral

– hiphip

– forearmforearm

FIT = Fracture Intervention Trial.

aSignificant cumulative difference from placebo (P <0.05).

Adapted from Black DM, et al. J Clin Endocrinol Metab. 2000;85:4118–4124..

EVIDENCE OF EARLY EFFICACY ATEVIDENCE OF EARLY EFFICACY AT



N = 3658

Age = 55 to 80 years

Patients with preexisting

VFx’s or FN BMD

T-score < –2.5 at baseline

J Bone Miner Res. 1999 Supplement.

EVIDENCE OF EARLY EFFICACY ATEVIDENCE OF EARLY EFFICACY AT

THE SPINETHE SPINE

ALENDRONATEALENDRONATE: FRACTURE INTERVENTION TRIAL: FRACTURE INTERVENTION TRIAL

COMBINED ANALYSISCOMBINED ANALYSIS11

Clinical (Symptomatic) Vertebral Fractures

12 18 24 30 36600

1

2

3

4

Months

%

ofP

atientsw

ithFracture

PBO (n = 1817)

ALN 5/10 mg (n = 1841)

59%

Reduction

§

§

§

§§

§ P < 0.030



FIT TRIAL - Summary of FIT TRIAL - Summary of

Fracture ResultsFracture ResultsType of fractureType of fracture % incidence% incidence

P valueP value

reductionreduction

At least one newAt least one new

vertebral fracturevertebral fracture 4747

<0.001<0.001

Multiple (Multiple (>>2) new2) newvertebral fracturesvertebral fractures 9090

<0.001<0.001

Clinical (symptomatic)Clinical (symptomatic)

vertebral fracturevertebral fracture 5555

<0.001<0.001Lancet, 348, 1996



ALENDRONATE PROVIDED SUSTAINED

IMPROVEMENT IN BMD OVER 10 YEARS

BMD = bone mineral density.

Adapted from Bone HG, et al. N Engl J Med. 2004;350:1189–1199.

FOSAMAX™ (alendronate) is a trademark of Merck & Co., Inc., Whitehouse Station, NJ, USA.

0

2

4

6

8

10

12

14

Spine 13.7%

(P <0.001)

M

ean

(±SE)%Chang

e

0

Year

1 2 3 4 5 6 7 8 9 10

Total Hip 6.7%

(P <0.001)

Hip Trochanter 10.3%

(P <0.001)

n=196 n=151 n=122 n=86

Alendronate10 mg daily



RESIDRONATERESIDRONATE





Year 1Year 1

Year 2Year 2

Year 3Year 3

110.750.750.50.50.250.25

65%

55%

41%

New Morphometric Vertebral FracturesRisedronate USPI

Harris ST, et al. JAMA 1999;282:1344–52

Antifracture efficacy of RisedronatAntifracture efficacy of Risedronate

over timeover time



IBANDRONATEIBANDRONATE

Meta anal sis comparesMeta analysis compares



Lower dose

Meta-analysis comparesMeta-analysis compares

dosedose

groups defined by ACE*groups defined by ACE*Higher doses

Monthly oral†

150mg

Quarterly IV 3mg

Daily oral† 2.5mg

Bimonthly i.v. 2mg

NOT LICENSED

*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%1

1Barrett J, et al. J Clin Pharmacol 2004;44:951–65

(ACE 10.8–12mg) (ACE 5.5mg)

compared

with

D ilD il ib d tib d t



DailyDaily ibandronateibandronate

reduces vertebralreduces vertebral

fracture riskfracture risk

Placebo Daily

ibandronate

10

8

6

4

2

0

Fractur e

rate

at3ye

ars(%)

Chesnut CH, et al. J Bone Miner Res 2004;19:1241–9

62% RRR

(p=0.0001vs placebo)

Fast and consistentFast and consistent



Year 1Year 1

Year 2Year 2

Year 3Year 3

110.750.750.50.50.250.25

58%

61%

62%

Fast and consistentFast and consistent

efficacy of Ibandronateefficacy of Ibandronate

over timeover time

Relative risk 95% CI for new vertebral fractures



Zoledronic acidZoledronic acid



Zoledronic acid /HorizonZoledronic acid /Horizon

trialtrial

In a 3 year trial ,once yearly treatment reducedIn a 3 year trial ,once yearly treatment reduced

