ADVANCES IN DIAGNOSIS & ADVANCES IN DIAGNOSIS & TREATMENT OF TREATMENT OF OSTEOPOROSISOSTEOPOROSIS

Jerry Tenenbaum MD FRCPCJerry Tenenbaum MD FRCPC

Professor of Medicine:University of TorontoProfessor of Medicine:University of Toronto

Mount Sinai HospitalMount Sinai Hospital

DISCLOSURESDISCLOSURES

SPEAKER ON OCCASION FORSPEAKER ON OCCASION FOR

1.1. P&GP&G

2.2. PfizerPfizer

3.3. MerckMerck

4.4. NovartisNovartis

GOALGOAL

Review advances in the diagnosis and Review advances in the diagnosis and treatment of osteoporosistreatment of osteoporosis

OBJECTIVESOBJECTIVES

1.1. Show the impact of osteoporosis on the Show the impact of osteoporosis on the health of the elderlyhealth of the elderly

2.2. Advise on screening and diagnosis of Advise on screening and diagnosis of osteoporosisosteoporosis

3.3. Outline evidence-based treatmentOutline evidence-based treatment

OsteoporosisOsteoporosis

Osteoporosis is defined as a skeletal disorder Osteoporosis is defined as a skeletal disorder characterized by compromised bone strength characterized by compromised bone strength predisposing to an increased risk of predisposing to an increased risk of fracturefracture. . NIH Consensus Development Conference, March 2000NIH Consensus Development Conference, March 2000

Normal Bone Osteoporotic Bone

Vertebral Fracture Cascade

THE HUMAN COSTTHE HUMAN COSTDownward SpiralDownward Spiral

Definition of a Fragility FractureDefinition of a Fragility Fracture

A fragility fracture is one that results A fragility fracture is one that results from mechanical forces that would from mechanical forces that would not ordinarily cause fracture in a not ordinarily cause fracture in a healthy young adult.healthy young adult.

This is quantified as forces This is quantified as forces equivalent to a fall from a standing equivalent to a fall from a standing height or less.height or less.

OsteoporosisOsteoporosis8 million Osteoporotic Women and 2.5 million Osteoporotic Men in USA8 million Osteoporotic Women and 2.5 million Osteoporotic Men in USA

Expected to increase by about 40% by 2020 Expected to increase by about 40% by 2020 11

Estimated Estimated DirectDirect costs in 2001 = $ 11.6 - 17.1 billion annually costs in 2001 = $ 11.6 - 17.1 billion annually 11

Based on relative older Canadian population Based on relative older Canadian population 2 2 &&

Australian estimates of 7:1 ratio for Indirect to direct costs Australian estimates of 7:1 ratio for Indirect to direct costs 33

$6 - $40 million every single day in Canada$6 - $40 million every single day in Canada

Mortality increased 2-3 fold in women and womenMortality increased 2-3 fold in women and women

after all types of Osteoporotic fractures after all types of Osteoporotic fractures 44

1 Surgeon-Generals Report2 Canadian and US census data

3 Access Economics, 4 Center 1999

Prevalence of VCF’sPrevalence of VCF’s

Lifetime prevalence in Caucasians:Lifetime prevalence in Caucasians:15% in women15% in women

5-9% in men5-9% in men

Higher than risk of breast cancerHigher than risk of breast cancer

Osteoporotic fractures, Cardiovascular events & Osteoporotic fractures, Cardiovascular events & Breast cancerBreast cancer

in osteoporotic postmenopausal women in osteoporotic postmenopausal women

Any fracture

Spine #

Clinical S

pine #

Hip fracture

CVS event

Breast

Cancer

No prior spine fracture (938)

Prior spine fracture (1627)0

20

40

60

80

100

120

from Silverman et al, 2004J Am Geriatr Soc 52:1543-8

Eventsper 1000 women-yr

MORE studyplacebo armover 3 years

SITESITE INCREASE IN INCREASE IN MORTALITY RISKMORTALITY RISK

VertebraeVertebrae 8.68.6

HipHip 6.76.7

Any Clinical FractureAny Clinical Fracture 2.22.2

Fracture and Mortality Risk

Each year, one in three Ontarians over the ageof 65 will take a serious tumble that may landthem in hospital with a broken hip. One in threeof those who do break their hip will die withina year. Two thirds will experience dementia-likesymptoms. Most will never see home again.

