pm 12.15 lindsay

Osteoporosis Management: Osteoporosis Management: the Science and the Artthe Science and the Art

Robert Lindsay, MD, PhDRobert Lindsay, MD, PhDChief of MedicineChief of Medicine

Helen Hayes HospitalHelen Hayes HospitalProfessor of Clinical MedicineProfessor of Clinical Medicine

Columbia University Columbia University New YorkNew York

Competing Interests

• Consultant – Amgen, Eli Lilly, Azelon

• Speaker – Amgen, Eli Lilly

Learning Objectives

Upon completion of this educational activity, the participant should be able to:

• Outline the signs and symptoms of osteoporosis that warrant further evaluation.

• Delineate the risk of osteoporosis among patients of different races.

• Describe how to utilize guideline-recommended strategies for the prevention and treatment of osteoporosis.

• Describe methods for improving patient adherence to pharmacotherapies and other strategies designed to prevent or slow the progression of osteoporosis.

Osteoporosis

• A serious and common disease that causes (through fractures) significant mortality and high morbidity

• Despite that, only about 21% of Medicare hip fracture patients get assessed, diagnosed, or treated!

NCQA 2011 benchmarks and thresholds

“If you can get people to ask the wrong questions, you don’t have to worry about what the answers are.”Pynchon T. Proverbs for paranoids. In: Gravity’s Rainbow. New York: Penguin; 1995.

Question 1

• For persons with osteoporosis, should only fractures that occur on modest trauma be considered “osteoporotic”?

Answer

• Fractures are never osteoporotic, only bones can be osteoporotic

• A person with osteoporosis is at higher risk of fracture – any fracture (exceptions finger toes skull and facial bones)

• The level of trauma needed to fracture is lower, thus at higher levels of trauma fracture is more likely

Fractures in patient with osteoporosis

Tra

um

a le

vel

Trauma required to break a bone that is osteoporotic

Trauma required to break a normal

bone

Question 2

• You can only have osteoporosis when BMD falls below the normal range?

• Osteoporosis is diagnosed by fracture and/or BMD testing

• BMD osteoporosis is determined when BMD falls below the normal range (a T-score of =/< -2.5)

• The lower BMD is the greater the fracture risk

• Osteoporosis is diagnosed by fracture and/or BMD testing

• BMD osteoporosis is determined when BMD falls below the normal range (a T-score of =/< -2.5)

• But is risk much different at a T score of -2.4?

0

10

20

30

40

_3 _2.5 _2 _1.5 _1 _0.5 0 0.5 1

BM D T -S co re

50

60

7080

AgeO

steo

poro

tic F

ract

ure

Ris

k(%

per

10

Yea

rs)

BMD and Fracture Risk

Kanis JA, et al. Kanis JA, et al. Osteoporos Int.Osteoporos Int. 2001;12:989–995. 2001;12:989–995.

Speculation?

• The increased fragility in the skeleton occurs mostly because of loss of tissue and thus deteriorating architecture

• Coupled to that is the increase in risk of injury that occurs with aging

Normal Osteoporosis

© 2000, David W. Dempster, PhD.

MICROARCHITECTURAL CHANGES IN OSTEOPOROSIS

Thank you for referring Ms Smith (at age 65 yrs) for bone density evaluation. Her T-score is -2.0 which increases her risk of fracture by 4 times.

Thank you for referring Ms Smith (at age 65 yrs) for bone density evaluation. Her T-score is -2.0 which increases her risk of fracture by 4 times.

A convenient retrospectoscope tells us her BMD T-score at age 40 was +1.0

Thank you for referring Ms Jones (at age 65 yrs) for bone density evaluation. Her T-score is -2.0 which increases her risk of fracture by 4 times.

But what if her BMD T-score at BMD T-score at age 40 was -2.0

Risk Assessment

• For the first Ms Smith, risk is increased because of loss of mass and, concurrently, architecture

• For the second, risk may be elevated because she is likely to be slim! (bones are thus small)

• This is not an advertisement for obesity!

• Overweight folks are not immune from fracture risk, but small slim bones like pencils break more easily

• There is nothing we can do about small slim bones

Thank you for referring Ms Jones (at age 85 yrs) for bone density evaluation. Her T-score is -2.0 which increases her risk of fracture by 4 times.

