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Update Treatment in Osteoporosis

Update Treatment in Osteoporosis. Chatlert Pongchaiyakul, MD. Department of Medicine, Faculty of Medicine Khon Kaen University. Falling. Fracture. BMD + Bone quality Bone strength. PATHWAY OF OSTEOPOROTIC FRACTURES. INCREASED RESORPTION. DECREASED FORMATION. TENDENCY TO FALL.

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Update Treatment in Osteoporosis

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  1. Update Treatment in Osteoporosis Chatlert Pongchaiyakul, MD. Department of Medicine, Faculty of Medicine Khon Kaen University

  2. Falling Fracture BMD + Bone quality Bone strength

  3. PATHWAY OF OSTEOPOROTIC FRACTURES INCREASED RESORPTION DECREASED FORMATION TENDENCY TO FALL HEIGHT OF FALL PROTECTIVE RESPONSE LOW BONE MASS MICROARCHITECTURE DETERIORATION SOFT TISSUE CUSHION FORCE OF IMPACT ON BONE OSTEOPOROSIS DECREASED BONE STRENGTH FRACTURE POOR QUALITY

  4. 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

  5. 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

  6. POSTMENOPAUSAL OSTEOPOROSISWHO 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

  7. 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)

  8. 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

  9. 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.

  10. 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

  11. POSTMENOPAUSAL OSTEOPOROSISWHO 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

  12. PATHWAY OF OSTEOPOROTIC FRACTURES Prevent falling Hip protector INCREASED RESORPTION DECREASED FORMATION TENDENCY TO FALL HEIGHT OF FALL PROTECTIVE RESPONSE LOW BONE MASS MICROARCHITECTURE DETERIORATION SOFT TISSUE CUSHION Drug FORCE OF IMPACT ON BONE OSTEOPOROSIS DECREASED BONE STRENGTH FRACTURE POOR QUALITY

  13. OSTEOPOROTIC FRACTURESPREVENTION AND TREATMENT • General interventions for all • Pharmacologic interventions Antiresorbing agents Bone formation stimulating agents • Prevention of falls and other forces or impacts on bone

  14. OSTEOPOROSISGENERAL 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

  15. Inhibit bone resorption Maintain or increase bone mass Reduce fracture risk Pharmacologic Treatment of PMO: Overview Treatment Estrogen replacement therapy (ERT)….???? Action Selective estrogen receptor modulators (SERMs): raloxifene Calcitonin Bisphosphonates

  16. 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

  17. Current treatment options for osteoporosis TreatmentDosage 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)

  18. 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

  19. EVIDENCE-BASED MEDICINE • A new paradigm for medical practice • Stresses the evidence from clinical research • De-emphasizes Intuition (การหยั่งรู้, สังหรณ์ใจ) Unsystematic clinical experience Pathophysiologic rationale (only)

  20. 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

  21. PREVENTION OF OSTEOPOROSISFROM CLINICAL RESEARCH TOAN 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

  22. ASSESSMENT OF THE EFFICACY OFAN 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

  23. PREVENTION OF OSTEOPOROSISFROM CLINICAL RESEARCH TOAN 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.

  24. Treat to targets • Treatment • Osteoporosis High turnover Low BMD High fracture Mortality&Morbidity Dec turnover Maintain or inc. BMD Dec. fracture Dec. Mortality&Morbidity

  25. 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 +++ +

  26. BMD increase does not reflect a proportional to reduction of relative risk of fracture

  27. Approved drug for treatment and prevention for osteoporosis • Alendronate 10 mg/d or 70 mg/wk รักษา postmenopausal osteoporosis and male osteoporosis 5 mg/d or 35 mg/wk ป้องกัน postmenopausal osteoporosis 10 mg/d รักษา glucocorticoid-induced osteoporosis • Risedronate 5 mg/d or 35 mg/wk รักษาและป้องกัน postmenopausal osteoporosis and male osteoporosis 5 mg/d รักษาและป้องกัน glucocorticoid-induced osteoporosis • Ibandronate 2.5 mg/d or 150 mg/mo รักษาและป้องกัน postmenopausal osteoporosis

  28. Approved drug for treatment and prevention for osteoporosis • Raloxifene 60 mg/d รักษาและป้องกัน postmenopausal osteoporosis • Calcitonin 200 IU/d รักษา postmenopausal osteoporosis • PTH 20 µg/d รักษา severe osteoporosis in men and women with high risk of fracture • Strontium renelate 2 g/d รักษา postmenopausal osteoporosis

  29. Efficacy for fracture reduction: update 2005

  30. 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

  31. 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

  32. 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.

  33. 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

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