Osteoporosis-associated Osteoporosis-associated MortalityMortality

Age-standardised mortality riskAge-standardised mortality riskincreased 2-3 foldincreased 2-3 fold

after all types of osteoporotic fractureafter all types of osteoporotic fracture

WomenWomen Men Men

Proximal femur Proximal femur 2.22.2 3.2 3.2

VertebralVertebral 1.71.7 2.4 2.4

Other majorOther major 1.91.9 2.2 2.2

Center et al, Lancet 1999

““THE CARE GAP”THE CARE GAP”IN OSTEOPOROSISIN OSTEOPOROSIS

Despite the introduction of methods to Despite the introduction of methods to identify those with osteoporosis and identify those with osteoporosis and despite effective treatment, a large despite effective treatment, a large ‘care gap’ continues to exist for these ‘care gap’ continues to exist for these patients. patients.

THE TIP OF THE ICEBERG

ASSESSMENT MANAGEMENT

Recommendations for Bone Recommendations for Bone Mineral Density Reporting in Mineral Density Reporting in

CanadaCanada..

Siminoski K, Leslie WD, Brown JP, Frame H, Hodsman A, Josse RG, Khan A, Lentle BC, Levesque J, Lyons DJ, Tarulli G

Can Assoc Radiol J 2005; 56: 178-188

2002 Definitions: BMD Results2002 Definitions: BMD Results

1. Kanis JA, et al. J Bone Miner Res 1994;9:1137-1141.2. WHO, Geneva 1994.

StatusStatus 1, 21, 2 T-scoreT-score

NormalNormal +2.5 to +2.5 to −−1.0, inclusive1.0, inclusive

OsteopeniaOsteopenia Between Between −−1.0 and 1.0 and −−2.52.5

OsteoporosisOsteoporosis ≤−≤−2.52.5

Severe osteoporosisSevere osteoporosis ≤−≤−2.5 + fragility fracture2.5 + fragility fracture

ABOUTABOUTT-SCORES?T-SCORES?

Advantages

Unitless

Basis for the majority of osteoporosis guidelines

Simplicity

Disadvantages

Depends on site measured

Depends on technology

Depends on reference database—population mean

and standard deviation

Only includes BMD information and not additional

risk factors

Adapted from Faulkner K. Osteoporos Int 2005;16(4):347-52.

Fracture RiskFracture Riskvs. BMDvs. BMDAt Different AgesAt Different Ages

Fracture RiskFracture Riskvs. BMDvs. BMDAt Different AgesAt Different Ages

BMD PREDICTS FRACTURESBMD PREDICTS FRACTURES

Hui et al. J Clin Invest 1988; 81:1804-9

AGEAGE T-Score T-Score

= -1.0= -1.0

T-ScoreT-Score

= -2.5= -2.5

5050 6 %6 % 11 %11 %

6060 8 %8 % 16 %16 %

7070 12 %12 % 23 %23 %

8080 13 %13 % 26 %26 %

Risk of Fractures Over 10 Years in WomenRisk of Fractures Over 10 Years in Women

Proposed ChangeProposed Change

Previous OSC guidelines advised intervention Previous OSC guidelines advised intervention based on WHO category as a marker of relative based on WHO category as a marker of relative fracture risk.fracture risk.

Now propose that an Now propose that an individual’s 10-year individual’s 10-year absolute fracture riskabsolute fracture risk, rather than BMD alone, , rather than BMD alone, be used for fracture risk categorizationbe used for fracture risk categorization

5-STEPS IN5-STEPS IN TREATING OSTEOPOROSISTREATING OSTEOPOROSIS

STEPS 1 and 2STEPS 1 and 2

Begin with the table appropriate for Begin with the table appropriate for the patient’s sex the patient’s sex Identify the row that is closest to Identify the row that is closest to the patient's agethe patient's age

CATEGORIZATION BASED ON 10-YEAR CATEGORIZATION BASED ON 10-YEAR FRACTURE RISKFRACTURE RISK

Absolute fracture risk in 10 years:Absolute fracture risk in 10 years:

low: low: <10%<10%

moderate: moderate: 10-20%10-20%

high: high: >20%>20%

USING LOWEST T-SCORE TO FIND 10-YEAR USING LOWEST T-SCORE TO FIND 10-YEAR FRACTURE RISK - WOMENFRACTURE RISK - WOMEN

WOMEN

-4.5

-4.0

-3.5

-3.0

-2.5

-2.0

-1.5

-1.0

-0.5

0.0

50 55 60 65 70 75 80 85

AGE (years)

LO

WE

ST

T-S

co

re

Moderate RiskModerate Risk

High RiskHigh Risk

Low Risk

5-STEPS IN5-STEPS IN TREATING OSTEOPOROSISTREATING OSTEOPOROSIS

STEP 3STEP 3

Determine the preliminary fracture risk Determine the preliminary fracture risk category by using the lowest T-score category by using the lowest T-score from the recommended skeletal sitesfrom the recommended skeletal sites

