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Osteoporosis and Bisphosphonate Treatment

Osteoporosis and Bisphosphonate Treatment. Kate Bottomley ST2. Outline. Osteoporosis Making the Diagnosis Bisphosphonates Primary Prevention Secondary Prevention Compliance Safety issues References. Osteoporosis. World Health Organization (WHO)

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Osteoporosis and Bisphosphonate Treatment

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  1. Osteoporosis and Bisphosphonate Treatment Kate Bottomley ST2

  2. Outline • Osteoporosis • Making the Diagnosis • Bisphosphonates • Primary Prevention • Secondary Prevention • Compliance • Safety issues • References

  3. Osteoporosis • World Health Organization (WHO) • Osteoporosis defined in women as a bone mineral density 2.5 standard deviations below peak bone mass (20-year-old healthy female average) as measured by DEXA (T score) • Decreased bone density and degeneration/distortion of microarchitecture • Increased fragility and risk of # • 200,000 fractures/ yr in UK • >1:3 women and 1:12 men suffer OP # • What about men?

  4. Osteoporosis • Osteoporosis costs the NHS and government £2.3 billion a year – that’s £6 million a day • Morbidity and Mortality following #: • Mortality rates increased in year following hip fracture by 15-25% • How many return to same level of functioning? • 17% of remaining life was spent in a nursing facility. • Reduced life expectancy by 1.8 years

  5. Age Body mass index Smoking status Use of HRT Alcohol use Parental Hx of OP Rheumatoid Arthritis Cardiovascular disease Type 2 diabetes Asthma TCA’s Corticosteriods Hx of falls Menopausal Sx’s Chronic liver disease GI malabsorption Other endocrine disorders Risk Factors for sustaining an osteoporotic fracture

  6. Bisphosphonates • Adsorbed onto hydroxyapatite crystals in bone • Slows rate of growth and dissolution (turnover rate) • Inhibit recruitment and promote apoptosis of osteoclasts • Indirectly stimulate osteoblast activity • First approved mid 1990’s • PO preparation • Poorly absorbed • Impaired by food esp milk • Calcium and Vit D too

  7. Bisphosphonates Licensed for use in : • Postmenopausal OP (prevention/ treatment) • Corticosteroid induced OP (prevention/ treatment) • Pagets disease • Hypercalcaemia of malignancy • Osteolytic lesions and bone pain (mets) in breast cancer (?) • Mulitple myeloma • Etidronate can increase the risk of fractures, less likely if given cyclically

  8. Do bisphosphonates work? • Primary prevention of a #: (4 yrs) • 4272 women alendronate or placebo, low BMD but no # • vertebral fractures on XR • RR 0.56; 95% CI, 0.39-0.80 • NNT = 60 - over 4 years to prevent 1st # • Secondary Prevention of a # (3 yrs) • 1946 women alendronate or placebo • Lat spine XR 0, 24, 36/12 • # on XR RR 0.53; 95% CI, 0.41-0.68 • NNT = 9 – over 3 years to prevent 2nd # • Cummings et al. Effect of alendronate on risk of fracture in women with low bone density but without vertebral fractures: results from the Fracture Intervention Trial. JAMA Dec 1998. 280 (24):2077-82 • Black et al. Randomised trial of effect of alendronate on risk of fracture in women with existing vertebral fractures. Lancet Dec 1996. 348 (9041) 1535-1541

  9. Do bisphosphonates work? • Meta-analysis of risk reduction for fracture with alendronate: • Statistically significant risk reduction for secondary prevention of fracture at all sites • For primary prevention only statistically significant for vertebral fractures Holder et al. Alendronate for fracture prevention postmenopause. Am Fam Physician, Sept 2008. Vol./is. 78/5 (579-81), 0002-838X

  10. Do bisphosphonates work? • RCT to test efficacy and safety of OD risedronate • 5mg v’s placebo, Secondary prevention only • New vertebral #: • NNT 20 (to prevent a second fracture) • New non vertebral # • NNT 43 (to prevent a second fracture) Harris et al, Effects of risedronate treatment on vertebral and nonvertebral fractures in women with postmenopausal osteoporosis:a randomised controlled trial. JAMA. Oct 1999. Vol 282, Iss 14 (1344-52)

  11. Primary Prevention - NICE • Postmenopausal with osteoporosis • Not normal BMD or osteopenia • Alendronate if: • >70 with with confirmed OP (T score) AND: independent clinical risk factor for fracture OR an indicator of low BMD • 65-69 y.o. with confirmed OP (T score) AND independent clinical risk factor for fracture • Postmenopausal women <65 y.o. with confirmed OP (T score) AND independent clinical risk factor for fracture AND an indicator of low BMD • If >75 y.o. doesn’t need DEXA

  12. Primary Prevention - NICE • If Alendronate CI – Risedronate/ etidronate: • Interestingly: • >70 with OP AND risk factor OR low BMD • 65-69 with OP AND risk factor • Postmenopausal <65 with OP AND risk factor AND low BMD *Parental Hx of hip # Alcohol intake ≥ 4 units/day RA

