Prevention Treatment of Osteoporosis in Geriaterics

Dr H. Soleimani

Department of Rheumatology

Shahid Sadughi Hospital

Fracture Risk Assessment

Intervention Thresholds

Treatment

Follow-up

Will I end up like my mother?

But, do I really have

to take those

medicines? I saw on the News

last night.....

Pyramid for Osteoporosis Prevention and Treatment

Pharmacotherapy(antiresorptives and anabolics)

Address Secondary Factors(drugs and diseases)

Lifestyle Changes(nutrition, physical activity, and fall prevention)

What does this mean for your patients?What does this mean for your patients?

Leading the Effort to Help Prevent and Treat Osteoporosis

US Department of Health and Human Services. Bone Health and Osteoporosis: A Report of the Surgeon General. US Department of Health and Human Services, Office of the Surgeon General; 2004.

A Few Facts about Osteoporosis

and

Bone Density Measurement

Osteoporosis Osteoporosis is defined as a skeletal disorder characterized by

compromised bone strength predisposing to an increased risk of fracture. NIH Consensus Development Conference, March 2000

Normal Bone Osteoporotic Bone

1. Riggs BL, Melton LJ III. Bone. 1995;17(suppl):505S–511S. 2. American Stroke Association. Heart disease and stroke statistics––2005 update. Available at:

http://www.americanheart.org. Accessed August 24, 2005. 3. American Cancer Society. Cancer facts & figures; 2005. Available at: http://www.cancer.org. Accessed

August 24, 2005.

Fractures in Women Are Common:Incidence of Chronic Diseases

1,500,000

345,000 373,000211,240250,000

0

0.5

1.0

1.5

2.0

Fracture1 Heart attack2 Stroke2 Breast cancer3

An

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al I

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Risk of osteoporotic fracture in 1 year is greater than combined risk of heart attack, stroke, and breast cancer.

Hip fracture1

Women with osteoporosis All women

Practical Definition of Osteoporosis

• A fall from a sitting or standing height that causes a fracture

Bone Mineral Density Testing

“Quantitating the Bone Mass”

Central Devices

Hologic Hologic DelphiDelphi

GE Lunar GE Lunar ProdigyProdigy

Central DXA Measures bone density at the hip and spine

DXA image of the hip DXA image of the lumbar spine

NOF 2008 GuidelinesNOF 2008 GuidelinesWho Should be Tested?Who Should be Tested?

• Women age 65 and olderWomen age 65 and older

• Men age 70 and olderMen age 70 and older

• Women and men over 50 with risk Women and men over 50 with risk factorsfactors

• Patients with a fracture after age 50Patients with a fracture after age 50

Lateral Spine Imaging with

Fan-ArrayDual Energy

X-ray Absorptiometry

Vertebral Fracture Assessment

Surgeon General’s Report

on Bone Health and

Osteoporosis

Pyramid for Osteoporosis Prevention and Treatment

Pharmacotherapy(antiresorptives and anabolics)

Address Secondary Factors(drugs and diseases)

Lifestyle Changes(nutrition, physical activity, and fall prevention)

What does this mean for your patients?What does this mean for your patients?

Leading the Effort to Help Prevent and Treat Osteoporosis

US Department of Health and Human Services. Bone Health and Osteoporosis: A Report of the Surgeon General. US Department of Health and Human Services, Office of the Surgeon General; 2004.

Lifestyle Issues

• Tobacco- eliminate it

• Alcohol – moderate it

• Food – eat it

• Exercise – do it

• Fall Prevention – work on it

Lifestyle Issues

• Tobacco - eliminate it• Alcohol – moderate it• Nutrition - adequate weight, protein--

magnesium, trace elements....multivite• Exercise – strength, aerobic, flexibility,

balance• Fall prevention- home safety, shoes,

walking aids, glasses

Nutrition

• Appropriate Body Weight – BMI 22 - 25

• Adequate nutrition– Protein

• Multi-vitamin daily – C, D, K, Copper, Manganese, Zinc, Phosphorus

• Nutritional supplements– Ensure, Boost

Nutrition

Milk, Yogurt• Calcium, magnesium, potassium,

phosphorus, zinc, protein, vitamin A, vitamin D, vitamin B12, riboflavin

Risk reduction for• Osteoporosis, hypertension, obesity, colon cancer,

diabetes, metabolic syndrome

What are the therapeutic options?