0

10

20

30

40

-0.50

0.51

BMD T-Score

50

60

7080

Age

Os

teo

po

roti

c F

rac

ture

R

isk

(% p

er

10 Y

ears

)

Fracture Risk Treatment Threshold

Recommendations for treatment are based on absolute risk of an individual patient, based on BMD and other important risk factors 1

Core data from Kanis JA, et al. Core data from Kanis JA, et al. Osteoporos Int.Osteoporos Int. 2001;12:989–995. 2001;12:989–995.

1 1 Kanis JA, et al. Kanis JA, et al. BoneBone. 2002;31:26–31.. 2002;31:26–31.

Thank you for referring Ms Smith for bone density evaluation. Her T-score is -2 which increases her risk of fracture by 4 times.

4 times what and over what time?

• One in a million?

• One in ten?

• One year?

• Lifetime?

“Absolute” Risk Assessment

• Defines the likelihood that an event will occur specifically for an individual over a reasonable horizon (e.g. a 20% risk in next 10 years)

• Model built from epidemiologic data bases • Includes common risk factors + BMD to calculate

risk• Intervention depends on absolute risk and threshold

depends on cost effectiveness

• Thank you for referring Ms Smith for BMD evaluation. Given her age, fracture history, weight, cigarette use, family history, and BMD, her estimated risk of fracture in the next five years is 25% with a variance of +/- 5% (range 20-30%)

0

10

20

30

40

-0.50

0.51

BMD T-Score

50

60

7080

Age

Os

teo

po

roti

c F

rac

ture

R

isk

(% p

er

10 Y

ears

)

Fracture Risk Treatment Threshold

Recommendations for treatment are based on absolute risk of an individual patient, based on BMD and other important risk factors 1

High Fracture Risk

Core data from Kanis JA, et al. Core data from Kanis JA, et al. Osteoporos Int.Osteoporos Int. 2001;12:989–995. 2001;12:989–995.

1 1 Kanis JA, et al. Kanis JA, et al. BoneBone. 2002;31:26–31.. 2002;31:26–31.

Defining osteoporosis as a T-score below –2.5 does not effectively capture many patients at risk for

fracture

It has been difficult for clinicians to identify persons with elevated fracture risk but with T-score above -2.5

The Problems: The Problems:

The clinical community is still not equating most fractures with osteoporosis – nor is the public

Fracture Rates, Population BMD Distribution and Number of Fractures

Primary Care Arm

BMD T-scores

60

50

40

30

20

10

0

450

350

300

250

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100

0

150

50

400

Fra

ctu

re r

ate

pe

r 10

00

pe

rso

n-y

ear

s

# F

rac

ture

s

>1.0 1.0 to 0.50.5 to 0.0

0.0 to –0.5–0.5 to –1.0

–1.0 to –1.5–1.5 to –2.0

–2.0 to –2.5–2.5 to –3.0

–3.0 to –3.5 < –3.5

Adapted from Siris ES, et al.Adapted from Siris ES, et al.JAMA.JAMA. 2001;286:2815-22. 2001;286:2815-22.

BMD distribution

Fracture Rates, Population BMD Distribution and Number of Fractures

Primary Care Arm

BMD T-scores

60

50

40

30

20

10

0

450

350

300

250

200

100

0

150

50

400

Fra

ctu

re r

ate

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r 10

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pe

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n-y

ear

s

# F

rac

ture

s

>1.0 1.0 to 0.50.5 to 0.0

0.0 to –0.5–0.5 to –1.0

–1.0 to –1.5–1.5 to –2.0

–2.0 to –2.5–2.5 to –3.0

–3.0 to –3.5–3.5

Adapted from Siris ES, et alAdapted from Siris ES, et al.JAMA..JAMA. 2001;286:2815-22. 2001;286:2815-22.

BMD distribution

Fracture Rate

<-3.5

Fracture Rates, Population BMD Distribution and Number of Fractures

Primary Care Arm

# Fractures

BMD T-scores

60

50

40

30

20

10

0

450

350

300

250

200

100

0

150

50

400

Fra

ctu

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rso

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ear

s

# F

rac

ture

s

>1.0 1.0 to 0.50.5 to 0.0

0.0 to –0.5–0.5 to –1.0

–1.0 to –1.5–1.5 to –2.0

–2.0 to –2.5–2.5 to –3.0

–3.0 to –3.5 < –3.5

BMD distribution

Adapted from Siris ES, et al. Adapted from Siris ES, et al. JAMA.JAMA. 2001;286:2815-22. 2001;286:2815-22.