5-STEPS IN5-STEPS IN TREATING OSTEOPOROSISTREATING OSTEOPOROSIS

STEP 4STEP 4

Evaluate clinical factors that may move Evaluate clinical factors that may move the patient into an even higher fracture the patient into an even higher fracture risk categoryrisk category

USING LOWEST T-SCORE TO FIND 10-YEAR USING LOWEST T-SCORE TO FIND 10-YEAR FRACTURE RISK - MENFRACTURE RISK - MEN

MEN

-4.5

-4.0

-3.5

-3.0

-2.5

-2.0

-1.5

-1.0

-0.5

0.0

50 55 60 65 70 75 80 85

AGE (years)

LOW

EST

T-Sc

ore

Low RiskLow Risk

High RiskHigh Risk

Moderate RiskModerate Risk

Additional Clinical FactorsAdditional Clinical Factors

Certain clinical factors increase fracture Certain clinical factors increase fracture risk independent of BMD.risk independent of BMD.

The most important are:The most important are:– Fragility fractures after age 40 (especially Fragility fractures after age 40 (especially

vertebral compression fractures)vertebral compression fractures)– Systemic glucocorticoid therapy >3 months Systemic glucocorticoid therapy >3 months

duration.duration.

Additional Risk FactorsAdditional Risk Factors

Each factor effectively increases risk Each factor effectively increases risk categorization to the next level:categorization to the next level:– from low risk to moderate risk, orfrom low risk to moderate risk, or– from moderate risk to high riskfrom moderate risk to high risk

When both factors are present the When both factors are present the patient should be considered at high patient should be considered at high risk regardless of the BMD result.risk regardless of the BMD result.

5-STEPS IN5-STEPS IN TREATING OSTEOPOROSISTREATING OSTEOPOROSIS

STEP 5STEP 5

Determine the individual’s final Determine the individual’s final absolute fracture risk category.absolute fracture risk category.

Woman – age 52Woman – age 52

- t is -2.6- t is -2.6

Fracture Risk Category?Fracture Risk Category?

CASE EXAMPLECASE EXAMPLE

High RiskHigh Risk

Moderate RiskModerate Risk

Low RiskLow Risk

WOMEN

-4.5

-4.0

-3.5

-3.0

-2.5

-2.0

-1.5

-1.0

-0.5

0.0

50 55 60 65 70 75 80 85

AGE (years)

LO

WE

ST

T-S

core

CASE EXAMPLECASE EXAMPLE

Low Risk

Moderate Risk

High Risk

AGE LOW MODERATE HIGH<10% 10 to 20% >20%

50 >-2.3 -2.2 to -3.9 <-3.955 >-1.9 1.9 to -3.4 <-3.460 >-1.4 -1.4 to -3.0 <-3.065 >-1.0 -1.0 to -2.6 <-2.670 >-0.8 -0.8 to -2.2 <-2.275 >-0.7 -0.7 to -2.1 <-2.180 >-0.6 -0.6 to -2.0 <-2.085 >-0.7 -0.7 to -2.2 <-2.2

10-YEAR RISK

WOMEN

CASE EXAMPLECASE EXAMPLE

-2.2- -3.9

Fracture Risk CategoryFracture Risk CategoryModerate RiskModerate Risk

CASE EXAMPLECASE EXAMPLE

Fracture Risk CategoryFracture Risk Category

High RiskHigh Risk

Moderate RiskModerate Risk

If Fragility Fracture HistoryIf Fragility Fracture History

CASE EXAMPLECASE EXAMPLE

70 year-old man70 year-old man

CASE EXAMPLE CASE EXAMPLE

Lowest T-score –2.7 in total hipLowest T-score –2.7 in total hip

BMD done because of strong family BMD done because of strong family history of osteoporosis history of osteoporosis (mother fractured hip, sister (mother fractured hip, sister

has OP)has OP)

USING LOWEST T-SCORE TO FIND 10-YEAR USING LOWEST T-SCORE TO FIND 10-YEAR FRACTURE RISK - MENFRACTURE RISK - MEN

MEN

-4.5

-4.0

-3.5

-3.0

-2.5

-2.0

-1.5

-1.0

-0.5

0.0

50 55 60 65 70 75 80 85

AGE (years)

LOW

EST

T-Sc

ore

Low RiskLow Risk

High RiskHigh Risk

Moderate RiskModerate RiskX

Fracture Risk CategoryFracture Risk Category

Moderate RiskModerate Risk

CASE EXAMPLECASE EXAMPLE

OTHER ISSUES FOR THIS 70 OTHER ISSUES FOR THIS 70 YEAR OLD MALEYEAR OLD MALE

Chest x-ray – mild loss of vertebral height Chest x-ray – mild loss of vertebral height at T4, T5at T4, T5

What if he had had polymyalgia What if he had had polymyalgia rheumatica at age 69 and was on rheumatica at age 69 and was on prednisone 10 mg./day?prednisone 10 mg./day?

