Transcript Update Treatment in Osteoporosis

Update Treatment in
Osteoporosis
Chatlert Pongchaiyakul, MD.
Department of Medicine, Faculty of Medicine
Khon Kaen University
Falling
BMD + Bone quality
Bone strength
Fracture
PATHWAY OF OSTEOPOROTIC FRACTURES
INCREASED
RESORPTION
DECREASED
FORMATION
TENDENCY TO FALL
HEIGHT
OF FALL
PROTECTIVE
RESPONSE
LOW BONE MASS
MICROARCHITECTURE
DETERIORATION
FORCE OF IMPACT
ON BONE
OSTEOPOROSIS
POOR
QUALITY
SOFT
TISSUE
CUSHION
DECREASED
BONE
STRENGTH
FRACTURE
Goals of Therapy
• Prevent first fragility fracture or future
fractures if one has already occurred
• Stabilize/increase bone mass
• Relieve symptoms of fractures and/or
skeletal deformities
• Improve mobility and functional status
• Initiate lifestyle changes to enhance
prevention of fractures
INTERVENTIONS FOR OSTEOPOROSIS
• Who should be treated?
• When the intervention should be started?
• How long should the intervention be
applied?
• What parameter(s) should be assessed for
the efficacy?
• What agent(s) should be used?
Dosage and regimen
Efficacy and other benefits
Cost and adverse effects
POSTMENOPAUSAL OSTEOPOROSIS
WHO SHOULD BE TREATED ?
THE NOF EVIDENCE-BASED ANALYSES 1998
• AT MENOPAUSE
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All eligible women should be offered HRT
AGE <65 Y AND NOT RECEIVING HRT
T-score <-1.5
AGE >65 Y AND NOT RECEIVING HRT
T-score <-1.5 with risk factor(s)
T-score <-2 without a risk factor
WOMEN WITH SPINE OR HIP FRACTURE
Women’s Health Initiative (WHI): Overview
• Large investigation of prevention strategies
for cancer, cardiovascular disease, and
osteoporotic fracture
• Initiated 1992, planned completion 2007
• Postmenopausal women aged 50-70 in to
clinical trial (N=64,500) or observational
study (N=100,000)
Women’s Health Initiative (WHI): Design
• Randomized, controlled, primary prevention trial
(HRT: 8.5 yrs planned)
• 16,608 postmenopausal women aged 50-79
(mean 63.3) with intact uterus at baseline
• Received conjugated equine estrogens (CEE),
0.625 mg/d plus medroxyprogesterone acetate
(MPA) 2.5 mg/d (n=8,506) or placebo (n=8,102)
• Primary outcome = CHD
• Primary adverse outcome = invasive breast cancer
• Global index summarizing risks vs. benefits included
stroke, pulm embolism, endometrial CA, colorectal
CA, hip fracture, death
Reductions in Fx rates vs. PBO
HRT: Women’s Health Initiative
Fracture Outcomes
Hip
Vertebral
Other Fx
Total Fx
-23%
-34%
-34%
Writing group for WHI investigators JAMA 2002,288:321-33.
-24%
HRT component of the WHI
Summary of Results at 5.2 years (Early termination)
In postmenopausal women with intact uterus, HRT
Was associated with:
• 15% increase in global index (risks > benefits)
• 29% increase in coronary heart disease events
• 22% increase in total cardiovascular disease
• 26% increase in invasive breast cancer
• 41% increase in stroke
• 111% increase in venous thromboembolic disease
• 37% decrease in colorectal cancer
• 34% decrease in hip and clinical vertebral fractures
POSTMENOPAUSAL OSTEOPOROSIS
WHO SHOULD BE TREATED ?