Fracture Rate

Hip Fractures in Women without Osteoporosis

0

20

40

60

80

100

120

140

160

-4 -3 -2 -1 0

Hip Fractures

Subjects

Total hip BMD T-Score

No

of s

ubje

cts

(*10

)

Modified from Wainwright et al JCEM 90 2787 2005

Total n = 8065Hip Fractures = 243 (54%) above -2.5

Let’s shift gears

• What about the persons who present with fracture over age 50 yrs?

• These are our patients at the highest risk of future fractures!

Osteoporosis, Fracture Risk Vary by Ethnicity

• Ethnic differences in BMD are strongly influenced by body weight

• Fracture risk is strongly influenced by BMD in each group

• Ethnic differences in absolute fracture risk remain, which may warrant ethnic-specific clinical recommendations

Barrett-Connor E, et al. J Bone Miner Res. 2005; 20:185-194.

Odds of Osteoporosis (T score −2.5 and 95% CI) by Ethnicity

Barrett-Connor E, et al. J Bone Miner Res. 2005; 20:185-194.

Confirmed: Prevalent Vertebral Fractures Predict Future Fracture

0

1

23

4

56

7

8

Black '99 McClung '99 Ross '93 Risedronate vsPlacebo Patients

RelativeRisk

(RR)

3.7 years 3 years 3 years

RR = Fractures in Patients With Prevalent Fractures vs Those Without

5.04.5

7.4

4.0

3 years Black DM, et al. J Bone Min Res. 1999;14:821-828.McClung M, et al. Abstract.Ross PD, et al. Osteoporos Int. 1993;3:120-126.Data on File. Procter & Gamble Pharmaceuticals Inc.

Fracture Risk is Higher Immediately Following an Incident Fracture

0

4

8

12

16

20

24

Incidence of VertebralFracture in Year 0-1

Incidence Within 1 Year Following First Fracture

20% Will Fracture Again Within 1 Year of Incident Fracture

7%

20%

Lindsay R, et al. JAMA. 2001;285:320-323.

Patients(%)

• Bones break when load exceeds strength

• Low BMD and architecture contribute to strength

• Loads are dependent on other things (Falls, frailty, height, weight, nutrition, co-morbidities, medicines etc)

Osteoporosis

Risk Factors for Fracture

Fallsand

Trauma

Therapy:

Bisphosphonates Calcium and Vitamin D

Injury prevention

Reducing Fall Risk• Eliminate sedatives• Monitor antihypertensives• Ensure adequate vitamin D intake• Modify environment (i.e., lighting, floor

coverings, pets, grab-bars, etc.) • Gait and transfer training• Exercises (i.e., Tai Chi)• Correct vision and hearing problems• Use proper footwear

FATIGUE CRACKS : MECHANICAL STRESS RISERS

www.tam.uiuc.edu

What about treatment?

• Background therapy refers to calcium and vitamin D

• What do we know about these as nutrients and for D a hormone?

The calcium controversy

• Having too little calcium in the diet increases bone remodeling which when imbalanced leads to bone loss

• Diets with averages of less than 800-1000mg/day cited as too low.

• Calcium intakes above this do not produce further skeletal effects

• Higher intakes, especially with supplements may be harmful

The calcium controversy

• An adequate diet with average intakes between 1000 and 1500mg/day is sufficient

• Supplements should only be used when these averages cannot be met from diet, and only enough to bring total intake to that level

• For calcium calculator go to nof.org

The vitamin D story

• Vitamin D has become the vitamin of the decade

• There is a lot of basic science evidence supporting the effects of 1,25(OH)2D on multiple tissues

• Most human studies are observational

• IOM recommendations may be set too low for many older individuals

Vitamin D

• A large study is now underway to evaluate non-skeletal outcomes of vitamin D intake

Pharmacology

• How well do we understand available treatments?

Pharmacology

• All treatments reduce bone remodeling, except teriparatide which stimulates formation and remodeling in bone

• Teriparatide is used only for a maximum of 2 yrs in any lifespan

• Most patients will require long-term treatment

• How do you choose the treatment for any particular patient?

