Transcript OSTEOPOROSIS THE SILENT DISEASE

Prevention Treatment of
Osteoporosis in Geriaterics
Dr H. Soleimani
Department of Rheumatology
Shahid Sadughi Hospital
Will I end
up like my
mother?
But, do I
really have
to take
those
medicines?
Fracture Risk Assessment
I saw on
the News
Intervention Thresholds
last
night.....
Treatment
Follow-up
Leading the Effort to Help Prevent and
Treat Osteoporosis
Pharmacotherapy
(antiresorptives and anabolics)
Address Secondary Factors
(drugs and diseases)
Lifestyle Changes
(nutrition, physical activity, and fall prevention)
Pyramid for Osteoporosis Prevention and Treatment
What does this mean for your patients?
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
Fractures in Women Are Common:
Incidence of Chronic Diseases
Annual Incidence, million
2.0
1,500,000
1.5
1.0
0.5
0
250,000
Fracture1
345,000
Hip fracture1 Heart attack2
Women with osteoporosis
373,000
211,240
Stroke2
Breast cancer3
All women
Risk of osteoporotic fracture in 1 year is greater than
combined risk of heart attack, stroke, and breast cancer.
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.
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
GE Lunar
Prodigy
Hologic
Delphi
Central DXA
Measures bone density at the hip and spine
DXA image of the hip
DXA image of the lumbar spine
NOF 2008 Guidelines
Who Should be Tested?
• Women age 65 and older
• Men age 70 and older
• Women and men over 50 with risk
factors
• Patients with a fracture after age 50
Vertebral Fracture
Assessment
Lateral Spine
Imaging with
Fan-Array
Dual Energy
X-ray
Absorptiometry
Leading the Effort to Help Prevent and
Treat Osteoporosis
Surgeon
General’s Report
on
Bone Health and
Osteoporosis
Pharmacotherapy
(antiresorptives and anabolics)
Address Secondary Factors
(drugs and diseases)
Lifestyle Changes
(nutrition, physical activity, and fall prevention)
Pyramid for Osteoporosis Prevention and Treatment
What does this mean for your patients?
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 women
JAMA 2002
• Activity of any type reduces fracture riskBalance, 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 2007
Medical 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................
Leading the Effort to Help Prevent and
Treat Osteoporosis
Pharmacotherapy
(antiresorptives and anabolics)
Address Secondary Factors
(drugs and diseases)
Lifestyle Changes
(nutrition, physical activity, and fall prevention)
Pyramid for Osteoporosis Prevention and Treatment
What does this mean for your patients?
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
Age (50-90), gender and clinical risk factors:
• BMI
• Prior fragility fracture
• Parental history of hip fracture
• Current tobacco smoking
• Ever long-term use of glucocorticoids
• Rheumatoid arthritis or other secondary causes
• Alcohol 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)
Leading the Effort to Help Prevent and
Treat Osteoporosis
Pharmacotherapy
(antiresorptives and anabolics)
Address Secondary Factors
(drugs and diseases)
Lifestyle Changes
(nutrition, physical activity, and fall prevention)
Pyramid for Osteoporosis Prevention and Treatment
What does this mean for your patients?
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 diagnosis
and management of osteoporosis in Canada: summary
Alexandra 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 of
Osteoporosis Canada
2008 NOF
Clinician’s
Guide
&
FRAX
www.nof.org/professionals/Clinicians_Guide.htm
http://www.shef.ac.uk/FRAX
NOF 2008 Guidelines
Who Should Be Treated?
– Fragility fracture- hip or spine
– T-score ≤ -2.5
– T-score -1.0 to -2.5 (osteopenia) and
• 10-year all major osteoporosis-related
fracture probability of ≥ 20% or a
• 10-year hip fracture probability ≥ 3%
(FRAX)
www.nof.org
WHO Risk Factors
Age (50-90), gender and clinical risk factors:
• BMI
• Prior fragility fracture
• Parental history of hip fracture
• Current tobacco smoking
• Ever long-term use of glucocorticoids
• Rheumatoid arthritis or other secondary causes
• Alcohol intake 3 or more units daily
Kanis Osteoporos Int 2008;19:385-397
Fracture
probability
calculated
from 12
world-wide
cohorts
(59,232
individuals,
250K personyears),