THE NOF EVIDENCE-BASED ANALYSES 2004
• Initiate therapy to reduce fracture
risk in women with:
• BMD T-score <-2.0 by hip DXA with no
•
risk factors
BMD T-score <-1.5 by hip DXA with one
or more risk factors
• A prior vertebral or hip fracture
http://www.nof.org/physguide/pharmacologic.htm
PATHWAY OF OSTEOPOROTIC FRACTURES
INCREASED
RESORPTION
DECREASED
FORMATION
Prevent falling
Hip protector
TENDENCY TO FALL
HEIGHT
OF FALL
PROTECTIVE
RESPONSE
LOW BONE MASS
Drug
MICROARCHITECTURE
DETERIORATION
FORCE OF IMPACT
ON BONE
OSTEOPOROSIS
POOR
QUALITY
SOFT
TISSUE
CUSHION
DECREASED
BONE
STRENGTH
FRACTURE
OSTEOPOROTIC FRACTURES
PREVENTION AND TREATMENT
• General interventions for all
• Pharmacologic interventions
Antiresorbing agents
Bone formation stimulating agents
• Prevention of falls and other forces or
impacts on bone
OSTEOPOROSIS
GENERAL INTERVENTIONS FOR ALL
• Adequate calcium intake (0.5 -1 g. Eca/d)
• Adequate vitamin D intake (400 - 800 u/d)
• Adequate vitamin and trace elements
• Appropriate weight bearing exercise
• Avoid agents known to toxic bone
Cigarette, alcohol, coffee, carbonated drinks
High protein intake
Glucocorticoids, thyroid hormone
Pharmacologic Treatment of PMO:
Overview
Treatment
Estrogen replacement therapy
(ERT)….????
Selective estrogen receptor
modulators (SERMs): raloxifene
Calcitonin
Bisphosphonates
Action
Inhibit bone resorption
Maintain or increase bone mass
Reduce fracture risk
Therapeutic agents used in Osteoporosis
Inhibitors
of Bone Resorption
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Stimulator
of Bone formation
Estrogens +/- progestogens
• Fluoride
SERMs
• Parathyroid hormone
Bisphosphonates
• Strontium
Calcitonin
• Vit K2
Calcium
Complex Action
Strontium
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Vitamin D and its derivatives
Anabolic steriods
Tibolone
Current treatment options for osteoporosis
Treatment
Dosage Form
Calcium and vitamin D
Oral (daily)
Hormone replacement therapy (HRT)
Oral, transdermal
Calcitonin
Nasal spray (daily)
Selective estrogen receptor modulators (SERMs)
Oral (daily)
Bisphosphonate: alendronate
Oral (daily or weekly)
Bisphosphonate: risedronate
Oral (daily or weekly)
Bisphosphonate: Ibandronate
Oral (daily or monthly)
Parathyroid hormone (PTH) (teriparatide)
Daily subcutaneous
Strontium ranelate
Oral (daily)
Expectations of an Agent for
Treatment of Osteoporosis
• Consistency across efficacy endpoints
• Increase in BMD at all sites
• Consistent fracture reduction
– Vertebral fracture (morphometric and clinical)
– Non-vertebral fracture
– Hip fracture
• Results reproducible and consistent across
– Subgroups
– Multiple trials
– Differing populations
• Established long-term efficacy and safety
EVIDENCE-BASED MEDICINE
• A new paradigm for medical practice
• Stresses the evidence from clinical
research
• De-emphasizes
Intuition (การหยัง่ รู ้, สังหรณ์ใจ)
Unsystematic clinical experience
Pathophysiologic rationale (only)
CLINICAL DATA SUITABLE FOR USING AS
AN EVIDENCE-BASED
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Good research methodology and design
Large sample size
Specific study objective(s)
Randomized controlled trial
Meta-analysis
Longitudinal cohort
Gold standard control
PREVENTION OF OSTEOPOROSIS
FROM CLINICAL RESEARCH TO
AN EVIDENCE-BASED CLINICAL PRACTICE
• Research design
• Target population: cases, controls
• Type and regimen of an intervention
• Assessment of benefits of an intervention
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•
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Fracture rate/risk, Bone mass, Skeletal sites,
Cost and adverse effects of an intervention
Duration of an intervention to achieve the
benefit
Co-intervention: Ca, vit D supplements
ASSESSMENT OF THE EFFICACY OF
AN INTERVENTION FOR OSTEOPOROSIS
• Mortality and morbidity (Ideal goal)
• Fracture rate / risk (gold standard)
Clinical vs. Radiographic
% of cases vs. number/…. patient years
Absolute risk vs. Relative risk
• Bone mass: DXA (BMD), QUS
• Bone quality: QUS
• Bone markers: OC, PYD, dPYD, NTX, CTX
• Cost-benefit: number needed to treat
PREVENTION OF OSTEOPOROSIS
FROM CLINICAL RESEARCH TO
AN EVIDENCE-BASED CLINICAL PRACTICE
• Subjects usually received Eca 0.5-1 g/d and
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•
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vitamin D 400-800 U/d in most study.