• Exercise and prevention of falls

improve quality of life

improve muscle strength and balance

moderate walking reduced risk of hip Fx*

treat cataract

Use of hip protectors*

Exercise

• Walking reduces hip fracture risk– 4 hours per week reduced hip fracture by 41%

in a study of 61,200 womenJAMA 2002

• Activity of any type reduces fracture risk- Balance, Strength, Flexibility, Aerobic

Exersice• 1. Exercises involving resistance training

appropriate for the individual’s age and functional capacity and/or weightbearing aerobic exercises are recommended for those with osteoporosis or at risk for osteoporosis [grade B].

Exersice

• Exercises to enhance core stability and thus to compensate for weakness or postural abnormalities are recommended for individuals who have had vertebral fractures [grade B].

Exersice

• Exercises that focus on balance, such as tai chi, or on balance and gait training should be considered for those at risk of falls [grade A].

Falling

• Medications, Alcohol

• Balance programs

• Strength training

• Safety at home

• Hip protectors

• Walking aids

Hip Protectors

Hip Protector

• Use of hip protectors should be considered for older adults residing in long-term care facilities who are at high risk for fracture [grade B].

Calcium 1200 mg

“Calcium has been singled out as a major health concern today because it is critically important to bone health and the average American consumes levels of calcium that are far below the amount recommended for optimal bone health.”

General’s Report on Bone Health 2004

Calcium 1200 mg

• Dietary

• Fortified foods

• Calcium citrate– Taken with or without food

• Calcium carbonate– Taken with food

• Divided doses

Calcium

• The total daily intake of elemental calcium (through diet and supplements) for individuals over age 50 should be 1200 mg [grade B].

Vitamin D 800-2000 IU ?

“Vitamin D is important for good bone health because it aids in the absorption and utilization of calcium. There is a high prevalence of Vitamin D deficiency in nursing home residents, hospitalized patients, and adults with hip fractures.”

…..and many others

General’s Report on Bone Health 2004

Vitamin D • Sufficiency > 32 ng/ml Comfort zone- 40s, 50s

– Many wellness relationships• Insufficiency < 32 ng/ml

– Disease states

New England Journal of Medicine July 19 2007Medical Progress: Vitamin D Deficiency

M F Holick

800-1000 IU daily for patients 50 +

...although some elderly patients may require 2000 IU/day......

NOF Clinician’s Guide 2008

Vit D

• For healthy adults at low risk of vitamin D deficiency, routine supplementation with 400–1000 IU (10–25 μg) vitamin D3 daily is recommended [grade D].

Vit D

• For adults over age 50 at moderate risk of vitamin D deficiency, supplementation with 800–1000 IU (20–25 μg) vita min D3 daily is recommended. To achieve optimal vitamin D status, daily supplementation with more than 1000 IU (25 μg) may be required. Daily doses up to 2000 IU (50 IU (25 μg) may be required.

Daily doses up to 2000 IU (50 μg) are safe and do not necessitate monitoring [grade C].

Vit D

• For individuals receiving pharmacologic therapy for osteoporosis, measurement of serum 25-hydroxyvitamin D should follow three to four months of adequate supplementation and should not be repeated if an optimal level

• (≥ 75 nmol/L) is achieved [grade D].

Vitamin D

• Improves calcium absorption

• Direct action on building bone matrix

• Decreases FALLS

• Increases muscle mass and strength

• Etc etc................

Pyramid for Osteoporosis Prevention and Treatment

Pharmacotherapy(antiresorptives and anabolics)

Address Secondary Factors(drugs and diseases)

Lifestyle Changes(nutrition, physical activity, and fall prevention)

What does this mean for your patients?What does this mean for your patients?

Leading the Effort to Help Prevent and Treat Osteoporosis

US Department of Health and Human Services. Bone Health and Osteoporosis: A Report of the Surgeon General. US Department of Health and Human Services, Office of the Surgeon General; 2004.

