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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
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ImpactImpact
Chronic painChronic pain
Height lossHeight loss
KyphosisKyphosis Decreased self-Decreased self-
esteemesteem
Restrictive lung dxRestrictive lung dx
Constipation,Constipation,
abdominal painabdominal pain
DepressionDepression
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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
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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)
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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
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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
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Graphic used with permission from The 2004 Surgeon General’s Report on Bone Health and Osteoporosis: What It Means To You.
Bone Growth Overtime
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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
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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
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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
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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
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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
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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
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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
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NATIONAL OSTEOPOROSISNATIONAL OSTEOPOROSIS
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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.
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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
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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!
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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)
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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))
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RALOXIFENERALOXIFENE
::
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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
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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.
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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)
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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
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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
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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
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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
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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
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IBANDRONATEIBANDRONATE
Meta anal sis comparesMeta analysis compares
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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
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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
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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
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Zoledronic acidZoledronic acid
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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
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HORIZON TRIALHORIZON TRIAL
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OSTEOPOROSIS TREATMENT INOSTEOPOROSIS TREATMENT IN
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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%
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TERIPERITIDETERIPERITIDE
I i PTH d i i i
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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)
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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
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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
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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
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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
OSTEOPOROSIS TREATMENT INOSTEOPOROSIS TREATMENT IN
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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 fx reductionNo hip fx reduction
• Zolendronic :Zolendronic : spine fxspine fx ≅≅ 65%;65%; hip fxhip fx ≅≅ 40%40%
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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
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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
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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
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““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.
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Future Treatment and PreventionFuture Treatment and Prevention
of Osteoporosis and Fractures:of Osteoporosis and Fractures:
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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
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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
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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.
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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.