– Risk of vertebral fractures by 70% compared withRisk of vertebral fractures by 70% compared with

placeboplacebo– Risk of hip fracture 41%compared with placeboRisk of hip fracture 41%compared with placebo

– Bone mineral density increased by 7% at spineBone mineral density increased by 7% at spine

– -Total hip Bone density increased by about 5.1%-Total hip Bone density increased by about 5.1%

– All three biochemical markers of bone turnoverAll three biochemical markers of bone turnover

decreased significantly as compared with thedecreased significantly as compared with the

placebo groupplacebo group



HORIZON TRIALHORIZON TRIAL



OSTEOPOROSIS TREATMENT INOSTEOPOROSIS TREATMENT IN




20092009

SUMMARYSUMMARY

• HRT:HRT: no prospective fracture datano prospective fracture data

• SERMS:SERMS: spine fx;spine fx; NoNo effect on peripheral fxeffect on peripheral fx

• Calcitonin:Calcitonin: possiblepossible

spine fx;spine fx; NoNo hip datahip data• Vitamin D analogues:Vitamin D analogues: possiblepossible spine fx;spine fx; NoNo hip datahip data

• Alendronate:Alendronate: spine fxspine fx ≅≅ 50%;50%; hip fxhip fx ≅≅ 50%50%

• Risedronate:Risedronate: spine fxspine fx ≅≅ 50%;50%; hip fxhip fx ≅≅ 30%30%

• Ibandronate:Ibandronate: spine fxspine fx ≅≅ 50%;50%; hip fxhip fx ≅≅ No hip fxNo hip fx

reductionreduction• Zolendronic :Zolendronic : spine fxspine fx ≅≅ 70;70; hip fxhip fx ≅≅ 40%40%



TERIPERITIDETERIPERITIDE

I i PTH d i i i



Intermittent PTH administrationIntermittent PTH administration

increased vertebral and femoralincreased vertebral and femoral

bone densitybone density

PTH (2 0 µg) PTH (40 µg)

Spine . %9 7 . %1 3 7

Hip . %2 8 . %5 1

Percent change from baseline over a 19 monthPercent change from baseline over a 19 monthfollowup period (length of randomization)followup period (length of randomization)



Basic Lab Tests BeforeBasic Lab Tests Before

Starting TeriparatideStarting Teriparatide

Serum calciumSerum calcium

Alkaline phosphataseAlkaline phosphatase

25 hydroxy-vitamin D25 hydroxy-vitamin D

PTHPTH

Serum creatinineSerum creatinine

Miller PD, et al. Endocrine Practice. 2004;10:139–148.

Decrease in the risk ofDecrease in the risk of



Decrease in the risk of Decrease in the risk of vertebral and non vertebralvertebral and non vertebral

fracturesfractures

Significant risk reduction of new vertebral fractures (vsSignificant risk reduction of new vertebral fractures (vs

placebo)placebo)

Significant risk reduction of new non vertebral fracturesSignificant risk reduction of new non vertebral fractures

PTH(2 0 µg)

PTH(4 0 µg)

One or more

new vertebral

fracture

%6 5 %6 9

Non vertebral

fractures%35 %4 0



Effect of Teriparatide on Risk of Effect of Teriparatide on Risk of

Vertebral Fractures inVertebral Fractures in

Postmenopausal WomenPostmenopausal Women

0

2

4

6

8

10

12

14

16

Placebo Teriparatide 20 µg

%ofP

atientsw

ith≥1F

racture

RR 0.35 (95% CI = 0.22–0.55)a

65%↓

aP <.001 vs placebo.

Neer RM, et al. N Engl J Med. 2001;344:1434-1441.Graphic courtesy of Dr. Paul Miller.