  13. Secondary Prevention - NICE • NICE likes alendronate: • Postmenopausal and osteoporosis (T≤ -2.5) • If >75 clinician decide if DEXA appropriate • Higher threshold for other bisphosphonates • Risedronate and etidronate (alendronate CI) and fulfil table: *Parental Hx of hip # Alcohol intake ≥ 4 units/day RA

  14. SIGN – Simpler! • Postmenopausal w OP on DEXA of spine/hip. With/out # (1°/2°) • PO alendronate or risedronate PLUS Calcium ± Vit D • Frail elderly woman (>80 years) • 1000mg Calcium and 800iu Vit D OD • Frail elderly woman (>80 years) OP on DEXA (1°) or multiple vertebral #’s (2°) • PO alendronate or risedronate PLUS Calcium ± Vit D • Men Dx of OP with/out fragility # (1°/2°) • PO alendronate or risedronate PLUS Calcium ± Vit D • Proven Hypogonadism – may benefit from testosterone

  15. Compliance • Difficult to take • Study in US 35,537 women w bisphosphonate Px • 20% persisted with Rx during 24/12 • Another study - adherence/persistence over 12/12 • Adherence/persistence rates • Alendronate 61%/21% • Risedronate 58%/19% • Weekly preparation 63%/22% Siris et al. Adherence to bisphosphonate therapy and fracture rates in osteoporotic women:relationship to vertebral and non-vertebral fractures from 2 US claim databases. Mayo Clinic Proceedings, Aug 2006. Vol 81, iss 8 (1013-22) Downey et al. Adherence and persistence associated with the pharmacological treatment of osteoporosis in a managed care setting. Southern Medical Journal. June 2006. Vol 99, Iss 6 (570-5)

  16. Safety concerns • Skeletal safety • atypical fractures and delayed healing • GI intolerance • Hypocalcaemia • Acute phase reactions • Chronic musculoskeletal pain • Renal safety • Cardiovascular safety inc AF • Osteonecrosis of the jaw

  17. Summary • More evidence for secondary prevention than primary • Site dependant • NICE guidance very confusing! • SIGN easier • Poor compliance • Rare but significant side effects

  18. References • Pharmacology. 4th Ed. Rang, Dale and Ritter. Churchill Livingstone, Edinburgh, 2001. • NICE: aldendronate, etidronate, risedronate, raloxifene and strontium ranelate for the primary prevention of osteoporotic fragility fractures in postmenopausal women. Oct 2008 • NICE: aldendronate, etidronate, risedronate, raloxifene, strontium ranelateand teriparatide for the secondary prevention of osteoporotic fragility fractures in postmenopausal women. Oct 2008 • Zoledronic Acid and Clinical Fractures and Mortality after Hip Fracture. Lyles et al. NEJM. Sept 17, 2007. 10.1056/NEJMoa074941 • Estimating Hip Fracture Morbidity, Mortality and Costs. Braithwaite et al. Journal of the American Geriatrics Society. Vol 51, Iss 3, p364-370. • http://bisphosphonates.legalview.info/ • BNF 55, March 2008. p406-410 • SIGN guidance. Management of Osteoporosis. Guideline 71. June 2003. • Schneider. Bisphosphonates and low-impact femoral fractures:current evidence on alendronate-fracture risk. Geriatrics, Jan 2009. vol/is 64/1 (18-23), 1936-5764 • Holder et al. Alendronate for fracture prevention postmenopause. Am Fam Physician, Sept 2008. Vol./is. 78/5 (579-81), 0002-838X • Harris et al, Effects of risedronate treatment on vertebral and nonvertebral fractures in women with postmenopausal osteoporosis:a randomised controlled trial. JAMA. Oct 1999. Vol 282, Iss 14 (1344-52) • Feldstein et al. Bone mineral density measurement and treatment for osteoporosis in older individuals with fractures: a gap in evidence based practice guideline implementation. Archives of Internal Medicine. Oct 2003. Vol 163, Iss 18 (2165-72) • Majumdar et al. Multifaceted intervention to improve diagnosis and treatment of osteoporosis in patients with recent wrist fracture:a randomised controlled trial. CMAJ. Feb 2008. Vol 178, Iss 5 (1488-2329) • Siris et al. Adherence to bisphosphonate therapy and fracture rates in osteoporotic women:relationship to vertebral and non-vertebral fractures from 2 US claim databases. Mayo Clinic Proceedings, Aug 2006. Vol 81, iss 8 (1013-22) • Downey et al. Adherence and persistence associated with the pharmacological treatment of osteoporosis in a managed care setting. Southern Medical Journal. June 2006. Vol 99, Iss 6 (570-5) • Cummings et al. Effect of alendronate on risk of fracture in women with low bone density but without vertebral fractures: results from the Fracture Intervention Trial. JAMA Dec 1998. 280 (24):2077-82 • Black et al. Randomised trial of effect of alendronate on risk of fracture in women with existing vertebral fractures. Lancet Dec 1996. 348 (9041) 1535-1541 • Hodsman et al. Do Bisphosphonates reduce the risk of osteoporotic fractuers? An evaluation of the evidence to date. JAMC. May 2002. 166 (11):1426-30.

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