WHO Risk Factors WHO Risk Factors

Age (50-90), gender and clinical risk factors:Age (50-90), gender and clinical risk factors:• BMIBMI• Prior fragility fracturePrior fragility fracture• Parental history of hip fractureParental history of hip fracture• Current tobacco smokingCurrent tobacco smoking• Ever long-term use of glucocorticoidsEver long-term use of glucocorticoids• Rheumatoid arthritis or other secondary causesRheumatoid arthritis or other secondary causes• Alcohol intake 3 or more units dailyAlcohol intake 3 or more units daily

Kanis Osteoporos Int 2008;19:385-397

Frailty Factor

Acute Medical Illnesses

Chronic Medical Illnesses

Inactivity

Falling

Medication Check

• Corticosteroids• Anticonvulsants• Aromatase inhibitors

Thyroid hormone• SSRIs

• DepoProvera• Lupron• Narcotics• Cancer Chemo

• Lithium• Thiazolidinediones

Check Lab Tests

Check Lab Tests“Secondary Cause Work Up”

Blood count (CBC)

Chemistries (CMP)

– Calcium, Phosphorus– Kidney tests– Liver tests– Alk Phos

Vitamin D (25hydroxyD)

Thyroid (TSH)

Parathyroid (intact PTH)

Celiac (IgA anti-t-TGase antibody)

Malabsorption/Hypercalciuria

(24 hr Urine Calcium)

Myeloma (SPIEP)

Arthritis (ESR etc.)

Hormones (Testosterone)

Bone Turnover markers (NTX,CTX)

Pyramid for Osteoporosis Prevention and Treatment

Pharmacotherapy(antiresorptives and anabolics)

Address Secondary Factors(drugs and diseases)

Lifestyle Changes(nutrition, physical activity, and fall prevention)

What does this mean for your patients?What does this mean for your patients?

Leading the Effort to Help Prevent and Treat Osteoporosis

US Department of Health and Human Services. Bone Health and Osteoporosis: A Report of the Surgeon General. US Department of Health and Human Services, Office of the Surgeon General; 2004.

“Pharmacotherapy”

(Medications)

Medications

• Prevent and Treat Thresholds

1. The Fracture Patient or < or = -2.5 T score

2. Bone density = or < - 2.0

3. Bone density = or < -1.5 with risk factors

– Guidelines for post menopausal women– And men over 50

2010 clinical practice guidelines for the diagnosisand management of osteoporosis in Canada: summaryAlexandra Papaioannou MD MSc, Suzanne Morin MD MSc, Angela M. Cheung

MD PhD,Stephanie Atkinson PhD, Jacques P. Brown MD, Sidney Feldman MD, David A.

Hanley MD,Anthony Hodsman MD, Sophie A. Jamal MD PhD, Stephanie M. Kaiser MD,

Brent Kvern MD,Kerry Siminoski MD, William D. Leslie MD MSc; for the Scientific Advisory

Council ofOsteoporosis Canada

2008 NOF 2008 NOF Clinician’s Clinician’s

GuideGuide&&

FRAXFRAX

www.nof.org/professionals/Clinicians_Guide.htm

http://www.shef.ac.uk/FRAX

NOF 2008NOF 2008 GuidelinesGuidelinesWho Should Be Treated?Who Should Be Treated?

– Fragility fracture- hip or spineFragility fracture- hip or spine– T-score ≤ -2.5T-score ≤ -2.5– T-score -1.0 to -2.5 (osteopenia) andT-score -1.0 to -2.5 (osteopenia) and

• 10-year all major osteoporosis-related 10-year all major osteoporosis-related fracture probability of ≥ fracture probability of ≥ 20%20% or a or a