Fracture Risk CategoryFracture Risk Category

Moderate RiskModerate Risk

If Fragility Fracture History, If Fragility Fracture History, Corticosteroid useCorticosteroid use

High RiskHigh Risk

CASE EXAMPLECASE EXAMPLE

EndorsementsEndorsements

Canadian Association of Nuclear MedicineCanadian Association of Nuclear Medicine

Canadian Association of RadiologistsCanadian Association of Radiologists

Canadian Rheumatology AssociationCanadian Rheumatology Association

International Society of Clinical DensitometryInternational Society of Clinical Densitometry

Society of Obstetricians and Gynecologists of CanadaSociety of Obstetricians and Gynecologists of Canada

Canadian Society of Endocrinology and Metabolism Canadian Society of Endocrinology and Metabolism

Canadian Orthopedic AssociationCanadian Orthopedic Association

College of Family Physicians of CanadaCollege of Family Physicians of Canada

Osteoporosis Prevention and Osteoporosis Prevention and TreatmentTreatment

Age

Hormonal Replacement

Bisphosphonates Strontium

SERM

20 40 60 80

Vitamin D

PTH

Life Style

Treatmentchoice

** with prev vert fracture(s) with prev vert fracture(s) **** without prev vert fractures without prev vert fractures ****** with or without prev verfractures with or without prev verfractures

Antifracture efficacy of antiosteoporotic agents

0.6 1.00.2

Incident nonvertebral fractures Relative risk

RLX 60, 120(MORE)***

CT 200 (PROOF)*

Teriparatide 20µg*

ALN 5/10 (FIT1)*

ALN 5/10 (FIT2)**

RIS 5 (VERT-NA)*

RIS 5 (VERT-MN)*

RIS 2.5/5 (Hip Study)***RIS 2.5/5 (Hip Study)***

Incident vertebral fractures Relative risk

0.60.6 1.01.00.20.2

RLX 60 (MORE)*

RLX 60 (MORE)**

CT 200 (PROOF)*

Teriparatide 20µg*

ALN 5/10 (FIT1)*

ALN 5/10 (FIT2)**

RIS 5 (VERT-NA)*

RIS 5 (VERT-MN)*

Strontium ranelate(SOTI)*

Strontium ranelate(SOTI +TROPOS)**

Strontium ranelate(TROPOS)***

Strontium ranelate(SOTI)*

Updated from Delmas, Lancet 2002

RR ± 95% CI

Medications Available for Medications Available for Post-Menopausal OsteoporosisPost-Menopausal Osteoporosis

ActonelActonel®® (risedronate sodium tablets) (1/day;1/wk; 1/mo) (risedronate sodium tablets) (1/day;1/wk; 1/mo)

Didrocal® (etidronate sodium tablets)Didrocal® (etidronate sodium tablets)

FosamaxFosamax®® (alendronate sodium tablets) 1day/1/wk; Fosovance) (alendronate sodium tablets) 1day/1/wk; Fosovance)

Aclasta Aclasta ® ® (zolendronate IV) (zolendronate IV)

Estrogen (some use)Estrogen (some use)

EvistaEvista®® (raloxifene HCl) (raloxifene HCl)

MiacalcinMiacalcin®® (calcitonin salmon) Nasal Spray (calcitonin salmon) Nasal Spray

Forteo (Teriparatide) (sc)Forteo (Teriparatide) (sc)

Consult with your physician to determine what medication may Consult with your physician to determine what medication may be best for yoube best for you

Bisphosphonates — Cyclical Bisphosphonates — Cyclical EtidronateEtidronate

pp=NS=NS

00

1010

2020

3030

4040

5050

1818

Etidronate (n = 20)Etidronate (n = 20)

4343

Placebo (n = 20)Placebo (n = 20)

Lum

bar

spin

e fr

actu

re r

ate

Lum

bar

spin

e fr

actu

re r

ate

(fra

ctur

es/1

00 p

atie

nt-y

ears

(fra

ctur

es/1

00 p

atie

nt-y

ears

))

Storm T. Storm T. N Engl J MedN Engl J Med 1990; 1990;322322:1265.:1265.