validated in
11
independent
cohorts
(>1 million
person years)
Advantages of 2008 Guidelines
 Includes men and other ethnic
groups
 Guides treatment decisions in the
osteopenic patient where most
fractures occur FRAX
 Utilizes absolute fracture risk
assessment
CASES 1 and 2
• 75 y/o caucasian female, h/o hip
fracture- father
– T-score femoral neck = -2.4
– spine +1.1
• FRAX- 10 year fracture probability = 30% & 20%
• 52 y/o 1 yr postmenopausal, h/o hip
fracture- mother
– T-score femoral neck = -2.4
– spine L1-L4 = -1.0
• FRAX- 10 year fracture probability = 14% & 1.5%
CASES 3 and 4
• 75 y/o caucasian female, h/o hip
fracture in father
– T-score femoral neck = -1.7
– spine +1.1
• FRAX- 10 year fracture probability = 20% & 11%
• 63 y/o, h/o hip fracture & 3 spine fractures
in mother
– T-score femoral neck = -2.3
– spine L1-L4 = -2.4
• FRAX- 10 year fracture probability = 19% & 1.8%
CASE 5
• 86 y/o caucasian female, h/o proximal
humerus fx, sacral fx, distal radius fx
with minor falls
– T-score femoral neck = -0.4
– spine doesn’t matter unless < -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 Limitations
• Does not apply to premenopausal patients
• Does not apply to treated patients
• Does 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:
– 3 personal pelvis fractures = 1 ankle fracture
– 5 mg prednisone for 3 months 2 years ago =
60 mg prednisone daily now
• BMD input limited to femoral neck
– Cannot use BMD of the spine .... or forearm
Leading the Effort to Help Prevent and
Treat Osteoporosis
Surgeon
General’s Report
on
Bone Health and
Osteoporosis
Pharmacotherapy
(antiresorptives and anabolics)
Address Secondary Factors
(drugs and diseases)
Lifestyle Changes
(nutrition, physical activity, and fall prevention)
Pyramid for Osteoporosis Prevention and Treatment
What does this mean for your patients?
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)
Tablets
INDICATION
• Increases BMD
• Reduces incidence of hip and spine
fractures
• GENERIC Alendronate
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
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
DOSING
Actonel 5 mg/day or
35 mg once weekly
Or with Calcium
75mg 2 days/month
150mgonce a month
ADMINISTRATION
Take at least 30 min before first
food of the day. Do not lie down
for at least 30 min after dosing.
Boniva
(ibandronate sodium) tablets
Boniva IV infusion
INDICATION
• Increases BMD
• Reduces incidence of vertebral
fracture
• Reclast IV 5 mg/year
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
Any Fragility Fracture (1)
2668
387
Hip Fracture (1)
Anaphylaxis from PCN Shot
32
Death by MVA
11
Death by Murder
6
ONJ- Osteoporosis Patient
0.7
Death by Lighting Strike in NM
0.6
0
(1) Women age 65-69 (from Swedish
National Bureau of Statistics and
database of Olmsted County, MN, USA.)
10
20
30
40
50
60
70
80
90 100
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
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
Placebo
5
Change, %
4
3
Alendronate
*,†
*,†
*,†
2
1
0
–1
–2
–3
Narrow Neck
Region
Intertrochanteric
Region
*P<0.05 vs baseline; †P<0.05 vs placebo.
Greenspan SL et al. J Bone Miner Res. 2005;20:1525–1532.
Femoral Shaft
Region
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 with
long-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
Forteo
Teriparitide (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
% of Women With
New Vertebral Fracture
Relative Risk 0.35
95% CI, 0.22 to 0.551
16
14
64
12
10
Risk Reduction
Relative: 65%*
Absolute: 9.3%*
8
6
4
22
2
0
Placebo
FORTEO
(n=448)
(n=444)
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.
*p <.001
BMD (Mean % Change ± SE)
FORTEO® (teriparatide [rDNA origin] injection)
Increased Lumbar Spine BMD in Postmenopausal Women With
Osteoporosis*,1
FORTEO (N=129)
Placebo (N=137)
14
*266
12
subjects treated for 18 months and with data available at all time points
for FORTEO vs. placebo at each post-baseline time point
†p<0.001
11.8%†
10
6.9%†
8
9.4%†
3.9%†
6
4
2
0
0
3
6
9
12
15
Months since randomization
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.
18
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
Prevention
GIO (Women, Men)
Treatment
Estrogen