Drug Therapy Classes 1

Antiresorptive Agents

Reduce the risk of all fractures:

• Calcium +/- vitamin D

• Hormone therapy (ET/HT)

• Bisphosphonates – Alendronate Risedronate Zoledronate

• RANK-L Inhibitor - Denosumab

Reduce vertebral fracture risk:

• Selective Estrogen Receptor Modulators (SERMs)

• Ibandronate

• Calcitonin

All drug therapies are usually given in conjunction with lifestyle modification, calcium and vitamin D.

TREATMENT: AlnCalcitonin

IbnRal

Ris

Non-vertebral fracture efficacy

Adapted from Boonen S et al. OI 2005; 16: 1291

PLACEBO FRACTURE INCIDENCE [%] * stat sig

RE

LA

TIV

E R

ISK

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

1.1

1.2

1.3

1.4

8 9 10 11 12 13 14 15 16 17 18

BONE

*

VERT-NA

*HIP

VERT-MN

MORE

FIT2FIT1

Liberman

PROOF

---------------------------------------------------------------------------------------------

2

Not head to head studiesWHI

Zoledronate

Bisphosphonates

• Concern about long term adverse events

Esophageal cancer

ONJ

Subtrochanteric fractures

• Led to concept of “drug holiday”

• Evidence to support this mostly lacking

Bisphosphonates and esophageal cancer: what is more likely?*

• Incidence of esophageal cancer in women over 65: 111/million/year

• Alendronate: 35 million years of experience• If consider 20% who take Alendronate for more than 5

years• Expected number of cases based upon epidemiology

should be around 800, not 23!• Similar data for Risedronate (Unpublished data, Klemes

et al, 2009)

*Siris E, Oster M, Bilezikian JP, NEJM Ltr , 2009 *Siris E, Oster M, Bilezikian JP, NEJM Ltr , 2009

Definition of ONJAn area of exposed bone in the maxillofacial region in which there is no healing over 8 weeks after being recognized by a healthcare provider

Related conditions: • Usually a triggering event/condition:

– Recent tooth extraction or oral surgical procedure– Abrasion in trauma-vulnerable anatomical location (eg,

mylohyoid ridge [edentulous patients], tori)– smoldering infection (eg, chronic severe periodontitis)

May be:• symptomatic or asymptomatic• infected or non-infected

ONJ and Comparative Risks1-4

0.6

0.7

6

11

32

0 10 20 30 40 50 60 70 80 90 100

Death by Lightning Strike in NM

ONJ- Osteoporosis Patient

Death by Murder

Death by MVA

Anaphylaxis from PCN Shot

Hip Fracture (1)

Any Fragility Fracture (1)

Risk per 100,000 People per Year

1. Kanis JA et al. Osteoporosis Int. 2001;12:417-427. 2. Kaufman DW. Pharmcoepidemiol Drug Saf. 2003;12:195-202. 3. National Center for Health Statistics. JADA. 2006;137:1144-1150. 4. NOAA Web site. www.nssl.noaa.gov/papers/techmemos/NWS-SR-193/techmemo-sr193-4.html. Accessed September 2008.

(1) Women age 65–69 (from Swedish National Bureau of Statistics and database of Olmsted County, MN )

2668

387

Subtrochanteric Fractures

• Epidemiology mostly unknown at present

• Publications mostly case series or from data derived from claims databases

• Shorter use of BPs

• Suggest incidence about 1/20 that of hip fracture

• No time trend toward increased incidence

Hip and Subtrochanteric Fractures in the United States

’96 ’’98 ’00 ’02 ’04 ‘06 p

Women*

Hip 546 489 497 449 445 428 <.001

SubT** 56 68 63 65 65 53 NS

Men*

Hip 274 327 265 252 261 248 <.03

SubT** 36 27 27 27 28 32 NS

*per 100,000*per 100,000**Includes Subtrochanteric, femoral shaft, and distal femur fractures**Includes Subtrochanteric, femoral shaft, and distal femur fractures

Nieves et al.Osteoporosis International 2010

Potential Mechanisms• Prolonged residence in the skeleton

non-metabolized• Irreversible functional osteoclast deficiency and OC apoptosis• Atypical non-functional large inactive osteoclast forms• Dramatic suppression of remodeling