FDA-APPROVEDFDA-APPROVED



FDA APPROVEDFDA APPROVED

MEDICATIONSMEDICATIONSINDICATIONSINDICATIONS

PostmenopausalPostmenopausalOsteoporosisOsteoporosis

Glucocorticoid-inducedGlucocorticoid-inducedOsteoporosisOsteoporosis

MenMen

DrugDrug PreventionPrevention TreatmentTreatment PreventionPrevention TreatmentTreatment

EstrogenEstrogen

CalcitoninCalcitonin(Miacalcin®, Fortical®)(Miacalcin®, Fortical®)

RaloxifeneRaloxifene

(Evista®)(Evista®)

IbandronateIbandronate

(Boniva®)(Boniva®)

AlendronateAlendronate(Fosamax®)(Fosamax®)

RisedronateRisedronate

(Actonel®)(Actonel®)

Zoledronic acidZoledronic acid

(Reclast®)(Reclast®)

TeriparatideTeriparatide

(Forteo®)(Forteo®)

www.fda.gov





20092009

SUMMARYSUMMARY

• HRT:HRT: no prospective fracture datano prospective fracture data

• SERMS:SERMS: spine fx;spine fx; NoNo effect on peripheral fxeffect on peripheral fx

• Calcitonin:Calcitonin: possiblepossible spine fx;spine fx; NoNo hip datahip data

• Vitamin D analogues:Vitamin D analogues: possiblepossible spine fx;spine fx; NoNo hip datahip data

• Alendronate:Alendronate: spine fxspine fx ≅≅ 50%;50%; hip fxhip fx ≅≅ 50%50%

• Risedronate:Risedronate: spine fxspine fx ≅≅ 50%;50%; hip fxhip fx ≅≅ 30%30%

• Ibandronate:Ibandronate: spine fxspine fx ≅≅ 50%;50%; hip fxhip fx ≅≅ No hip fx reductionNo hip fx reduction

• Zolendronic :Zolendronic : spine fxspine fx ≅≅ 65%;65%; hip fxhip fx ≅≅ 40%40%



Indications for IV - 1Indications for IV - 1

Inability to take oral bisphosphonateInability to take oral bisphosphonate

– Can’t swallow tabletsCan’t swallow tablets

– Poor compliance with dosing instructionsPoor compliance with dosing instructions

– Poor adherence/persistence in generalPoor adherence/persistence in general

– Cognitive impairmentCognitive impairment

Patient preferencePatient preference

Perhaps in context of polypharmacyPerhaps in context of polypharmacy

““Treatment failures”Treatment failures”

– Eg decreasing bone densities and furtherEg decreasing bone densities and further

fracturesfractures



Pro’s and Con’s of Available Osteoporosis Therapies

Agent Pro’s Con’s

Calcium/Vit D Cheap, accessible Partial efficacy

HRT Effective ↑breast ca, ↑DVT, ↑MI, ↑CVA

Raloxifene ↓vert Fx, ↓breast ca Less effect on BMD

Bisphosphonates ↓vert and nonvert Fx GI intolerance

Strontium Bulky, daily dosing ? Mechanism

Teriparatide Effective Expensive, daily injections



For More Information onFor More Information on

OsteoporosisOsteoporosisAmerican Dietetic Association

Phone: (800) 877-1600

Website: www.eatright.org

Michigan Public Health Institute- Osteoporosis Program

Phone: (517) 324-8363 Website:

www.michiganosteoporosisconnection.org

National Osteoporosis Foundation

Phone: (800) 223-9994

Website: www.nof.org

National Dairy Council

Website: www.nationaldairycouncil.org

National Institutes of Health Osteoporosis and Related Bone Disease~National Resource

Center

Phone: (800) 624-2663

Website: www.osteo.org

More information about the Surgeon General’s Report on Bone Health and Osteoporosis is

available on the Surgeon General’s website at: www.surgeongeneral.gov

Oth Ch

http://www.eatright.org/

http://www.michiganosteoporosisconnection.org/

http://www.nof.org/

http://www.nof.org/

http://www.michiganosteoporosisconnection.org/

http://www.eatright.org/



““Fall-proof” your homeFall-proof” your home

Other Changes

Graphic used with permission from The 2004 Surgeon General’s Report on Bone Health and Osteoporosis: What It Means To You.