Duration of an intervention to achieve goals
< 3 m: Changes in bone markers (>CV)
> 1 y: Changes in BMD (>CV)
> 2y: Changes in fracture rate
The more severe osteoporosis the more
benefits obtained from an intervention.
The benefit might be skeletal site specific.
Treat to targets
• Osteoporosis
High turnover
Low BMD
High fracture
Mortality&Morbidity
• Treatment
Dec turnover
Maintain or inc. BMD
Dec. fracture
Dec. Mortality&Morbidity
EFFICACY IN PRESERVING BMD AND DECREASING
FRACTRUE RISK OF VARIOUS INTERVENTIONS
INC.
BMD
• HRT
• Raloxifene
• Tibolone
• Etidronate
• Alendronate
• Risedronate
• Ibandronate
• Calcitonin
• Calcitriol
• Calcium + vitamin D
• Fluoride
• PTH
DEC. FRCATURE RISK
OBS.
RCT
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BMD increase does not reflect a proportional
to reduction of relative risk of fracture
Studies
Δ BMD (%)
%reduction of fracture
risk
PROOF
0.5
36
2.6
30
6.2
47
6.8
44
5.2
41
6.3
49
(Chesnut et al., Am.J.Med.2000)
MORE
(Ettinger et al., JAMA 1999)
FIT1
(Black et al., Lancet 1996)
FIT2
(Cummings et al., JAMA 1998)
VERT-NA
(Harris et al., JAMA 1999)
VERT-MN
(Reginster et al. , Osteoporosis
Int 2000)
Approved drug for treatment and prevention
for osteoporosis
• Alendronate
10 mg/d or 70 mg/wk
5 mg/d or 35 mg/wk
10 mg/d
• Risedronate
5 mg/d or 35 mg/wk
5 mg/d
• Ibandronate
รั กษา postmenopausal osteoporosis and male
osteoporosis
ป้องกัน postmenopausal osteoporosis
รั กษา glucocorticoid-induced osteoporosis
รั กษาและป้องกัน postmenopausal osteoporosis
and male osteoporosis
รั กษาและป้องกัน glucocorticoid-induced osteoporosis
2.5 mg/d or 150 mg/mo รั กษาและป้องกัน postmenopausal osteoporosis
Approved drug for treatment and prevention
for osteoporosis
• Raloxifene
60 mg/d
รั กษาและป้องกัน postmenopausal osteoporosis
• Calcitonin
200 IU/d
รั กษา postmenopausal osteoporosis
• PTH
20 µg/d
รั กษา severe osteoporosis in men and women with
high risk of fracture
• Strontium renelate
2 g/d
รั กษา postmenopausal osteoporosis
Efficacy for fracture reduction: update 2005
Drug
Vertebral fracture
Hip fracture
Alendronate
+++
++
Risedronate
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++
Ibandronate
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0
Raloxifene
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0
Calcitonin (nasal)
+
0
Vitamin D
derivatives
PTH
+
0
++++
0
Strontium ranelate
+++
++
INTERVENTIONS FOR OSTEOPOROSIS
• Who should be treated?
• When the intervention should be started?
• How long should the intervention be
applied?
• What parameter(s) should be assessed for
the efficacy?
• What agent(s) should be used?
Dosage and regimen
Efficacy and other benefits
Cost and adverse effects
How long?
• Bisphosphonates
Alendronate: 10 years
Risedronate: 7 years
Ibandronate: 2 years
• Serm: Raloxifene: 8 years
• Calcitonin: 5 years
• Intact PTH: 2 years
• Strontium ranelate: 3 years
Monitoring Treatment
• Needs lifelong management
• DXA 1-2 years interval
• Drugs may decrease risk of fracture
even when there is no apparent
increase in BMD.
• BMD has some precision error.
• Biochemical markers show
considerable variability within
individuals.
Take home
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Osteoporosis: Common
Identify risk factors & clinical risk index
Diagnosis: BMD- gold standard
Prevention: increase peak bone mass
prevent bone loss
• Treatment: pharmaco and non-pharmaco
• F/U: monitor
• All non-traumatic fracture: don’t forget
osteoporosis