• 10-year hip fracture probability ≥ 10-year hip fracture probability ≥ 3%3%

(FRAX)(FRAX)

www.nof.org

WHO Risk Factors WHO Risk Factors

Age (50-90), gender and clinical risk factors:Age (50-90), gender and clinical risk factors:• BMIBMI• Prior fragility fracturePrior fragility fracture• Parental history of hip fractureParental history of hip fracture• Current tobacco smokingCurrent tobacco smoking• Ever long-term use of glucocorticoidsEver long-term use of glucocorticoids• Rheumatoid arthritis or other secondary causesRheumatoid arthritis or other secondary causes• Alcohol intake 3 or more units dailyAlcohol intake 3 or more units daily

Kanis Osteoporos Int 2008;19:385-397

Fracture Fracture probability probability calculated calculated from 12 from 12 world-wide world-wide cohorts cohorts (59,232 (59,232 individuals, individuals, 250K person-250K person-years), years), validated in validated in 11 11 independent independent cohortscohorts (>1 million (>1 million person years)person years)

Fracture Fracture probability probability calculated calculated from 12 from 12 world-wide world-wide cohorts cohorts (59,232 (59,232 individuals, individuals, 250K person-250K person-years), years), validated in validated in 11 11 independent independent cohortscohorts (>1 million (>1 million person years)person years)

Advantages of 2008 GuidelinesAdvantages of 2008 Guidelines

Includes men and other ethnic Includes men and other ethnic groupsgroups

Guides treatment decisions in the Guides treatment decisions in the osteopenic patient where most osteopenic patient where most fractures occur fractures occur FRAXFRAX

Utilizes absolute fracture risk Utilizes absolute fracture risk assessmentassessment

CASES 1 and 2CASES 1 and 2• 75 y/o caucasian female, h/o hip 75 y/o caucasian female, h/o hip

fracture- fatherfracture- father– T-score femoral neck = -2.4T-score femoral neck = -2.4– spine +1.1spine +1.1

• FRAX- 10 year fracture probability = 30% & 20%FRAX- 10 year fracture probability = 30% & 20%

• 52 y/o 1 yr postmenopausal, h/o hip 52 y/o 1 yr postmenopausal, h/o hip fracture- motherfracture- mother– T-score femoral neck = -2.4T-score femoral neck = -2.4– spine L1-L4 = -1.0spine L1-L4 = -1.0

• FRAX- 10 year fracture probability = 14% & 1.5%FRAX- 10 year fracture probability = 14% & 1.5%

CASES 3 and 4CASES 3 and 4• 75 y/o caucasian female, h/o hip 75 y/o caucasian female, h/o hip

fracture in fatherfracture in father– T-score femoral neck = -1.7 T-score femoral neck = -1.7 – spine +1.1spine +1.1

• FRAX- 10 year fracture probability = 20% & 11%FRAX- 10 year fracture probability = 20% & 11%

• 63 y/o, h/o hip fracture & 3 spine fractures 63 y/o, h/o hip fracture & 3 spine fractures in in mother mother – T-score femoral neck = -2.3T-score femoral neck = -2.3– spine L1-L4 = -2.4spine L1-L4 = -2.4

• FRAX- 10 year fracture probability = 19% & 1.8%FRAX- 10 year fracture probability = 19% & 1.8%

CASE 5CASE 5• 86 y/o caucasian female, h/o proximal 86 y/o caucasian female, h/o proximal

humerus fx, sacral fx, distal radius fx humerus fx, sacral fx, distal radius fx with minor fallswith minor falls

– T-score femoral neck = -0.4 T-score femoral neck = -0.4 – spine doesn’t matter unless < -2.5spine doesn’t matter unless < -2.5

• FRAX- 10 year fracture probability = 14% & 2.5%FRAX- 10 year fracture probability = 14% & 2.5%

FRAX Benefits

– BMD + CRFs predict fracture risk better than BMD or CRFs alone

– Can be used without BMD when DXA is not available

– Quantitative assessment of fracture risk

– Can be used with cost-utility analysis

FRAX LimitationsFRAX Limitations• Does not apply to premenopausal patientsDoes not apply to premenopausal patients• Does not apply to treated patientsDoes not apply to treated patients

• Does not include all risk factorsDoes not include all risk factors– Important risk factors not considered

• (falls, BTMs, rare diseases, etc.)– Yes or No response to CRFs does not consider range of risk– May underestimate or overestimate fracture risk

