Transcript Update Treatment in Osteoporosis
Update Treatment in Osteoporosis
Chatlert Pongchaiyakul, MD.
Department of Medicine, Faculty of Medicine Khon Kaen University
BMD + Bone quality Bone strength Falling
Fracture
PATHWAY OF OSTEOPOROTIC FRACTURES INCREASED RESORPTION DECREASED FORMATION LOW BONE MASS MICROARCHITECTURE DETERIORATION TENDENCY TO FALL HEIGHT OF FALL PROTECTIVE RESPONSE SOFT TISSUE CUSHION OSTEOPOROSIS FORCE OF IMPACT ON BONE POOR QUALITY DECREASED BONE STRENGTH FRACTURE
Goals of Therapy
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Prevent first fragility fracture or future fractures if one has already occurred
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Stabilize/increase bone mass
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Relieve symptoms of fractures and/or skeletal deformities
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Improve mobility and functional status
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Initiate lifestyle changes to enhance prevention of fractures
INTERVENTIONS FOR OSTEOPOROSIS
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Who should be treated?
When the intervention should be started?
How long should the intervention be applied?
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What parameter(s) should be assessed for the efficacy?
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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
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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
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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 -34% -34% -23% -24% 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
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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 Drug DECREASED FORMATION LOW BONE MASS MICROARCHITECTURE DETERIORATION TENDENCY TO FALL HEIGHT OF FALL PROTECTIVE RESPONSE Prevent falling Hip protector SOFT TISSUE CUSHION OSTEOPOROSIS FORCE OF IMPACT ON BONE POOR QUALITY DECREASED BONE STRENGTH FRACTURE
OSTEOPOROTIC FRACTURES
PREVENTION AND TREATMENT
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General interventions for all Pharmacologic interventions Antiresorbing agents Bone formation stimulating agents
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Prevention of falls and other forces or impacts on bone
OSTEOPOROSIS
GENERAL INTERVENTIONS FOR ALL
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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 Stimulator of Bone formation Estrogens +/- progestogens SERMs Bisphosphonates Calcitonin Calcium Strontium • • • • Fluoride Parathyroid hormone Strontium Vit K2 Complex Action • • • Vitamin D and its derivatives Anabolic steriods Tibolone
Current treatment options for osteoporosis
Treatment
Calcium and vitamin D Hormone replacement therapy (HRT) Calcitonin Selective estrogen receptor modulators (SERMs) Bisphosphonate: alendronate Bisphosphonate: risedronate Bisphosphonate: Ibandronate Parathyroid hormone (PTH) (teriparatide) Strontium ranelate
Dosage Form
Oral (daily) Oral, transdermal Nasal spray (daily) Oral (daily) Oral (daily or weekly) Oral (daily or weekly) Oral (daily or monthly) Daily subcutaneous 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 ( การหยั่งรู ้ , 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
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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
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Mortality and morbidity (Ideal goal) Fracture rate / risk (gold standard) Clinical vs. Radiographic % of cases vs. number/…. patient years Absolute risk vs. Relative risk
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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
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Subjects usually received Eca 0.5-1 g/d and vitamin D 400-800 U/d in most study.
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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
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The more severe osteoporosis the more benefits obtained from an intervention.
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The benefit might be skeletal site specific.
Treat to targets
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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. DEC. FRCATURE RISK BMD OBS. RCT
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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 PROOF (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) Δ BMD (%) 0.5
2.6
6.2
6.8
5.2
6.3
%reduction of fracture risk
36 30 47 44 41 49
Approved drug for treatment and prevention
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osteoporosis for osteoporosis
Alendronate
10 mg/d or 70 mg/wk ร ักษา postmenopausal osteoporosis and male 5 mg/d or 35 mg/wk ป้องกัน postmenopausal osteoporosis 10 mg/d induced osteoporosis ร ักษา glucocorticoid-
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Risedronate
5 mg/d or 35 mg/wk 5 mg/d ร ักษาและป้องกัน postmenopausal osteoporosis and male osteoporosis ร ักษาและป้องกัน glucocorticoid-induced osteoporosis
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Approved drug for treatment and prevention for osteoporosis
• Raloxifene
60 mg/d ร ักษาและป้องกัน postmenopausal osteoporosis
• Calcitonin
200 IU/d ร ักษา postmenopausal osteoporosis
• PTH
20 µg/d ร ักษา severe osteoporosis in men and women with high risk of fracture
• Strontium renelate
2 g/d ร ักษา postmenopausal
Efficacy for fracture reduction: update 2005
Drug Alendronate Risedronate Ibandronate Raloxifene Calcitonin (nasal) Vitamin D derivatives PTH Strontium ranelate Vertebral fracture +++ +++ +++ +++ + + ++++ +++ Hip fracture ++ ++ 0 0 0 0 0 ++
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
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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: