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
nu
al I
nci
den
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n
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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