• Does not quantify risk factors; ie:Does not quantify risk factors; ie:– 3 personal pelvis fractures = 1 ankle fracture3 personal pelvis fractures = 1 ankle fracture– 5 mg prednisone for 3 months 2 years ago = 5 mg prednisone for 3 months 2 years ago =

60 mg prednisone daily now60 mg prednisone daily now

• BMD input limited to femoral neck– Cannot use BMD of the spine .... or forearmCannot use BMD of the spine .... or forearm

Surgeon General’s Report

on Bone Health and

Osteoporosis

Pyramid for Osteoporosis Prevention and Treatment

Pharmacotherapy(antiresorptives and anabolics)

Address Secondary Factors(drugs and diseases)

Lifestyle Changes(nutrition, physical activity, and fall prevention)

What does this mean for your patients?What does this mean for your patients?

Leading the Effort to Help Prevent and Treat Osteoporosis

US Department of Health and Human Services. Bone Health and Osteoporosis: A Report of the Surgeon General. US Department of Health and Human Services, Office of the Surgeon General; 2004.

Anti-Resorptives(Anti-Catabolics)

• Bisphosphonates

• Estrogens

• SERMs– Raloxifene (Evista)

• Calcitonin– (Miacalcin, Fortical, Calcimar)

Anti-Resorptives(Anti-Catabolics)

• Bisphosphonates

• Estrogens• SERMs

– Raloxifene (Evista)

• Calcitonin– (Miacalcin, Fortical, Calcimar)

Bisphosphonates Approved for Treating Postmenopausal Osteoporosis

Fosamax Plus D

(alendronate sodium/

cholecalciferol) Tablets

and

Fosamax (alendronate sodium)

TabletsINDICATION

• Increases BMD• Reduces incidence of hip and spine

fractures• GENERIC Alendronate

Actonel and calcium the other six days

(risedronate sodium tablets/calcium 500mg )

and

Actonel (risedronate sodium)

INDICATION• Increases BMD• Reduces incidence of vertebral

fracture and a composite end point of nonvertebral fracture

Boniva

(ibandronate sodium) tablets

Boniva IV infusion

INDICATION• Increases BMD• Reduces incidence of vertebral

fracture

• Reclast IV 5 mg/year

DOSING 5 & 10 mg daily

Fosamax plus D

70 mg/2800 IU once weekly

70 mg/5600 IU once weekly Fosamax

35 mg once weekly or 5mg/day

70 mg once weekly or 10 mg/day Fosamax Liquid

70 mg bottle once weekly

DOSING

Actonel 5 mg/day or 35 mg once weekly

Or with Calcium

75mg 2 days/month

150mgonce a monthADMINISTRATION

Take at least 30 min before first food of the day. Do not lie down for at least 30 min after dosing.

DOSING

Boniva 2.5 mg/day or

150 mg once monthly

ADMINISTRATION

Take at least 60 min before first food of the day. Do not lie down for at least 60 min after dosing.

Boniva 3 mg IV every 3 mos

Fosamax(alendronate)

• Cuts fracture risk by ~50%

Formulations:

5mg, 10mg, 35mg, 70mg

70mg + 2800IU D, 70mg + 5600IU D

70mg Liquid

GENERIC alendronate 70mg weekly

Actonel(risedronate)

• Cuts fracture risk ~50%

Formulations:

5mg, 35mg, 35mg + 6 day calcium packet

75mg two consecutive days monthly

150mg once monthly

Boniva(ibandronate)

• Cuts fracture risk ~50%

Formulations:

2.5mg, 150mg PO monthly

IV 3mg q 3 months

August 17th 2007 New ? Antiresorptive Therapies

Zoledronate (Aclasta)- 5 mg IV annually

Zoledronate (Reclast) 5 mg IV annually

Will this change the way we view pharmacological treatment of

osteoporosis? It has.

