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Update Treatment in
Osteoporosis
Chatlert Pongchaiyakul, MD.
Department of Medicine, Faculty of Medicine
Khon Kaen University
Falling
BMD + Bone quality Fracture
Bone strength
PATHWAY OF OSTEOPOROTIC FRACTURES
INCREASED DECREASED TENDENCY TO FALL
RESORPTION FORMATION
HEIGHT
OF FALL
PROTECTIVE
LOW BONE MASS RESPONSE
MICROARCHITECTURE SOFT
DETERIORATION TISSUE
CUSHION
OSTEOPOROSIS FORCE OF IMPACT
ON BONE
DECREASED FRACTURE
POOR
BONE
QUALITY
STRENGTH
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
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
HRT: Women’s Health Initiative
Fracture Outcomes
Hip Vertebral Other Fx Total Fx
Reductions in Fx rates vs. PBO
-23% -24%
-34% -34%
Writing group for WHI investigators JAMA 2002,288:321-33.
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 DECREASED TENDENCY TO FALL
Prevent falling
RESORPTION FORMATION Hip protector
HEIGHT
OF FALL
PROTECTIVE
LOW BONE MASS RESPONSE
MICROARCHITECTURE SOFT
Drug DETERIORATION TISSUE
CUSHION
OSTEOPOROSIS FORCE OF IMPACT
ON BONE
DECREASED FRACTURE
POOR
BONE
QUALITY
STRENGTH
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)….????
Action
Selective estrogen receptor
modulators (SERMs): raloxifene Inhibit bone resorption
Maintain or increase bone mass
Reduce fracture risk
Calcitonin
Bisphosphonates
Therapeutic agents used in Osteoporosis
Inhibitors Stimulator
of Bone Resorption of Bone formation
• Estrogens +/- progestogens • Fluoride
• SERMs • Parathyroid hormone
• Bisphosphonates • Strontium
• Calcitonin • Vit K2
• Calcium
• Strontium Complex Action
• 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 (การหยังรู ้, สังหรณ์ใจ)
่
Unsystematic clinical experience
Pathophysiologic rationale (only)
CLINICAL DATA SUITABLE FOR USING AS
AN EVIDENCE-BASED
• 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
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
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 • Treatment
High turnover Dec turnover
Low BMD Maintain or inc. BMD
High fracture Dec. fracture
Mortality&Morbidity Dec. Mortality&Morbidity
EFFICACY IN PRESERVING BMD AND DECREASING
FRACTRUE RISK OF VARIOUS INTERVENTIONS
INC. DEC. FRCATURE RISK
BMD OBS. RCT
• HRT +++ +++ +
• Raloxifene +++ ++
• Tibolone ++
• Etidronate +++ + ++
• Alendronate +++ +++
• Risedronate +++ +++
• Ibandronate +++
• Calcitonin +++ + ++
• Calcitriol ++ ++
• Calcium + vitamin D ++ ++ ++
• Fluoride +++ + +
• PTH +++ +
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
(Chesnut et al., Am.J.Med.2000)
MORE 2.6 30
(Ettinger et al., JAMA 1999)
FIT1 6.2 47
(Black et al., Lancet 1996)
FIT2 6.8 44
(Cummings et al., JAMA 1998)
VERT-NA 5.2 41
(Harris et al., JAMA 1999)
VERT-MN 6.3 49
(Reginster et al. , Osteoporosis
Int 2000)
Approved drug for treatment and prevention
for osteoporosis
• Alendronate
10 mg/d or 70 mg/wk รั กษา postmenopausal osteoporosis and male
osteoporosis
5 mg/d or 35 mg/wk ้
ปองกัน postmenopausal osteoporosis
10 mg/d รั กษา glucocorticoid-induced osteoporosis
• Risedronate
5 mg/d or 35 mg/wk ้
รั กษาและปองกัน postmenopausal osteoporosis
and male osteoporosis
5 mg/d ้
รั กษาและปองกัน glucocorticoid-induced osteoporosis
• Ibandronate
้
2.5 mg/d or 150 mg/mo รั กษาและปองกัน postmenopausal osteoporosis
Approved drug for treatment and prevention
for osteoporosis
• Raloxifene
60 mg/d ้
รั กษาและปองกัน 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 +++ ++
Ibandronate +++ 0
Raloxifene +++ 0
Calcitonin (nasal) + 0
Vitamin D + 0
derivatives
PTH ++++ 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
• 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