Alendronate PO (Fosamax®)


Risedronate PO (Actonel®)


Ibandronate PO (Boniva®)



Teriparatide SC (Forteo®)












Calcitonin IN (Miacalcin®, Fortical®)
Raloxifene PO (Evista®)
Treatment

Ibandronate IV (Boniva®)
Zoledronate IV (Reclast®)
Prevention
Men



BMD Response to Therapy
Medication
Spine
Hip
Zoledronate (Reclast®)










Salmon Calcitonin
(Miacalcin®, Fortical®)
-
-




Estrogen
Alendronate (Fosamax®)
Risedronate (Actonel®)
Ibandronate (Boniva®)
Raloxifene (Evista®)
Teriparatide (Forteo®)
Fracture Risk Reduction in RCTs
Medication
Spine
Nonvertebral
Hip






Zoledronate (Reclast®)







Calcitonin
(Miacalcin®, Fortical®)

Estrogen
Alendronate (Fosamax®)
Risedronate (Actonel®)
Ibandronate (Boniva®)
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
RANK Ligand Is Essential for Osteoclast Formation, Function, and Survival
RANKL
CFU-M
RANK
Pre-Fusion
Osteoclast
Multinucleated
Growth Factors
Hormones
Cytokines
Osteoclast
Activated
Osteoclast
Osteoblast
Lineage
Adapted from Boyle WJ, et al. Nature. 2003;423:337-342.
Bone
CFU-M = colony
forming unit
macrophage
Denosumab Mechanism of Action
RANKL
RANK
CFU-M
OPG
Dmab
Pre-Fusion
Osteoclast
Multinucleated
Growth Factors
Hormones
Cytokines
Osteoclast
Osteoclast
Osteoblast
Lineage
Bone
CFU-M = colony
forming unit
macrophage
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 Therapy
• Deciding who to treat
– Utility of DXA and VFA
– Using NOF 2008 & FRAX to guide clinical decisions
• Deciding how to treat
– Non-pharmacologic therapy
– Pharmacologic therapy
•
•
•
•
Initial choice of therapy- Anticatabolic or Anabolic agent
Prevention vs Treatment Dosing
Sequential therapy- Forteo
Repeat 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 stoppedThe Drug Holiday
• Managing side effects, perceived side effects, and fear of side
effects
Leading the Effort to Help Prevent and
Treat Osteoporosis
Surgeon
General’s Report
on
Bone Health and
Osteoporosis
Pharmacotherapy
(antiresorptives and anabolics)
Address Secondary Factors
(drugs and diseases)
Lifestyle Changes
(nutrition, physical activity, and fall prevention)
Pyramid for Osteoporosis Prevention and Treatment
What does this mean for your patients?
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
Clinician’s
Guide
&
FRAX
www.nof.org/professionals/Clinicians_Guide.htm
http://www.shef.ac.uk/FRAX
NOF 2008 Treatment Guidelines
Postmenopausal women and men age 50 and older
with the following should be considered for treatment,
after evaluation for secondary causes of osteoporosis:
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%
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
Will I end
up like my
mother?
But, do I
really have
to take
those
medicines?
Fracture Risk Assessment
I saw on
the News
Intervention Thresholds
last
night.....
Treatment
Follow-up
Thank You
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