• 3-year RCT, 66 subjects3-year RCT, 66 subjects• High risk subgroup: reduction in fracture rate with etidronate, High risk subgroup: reduction in fracture rate with etidronate, pp = 0.023 = 0.023 • No statistically significant effect at nonvertebral sitesNo statistically significant effect at nonvertebral sites

Cumulative Hip Fracture Cumulative Hip Fracture IncidenceIncidence

Baseline Month 6 Month 12

% o

f c

oh

ort

wit

h a

hip

fra

ctu

re

0.00

0.10

0.20

0.30

0.40

0.50

0.58

alendronate

risedronate

Silverman SL. Osteoporos Int 2007 Jan;18(1):25-34. Epub 2006 Nov 15.

↓ 43%*Adjusted Relative Rate Reduction at Month 12

p = 0.0195% CI: 13% - 63%

↓ 46%*Adjusted Relative Rate Reduction at Month 6

p = 0.0295% CI: 9% - 68%

80 fracturesn= 21,615

29 fracturesn = 12,215

Osteoporosis in MenOsteoporosis in MenHas Its Time Come?Has Its Time Come?

HEADLINESHEADLINES7.8.077.8.07

HIP FRACTURESHIP FRACTURES MORBIDITY AND MORTALITY MORBIDITY AND MORTALITY

“One-third of all hip fractures occur in men and are associated with as much illness and increased risk of death as those that occur in women .”

“The average 50-year-old Caucasian man has a 13 per cent chance of having a fracture related to osteoporosis sometime in his remaining lifetime. A 60-year-old Caucasian man has a 29 per cent chance.”

Dr. John Schousboe, Minneapolis 2007

Male Osteoporosis: Morbidity and Male Osteoporosis: Morbidity and MortalityMortality

As compared to women, while lifetime As compared to women, while lifetime fracture risk may be less,fracture risk may be less,– Men have higher rates of morbidity and Men have higher rates of morbidity and

mortality due to fracturesmortality due to fractures– Men are twice as likely to die in hospital after Men are twice as likely to die in hospital after

a hip fracturea hip fracture– Men have a higher mortality rate than women Men have a higher mortality rate than women

one year after a hip fractureone year after a hip fracture

Cooper C, et al. Osteoporos Int 1992;2:285-9; Singer BR, et al. J Bone Joint Surg Br 1998;80:243-8; Center JR, et al. The Lancet 1999;353:878-82; Forsen L, et al. Osteoporos Int 1999;10:73-8; Johnell O., et al. Calcif Tissue Int 2001;69:182-4; Amin S. Curr Osteoporos Rep 2003;1:71-7; Campion JM, et al. Am Fam Phys 2003;67:1521-6.

GLUCOCORTICOIDS and BONEGLUCOCORTICOIDS and BONE

Have a reflex! SGC > 3 mo > 7.5 mg./day Have a reflex! SGC > 3 mo > 7.5 mg./day

-Ca, vitamin D, bisphosphonate-Ca, vitamin D, bisphosphonate

Bone density evaluation?Bone density evaluation?

Back injuries.Back injuries. If you think that golf is for wimps, consider If you think that golf is for wimps, consider this: A this: A golf swinggolf swing puts a higher compressive load on the puts a higher compressive load on the low back (low back (8 times body weight8 times body weight) than ) than runningrunning ( (33 timestimes) or ) or even even rowingrowing ( (77 timestimes). That’s why a single swing can ). That’s why a single swing can produce a herniated disc or even a produce a herniated disc or even a compressioncompression fracturefracture of one of the vertebral bodies. Although these injuries of one of the vertebral bodies. Although these injuries are extremely painful and can be quite serious, they are are extremely painful and can be quite serious, they are rare. Muscle strains, however, are quite common rare. Muscle strains, however, are quite common because of the twisting that is required for a good swing. because of the twisting that is required for a good swing. The “modern” swing, with its inverted-C follow-through, The “modern” swing, with its inverted-C follow-through, may make for longer drives than the “classic” swing but it may make for longer drives than the “classic” swing but it also produces more torque — and more injuries (also produces more torque — and more injuries (seesee Golf injuries Golf injuries aboveabove). ).

Harvard Men’s Health Watch Aug 2004

SUMMARYSUMMARYREDUCING THE ‘CARE GAP’REDUCING THE ‘CARE GAP’

Assess bone health in woman >50 and in Assess bone health in woman >50 and in men > 60.men > 60.

Evaluate risk factors; evaluate BMDEvaluate risk factors; evaluate BMD

Consider preventative approach to Consider preventative approach to reduction of fracture risk (the way you reduction of fracture risk (the way you think of hypertension and MI and stroke)think of hypertension and MI and stroke)

Treat and monitor Treat and monitor