– increased secondary mineralization, crystal size and tissue mineral density

– loss of heterogenity in tissue mineral density causes increased stiffness and perhaps propagation of micro-cracks

– Aged collagen- weakened bone– Accumulated microdamage

• Heterozygous osteopetrosis profile with intermediate degree of osteoclast dysfunction

1. Nancollas GH, et al. Bone. 2006;38: 617-627. 2. Dunford JE, et al. J Pharmacol Exp Ther. 2001;296:235-242.

Binding to Hydroxyapatite1Binding to Hydroxyapatite1

0

1

2

4

3

KL

(L/m

ol x 1

06)

CLO ETD RIS IBA ALN ZOL

ALN IBA RIS ZOL

IC5

0 (

nM

)0.0

10

20

30

40

50rhFPP synthase2rhFPP synthase2

Bisphosphonates: Key Pharmacological Characteristics

• Binding affinity for bone in vitro– Determines attachment to

bone and duration of effect

• FPP synthase inhibition in vitro– Determines antiresorptive

potential

LOC NOC

Inactive Osteoclast vs. Normal Osteoclast

50 µm50 µm

< 22 nuclei/cell profile < 8 nuclei/cell profile

Dempster et al ASBMR Abstract 2007

Drug Therapy Classes 2

• “Anabolic” agents Teriparatide (1-34rhPTH)

Parathyroid Hormone (1-84PTH)

• Unclassified Strontium Ranelate

1-34hPTH increases trabecular connectivity and cortical width

Dempster et al JBMR 2001

Ct.Th: 0.32 mmCD: 2.9/mm3

Ct.Th: 0.42 mmCD: 4.6/mm3

Who should get Teriparatide?

• Persons with high fracture risk Patients with osteoporosis related fractures

Patients with very low BMD

Patients who fail other therapies(?)

• How long to treat?

Label – not more then 2 years in any lifetime

Treat and review after one year

Teriparatide Zoledronic Acid

These samples are representative of the median values for MS/BS for each treatment group (0.16%, zoledronic acid vs 5.60%, teriparatide)

Tetracycline Labels After 6 Months in Cancellous Bone

MS/BS = 0.20% MS/BS = 5.38%

65

Patients already on treatment

• Mostly bisphosphonate treated, and effects linger after BP discontinuation

• One study implies that patients should stay on BP while on TPTD

What are the Possible Causes of Poor Adherence?

• Cost• Osteoporosis eclipsed by other

chronic conditions• Concern about side effects• Poor patient education• Disruption to daily routine• Complex dosing guidelines• Lack of positive reinforcement

Sebalt, et al. J Bone Miner Res. 2004:19(Suppl 1): Abstract M423.

THE FUTURE BELONGS

TO THOSE WHO BELIEVE

IN THE BEAUTY

OF THEIR DREAMSEleanor Roosevelt

Pieter Brueghel

Oliviero Toscani

BODY IMAGEIT’S A MULTIFACTORIAL MENTAL CONSTRUCT

DYNAMICALLY SHAPED LIFELONG ROOTED BOTH

IN THE PSYCHOLOGICAL AND BIOLOGICAL DOMAIN

PSYCHOLOGY WITHOUT BODY & MEDICINE WITHOUT SOUL

LIFE EXPECTANCY (LE) VS HEALTH

EXPECTANCY(HE) Country LE HE Difference

Canada 73.0 67.0 6.0

U.K. 71.8 58.7 13.1

France 70.7 61.9 8.8

United States 70.1 55.5 14.6

Poland 67.0 60.0 7.0

China 66.6 61.6 5.1

from Bruno Lunefeld, Aging for men, 2000

Conclusions

• Bones break when load exceeds strength

• Low BMD and architecture contribute to skeletal strength

• Loads are dependent on other things (Trauma, falls, frailty, height, weight, nutrition, co-morbidities, medicines etc)

• Persons with high fracture risk encompass either or both

Conclusions 2

• Any fracture in a person over 50 yrs, should trigger an osteoporosis evaluation

• Risk assessment (e.g. FRAX) is one method of evaluating the need for treatment

• Treatment must include risk reduction as well as pharmacology