Future Treatment and PreventionFuture Treatment and Prevention

of Osteoporosis and Fractures:of Osteoporosis and Fractures:



New and EmergingNew and Emerging

TreatmentsTreatments

AntiresorptiveAntiresorptive (anticatabolic)(anticatabolic)

DenosumabDenosumab

OdanacatibOdanacatib

LasofoxifeneLasofoxifene BazedoxifeneBazedoxifene

CE/bazedoxifeneCE/bazedoxifene

New delivery systems –New delivery systems –

oral salmon calcitoninoral salmon calcitonin

Osteo-anabolicOsteo-anabolic (bone-forming)(bone-forming)

Sclerostin inhibitorSclerostin inhibitor Variations of PTHVariations of PTH Endogenous PTH stimulationEndogenous PTH stimulation

– calcium sensing receptor– calcium sensing receptorantagonist (calcilytic)antagonist (calcilytic)

New delivery systems –New delivery systems –transdermal PTHtransdermal PTH

Strontium ranelate

Combinations of antiresorptive and anabolic



Denusomab: ProliaDenusomab: Prolia

Its an anti RankL drug approved by FDA for post menopausalIts an anti RankL drug approved by FDA for post menopausalOsteoporosis.Osteoporosis.

AntiSclerostin:AntiSclerostin:

Sclerostin is produced by Osteocytes of a person who hasSclerostin is produced by Osteocytes of a person who hasinactive lifestyle. It blocks the of Wntinactive lifestyle. It blocks the of Wntββ / Catenin pathway,/ Catenin pathway,so reduced the bone formation. Anti sclerostin is soonso reduced the bone formation. Anti sclerostin is soonavailable for Osteoporosis treatment.available for Osteoporosis treatment.

Anti Cathepsin K: BaticalibAnti Cathepsin K: Baticalib

Cathepsin K is an Enzyme produced by Osteoclast, necessaryCathepsin K is an Enzyme produced by Osteoclast, necessaryfor bone resorption. Anti Cathepsin K is an oral drugfor bone resorption. Anti Cathepsin K is an oral drug



Denosumab (Dmab)Denosumab (Dmab)

Fully human monoclonal antibody-IgGFully human monoclonal antibody-IgG22 isotypeisotype

High affinity and specificity for human RANK ligandHigh affinity and specificity for human RANK ligand Does not bind to TNFα, TNFβ, TRAIL, or CD40LDoes not bind to TNFα, TNFβ, TRAIL, or CD40L Pharmacokinetics (SC): similar to other fully human IgGPharmacokinetics (SC): similar to other fully human IgG

22

monoclonal antibodiesmonoclonal antibodies– Absorption is rapid and prolonged (CAbsorption is rapid and prolonged (Cmaxmax ≈1–4 wks postdose)≈1–4 wks postdose)

– Long half-life ≈34 days with maximum doseLong half-life ≈34 days with maximum dose

– Distribution ≈ intravascular volumeDistribution ≈ intravascular volume

– Clearance ≈ reticuloendothelial systemClearance ≈ reticuloendothelial system

– No kidney filtration or excretion of intact moleculeNo kidney filtration or excretion of intact molecule

Abbreviations: TNF, tumor necrosis factor; TRAIL, TNF-related apoptosis-inducing ligand.

Bekker PJ, et al. J Bone Miner Res. 2004;19:1059-1066. Boyle WJ, et al. Nature. 2003;423:337-342.



New SERMs for PostmenopausalNew SERMs for Postmenopausal

OsteoporosisOsteoporosis

EfficacyEfficacy– Increases BMDIncreases BMD

– Reduces BTMsReduces BTMs

– Decreases risk of VFs and NVFsDecreases risk of VFs and NVFs

– Decreases risk of ER+ breastDecreases risk of ER+ breast

cancercancer– Improves signs and symptomsImproves signs and symptoms

of vulvovaginal atrophyof vulvovaginal atrophy

SafetySafety– Increases risk of venousIncreases risk of venous

thromboembolisms (VTEs), hotthromboembolisms (VTEs), hotflushes, muscle spasm, andflushes, muscle spasm, and

vaginal bleedingvaginal bleeding

EfficacyEfficacy

– Increases BMDIncreases BMD

– Reduces BTMsReduces BTMs

–Decreases risk of VFsDecreases risk of VFs

SafetySafety

– Increases risk of VTEs, hotIncreases risk of VTEs, hot

flushes, muscle crampsflushes, muscle cramps

Cummings SR, et al. J Bone Miner Res. 2008;23:S81. Silverman SL, et al. J Bone Miner Res.

2008;23:1923-1934. Eastell R, et al. J Bone Miner Res. 2008;23:S81.





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