HORIZON Pivotal Fracture Trial: Effect on Vertebral Fractures

HORIZON Pivotal Fracture Trial: Effect on Hip Fractures Over 3 Years

HORIZON Pivotal Fracture Trial: Effects on All Clinical Fractures Over 3 Years

HORIZON Pivotal Fracture Trial: Effect on Bone Mineral Density (BMD)

Zoledronate (Reclast) 5 mg IV annually

Given within 90 days of Hip Fracture with a D3 load, and FU Calcium and D

• Increase BMD FN and TH

• Reduction – Spine & non spine fractures 35%– Mortality 28%

» Lyles NEJM 2007 357: 1799-1809

Zoledronate (Aclasta) 5 mg IV annually

Approved for Use in Men

Approved for GIO 2009

Approved for Prevention 2009(2 year dosing regimen)

Bisphosphonates

• Adverse events– GI (same as placebo in studies)– Flu-like “Acute Phase Reaction”– Bone pain– Hypocalcemia – Iritis/Uveitis– ONJ– Unusual subtrochanteric fractures

Comparative Risks

0.6

0.7

6

11

32

387

2668

0 10 20 30 40 50 60 70 80 90 100

Death by Lighting 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

Kanis JA et al. Osteoporos Int. 2001;12:417-427. Pharmcoepidemiol Drug Saf. 2003;12:195-202. National Center for Health Statistics. JADA. 2006;137:1144-1150. www.nssl.noaa.gov/papers/techmemos/NWS-SR-193/techmemo-sr193-4.html

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

Comparative Risks

Data so far

Subtrochanteric fractures comprise 2-4% of all “Hip Fractures” (fairly uncommon)

• “Unusual or atypical Subtroch femur fractures”– Bisphosphonate associated fractures comprise 1/3 of

those- criteria are:• Thigh pain prodrome, “pseudo-fracture appearance”, lateral

“beaking”, transverse fracture pattern

Trabecular Bone Showed No Qualitative or Quantitative Abnormalities in FLEX*Alendronate/Placebo Group:

Average bone volume fraction, 16.5%

Alendronate/Alendronate Group: Average bone volume fraction,

16.6%

* On-edge view is depicted.1. Recker R et al. J Bone Miner Res. 2004;19(suppl 1):S45. 2. Data available on request from Merck & Co., Inc. Please specify 20650700(1)–FOS.

Alendronate Improved Cortical Thickness in Hip

Greenspan SL et al. J Bone Miner Res. 2005;20:1525–1532.*P<0.05 vs baseline; †P<0.05 vs placebo.

Ch

ang

e, %

*,†

*,† *,†

–3

–2

–1

0

1

2

3

4

5

Narrow NeckRegion

IntertrochantericRegion

Femoral ShaftRegion

Placebo Alendronate

Current Thought

Long term continuation: > 5 years+ Reduction in clinical vertebral fracture with

long-term ALN (10 years)• Suggests most benefit from continuing ALN in those at

high risk of new vertebral fracture Others might be discontinued

• No clinical evidence for compromise in bone quality withlong-term treatment (any bisphosphonates)

• Little guidance for long term continuation of bisphosphonates other than ALN

• (6 year trial of ZOL coming—study end 12/09)

Black 2010

Current Thought

Continuing ALN for 10 years instead of stopping after 5 years

• Reduces NVF risk in women even without prevalent vertebral fracture, whose FN T-scores, achieved after 5 years of ALN, are < or = -2.5

• But does not reduce risk of NVF in women whose T-scores are > -2.

Schwartz JBMR 5-2010

Current Thought

• 5 year plan

• 10 year plan

Anabolic Therapy

Action on the Osteoblast

rather than the

Osteoclast

ForteoTeriparitide (PTH 1-34)

• The only anabolic agent for osteoporosis– Acts on the osteoblast– Given SubQ daily– Approved November 2002– Indications- severe osteoporosis, GIO, men– Given for 12 - 24 months– Followed with an antiresorptive agent

FORTEO® (teriparatide [rDNA origin] injection) Reduces the Risk of 1 New Vertebral Fractures

*p <.001

Placebo(n=448)

FORTEO(n=444)

64

22

Risk ReductionRelative: 65%*Absolute: 9.3%*

20

8

4

6

10

12

14

16

Relative Risk 0.35 95% CI, 0.22 to 0.551

% o

f W

omen

Wit

h N

ew V

erte

bral

Fra

ctur

e

1. N Engl J Med. 2001;344:1434-1441.

• See Black Box Warning (slide 32) and Important Safety Information for FORTEO (slides 1, 16, 34-36). • Full Prescribing Information for FORTEO is available at this presentation.

FORTEO® (teriparatide [rDNA origin] injection) Increased Lumbar Spine BMD in Postmenopausal Women With

Osteoporosis*,1

BM

D (

Mea

n %

Ch

ange

± S

E)

11.8%†

Months since randomization

0

2

4

6

8

10

12

14

0 3 6 9 12 15 18

FORTEO (N=129)

Placebo (N=137)

3.9%†

6.9%†

9.4%†

*266 subjects treated for 18 months and with data available at all time points †p<0.001 for FORTEO vs. placebo at each post-baseline time point

1. Data on file, Lilly Research Laboratories.

• See Black Box Warning (slide 32) and Important Safety Information for FORTEO (slides 1, 16, 34-36). • Full Prescribing Information for FORTEO is available at this presentation.

Teriparatide

• Adverse events– Osteosarcoma in rats – Hypercalcemia 11% vs 1%– Dizziness 2.6% vs 1.4%– Leg cramps 2.6% vs 1.3%

FDA Indications for Osteoporosis

Drug PMO GIO (Women, Men) Men

Prevention Treatment Prevention Treatment

Estrogen

Alendronate PO (Fosamax®)

Risedronate PO (Actonel®)

Ibandronate PO (Boniva®)

Ibandronate IV (Boniva®)

Zoledronate IV (Reclast®) Calcitonin IN (Miacalcin®, Fortical®)

Raloxifene PO (Evista®)

Teriparatide SC (Forteo®)

BMD Response to TherapyMedication Spine Hip

Estrogen Alendronate (Fosamax®) Risedronate (Actonel®) Ibandronate (Boniva®) Zoledronate (Reclast®) Salmon Calcitonin

(Miacalcin®, Fortical®) - -

Raloxifene (Evista®) Teriparatide (Forteo®)

Fracture Risk Reduction in RCTs

Medication Spine Nonvertebral Hip

Estrogen Alendronate (Fosamax®) Risedronate (Actonel®) Ibandronate (Boniva®) Zoledronate (Reclast®) Calcitonin

(Miacalcin®, Fortical®) Raloxifene (Evista®) Teriparatide (Forteo®)

New and Emerging Treatments

Antiresorptive (anti-catabolic)

• Denosumab (Prolia)• Odanacatib• Lasofoxifene• Bazedoxifene• CE/bazedoxifene• New delivery systems -

oral salmon calcitonin

Osteo-anabolic (bone-forming)

• Sclerostin inhibitor• Variations of PTH• Endogenous PTH

stimulation - calcium sensing receptor antagonist (calcilytic)

• New delivery systems – transdermal PTH

Strontium ranelate Combinations of antiresorptive and anabolic

Denosumab (Prolia)(Anti-resorptive agent)

• Approved June 1, 2010

• Made by Amgen

• A fully human monoclonal antibody that binds with high affinity to, and inhibits the activity of, human RANK ligand, a key mediator of osteoclast activity

RANKL is Implicated in Bone Loss Across a Broad Range of Conditions

• Postmenopausal osteoporosis• Male osteoporosis• Disuse osteoporosis• Transplantation osteoporosis• Inflammatory arthritis• Periprosthetic osteolysis• Hyperparathyroidism• Cancer-induced bone loss

– Bone metastases, multiple myeloma• Treatment-induced bone loss

– Glucocorticoids, aromatase inhibitors, androgen deprivation therapy

RANKL Stimulates Bone Resorption

Growth Factors HormonesCytokines

RANK

RANKL

Activated

Osteoclast

CFU-M

Pre-Fusion

Osteoclast

Multinucleated

Osteoclast

RANK Ligand Is Essential for Osteoclast Formation, Function, and Survival

BoneCFU-M = colony forming unit macrophage

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

Osteoblast

Lineage

Denosumab Mechanism of Action

Growth Factors HormonesCytokines

BoneCFU-M = colony forming unit macrophage

Osteoblast

Lineage

Osteoclast

CFU-M

Pre-Fusion

Osteoclast

Multinucleated

Osteoclast

RANK

RANKL

OPGDmab

Dmab-FREEDOM Results

• 68% decrease in vertebral fractures – 2.3% vs 7.2%, P<0.0001

• 40% decrease in hip fractures – 0.7% vs. 1.2%, P=0.036

• 20% decrease in non-vertebral fractures – 6.5% vs. 8.0%, P=0.011

• Dmab increased BMD and reduced BTMs compared to placebo

• AEs and SAEs generally similar to placebo– No increased risk of cancer, infection, CV disease, delayed

fracture healing, hypocalcemia, no ONJ– Increased risk of cellulitis, eczema, flatulence– Decreased risk of falls, concussion

Cummings SR et al. N Engl J Med. 2009;361:1-10.

Choosing TherapyChoosing Therapy

• Deciding who to treatDeciding who to treat– Utility of DXA and VFAUtility of DXA and VFA– Using NOF 2008 & FRAX to guide clinical decisionsUsing NOF 2008 & FRAX to guide clinical decisions

• Deciding how to treatDeciding how to treat– Non-pharmacologic therapyNon-pharmacologic therapy– Pharmacologic therapyPharmacologic therapy

• Initial choice of therapy- Anticatabolic or Anabolic agentInitial choice of therapy- Anticatabolic or Anabolic agent• Prevention vs Treatment Dosing Prevention vs Treatment Dosing • Sequential therapy- Forteo Sequential therapy- Forteo • Repeat therapy- ForteoRepeat therapy- Forteo

Clinical Challenges after Starting Treatment

• Motivating the patient to fill the prescription, take it correctly, regularly, for a length of time to benefit- Cost?

• Determining how, when, (or if) to follow and monitor the patient to assure that benefit is achieved

• Managing Nonresponders? Suboptimal Responders?

• Deciding when (if ever) to stop or change therapy

• Knowing when (if ever) to restart, if treatment is stopped- The Drug Holiday

• Managing side effects, perceived side effects, and fear of side effects

Surgeon General’s Report

on Bone Health and

Osteoporosis

Pyramid for Osteoporosis Prevention and Treatment

Pharmacotherapy(antiresorptives and anabolics)

Address Secondary Factors(drugs and diseases)

Lifestyle Changes(nutrition, physical activity, and fall prevention)

What does this mean for your patients?What does this mean for your patients?

Leading the Effort to Help Prevent and Treat Osteoporosis

US Department of Health and Human Services. Bone Health and Osteoporosis: A Report of the Surgeon General. US Department of Health and Human Services, Office of the Surgeon General; 2004.

2008 NOF 2008 NOF Clinician’s Clinician’s

GuideGuide&&

FRAXFRAX

www.nof.org/professionals/Clinicians_Guide.htm

http://www.shef.ac.uk/FRAX

NOF 2008 Treatment Guidelines

Osteoporosis• T-score -2.5 or less at

FN or LS after evaluation for secondary causes, or

• Hip or vertebral (clinical or morphometric) fracture

Osteopenia• T-score between -1.0

and -2.5 at FN or LS, and

• FRAX 10-year probability of major osteoporotic fracture ≥20% or hip fracture ≥3%

Postmenopausal women and men age 50 and older with the following should be considered for treatment, after evaluation for secondary causes of osteoporosis:

National Osteoporosis Foundation. Clinician’s Guide to Prevention and Treatment of Osteoporosis. 2008.

Conclusions• Exercise, Fall Risk

• Nutrition

• No smoking, minimal drinking

• Calcium 1200 per day

• Vitamin D ~1200- 2000 per day

• Central bone density test - DXA & VFA

• Secondary Cause Review-Imaging & Lab workup

• Medications

Anti-resorptives, Anabolics

Fracture Risk Assessment

Intervention Thresholds

Treatment

Follow-up

Will I end up like my mother?

But, do I really have

to take those

medicines? I saw on the News

last night.....

Thank You

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