This house believes that HRT should be the first-line prevention for postmenopausal osteoporosis: the case against

Transcription

1 This house believes that HRT should be the first-line prevention for postmenopausal osteoporosis: the case against Juliet Compston Professor of Bone Medicine University of Cambridge School of Clinical Medicine Cambridge UK

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4 Incidence of age-related fractures in women Incidence/100,000 person-year 4,000 3,000 2,000 1,000 Cooper C, Melton LJ. Trends Endocrinol Metab 1992;3:24-9 Vertebrae Hip Colles 35 >85 Age group, year

5 Is HRT the first line option for prevention of osteoporosis: relevant issues Can fracture prevention be achieved by a finite duration of HRT in early postmenopausal women or is life-long HRT use after the menopause required? Who is the high risk population in whom treatment can be targeted most cost-effectively? What are the most clinically appropriate treatments in this population

6 Does a limited period of HRT in postmenopausal women have lasting skeletal benefits? Effects on withdrawal on bone mineral density: All studies show resumption of bone loss after withdrawal Some indicate accelerated bone loss Observational data indicate only a limited residual effect Effects of withdrawal on fracture risk: Study of Osteoporotic Fractures - no reduction in fracture risk in past users (even if >10 yrs use) Michaelsson et al - no significant reduction in hip fracture risk 5 years after discontinuation of HRT Bagger et al - no significant reduction in non-vertebral fracture incidence after limited HRT use

7 Risk of hip fracture according to HRT use (from Michaëlsson et al, BMJ 1998) OR cases 3262 controls All current All former Last use 1-5 yrs ago Last use > 5 yrs Duration of use > 5 yrs

8 Risk of fracture according to HRT use: the Study of Osteoporotic Fractures Adjusted RR (from Cauley et al, Ann Intern Med 1995) n= Hip Wrist All non-vert Current users Duration y Hip Wrist All non-vert Past users Duration y

9 HRT: long-term preventive effects on fracture? Placebo HRT Adjusted OR n=108 n=155 Vertebral ( ) Non-vertebral ( ) All ( ) (from Bagger et al, Bone 2003)

10 Prevention of osteoporosis: identification of individuals at high risk of fracture Fracture probability can be estimated from bone mineral density and clinical risk factors Age has a major independent effect on fracture risk

11 Effect of age on 10-year fracture probability according to BMD T score in women Fracture probability (%) Bone mineral density T score (from Kanis et al, 2001) Age 80 yr Age 70 yr Age 60 yr Age 50 yr

12 % Proportion of women with osteoporosis (BMD T score -2.5) (from Melton 1995) >80 years Spine Hip

13 99ca year probability of hip fracture in Swedish women 20 women Probability (%) Age (years) Courtesy of John Kanis

14 Number needed to treat (NNT) to prevent one vertebral fracture in low and high risk populations Drug Alendronate NNT in low risk population (early postmenopausal) 1790 ( ) NNT in high-risk population (late postmenopausal) 72 (61-99) Risedronate 2315 ( ) 96 (75-151) Raloxifene 2381 ( ) 99 (79-145) (from Guyatt, 2002)

15 Risk/benefit balance of HRT in older postmenopausal women Benefits Reduced fracture risk Reduced colon cancer risk Risks Stroke increased CHD increased (or neutral) VTE Cognitive function decreased Nausea, bloating, bleeding, breast tenderness, mood changes, headaches etc etc

16 Non-HRT pharmacological interventions for osteoporosis Anti-resorptives Bisphosphonates Alendronate Etidronate Ibandronate Risedronate Calcitonin Calcitriol Raloxifene Anabolic Preotact (PTH 1-84) Teriparatide (PTH 1-34) Uncertain Strontium ranelate

17 Anti-fracture efficacy of pharmacological interventions for osteoporosis Intervention Vertebral Non-vertebral Hip Alendronate Risedronate Etidronate - - Ibandronate - - Preotact - - Raloxifene - - Teriparatide - Strontium ranelate

18 Bisphosphonates approved for osteoporosis Cyclic etidronate: oral, intermittent calcium Alendronate: oral, 5 or 10 mg once daily or 70 mg once weekly Risedronate: oral, 5 mg once daily or 35 mg once weekly O OH P OH R1 C R2 OH P OH O Ibandronate: 150 mg once monthly (oral) or 3 mg once every three months (i.v.)

19 % women with fractures Onset of fracture risk reduction: effect of risedronate in postmenopausal women with osteoporosis n=2442 n= * * Control Clinical vertebral fractures * 69% (P<0.05) Risedronate 5mg % women with fractures 6 2 Non-vertebral fractures * * * 74% (p = 0.001) Time (months) Time (months) * p< 0.05 Roux C. et al., Current Med Research and Opinion 2004; 20(4): Harrington T. et al. Calcif. Tissue. Int. 2004; 74:

20 Safety and tolerability of bisphosphonates Dosing regimen is sometimes inconvenient Upper gastrointestinal adverse effects may occur with the aminobisphosphonates

21 Strontium ranelate - OOC CN Sr COO - - OOC S N Sr COO - Taken as a single daily dose Similar efficacy profile to alendronate and risedronate

22 Effect of strontium ranelate on fracture risk in women aged over 80 years Vertebral fracture Non-vertebral fracture 0.68 P = P = N = 895 RRR: - 32% over 3 years N = 1488 RRR: - 31% over 3 years From Seeman et al, JCEM 2006 Relative risk

23 Tolerability profile of strontium ranelate Pooled data from SOTI and TROPOS, N=6669 Mean age 75 y (23% 80 Y), up to 56 mths Strontium ranelate (n=3352) Placebo (n=3317) Nausea (% patients) Diarrhoea (% patients) Headache (% patients) Dermatitis (% patients) Eczema (% patients) Data on file. Small increase in VTE (OR 1.42, 95% CI 1.02, 1.98)

24 HRT for prevention of osteoporosis: time to move on A finite period of HRT does not produce lasting protection against fracture The vast majority of women at high risk of fracture are elderly; in this population tolerability of HRT is poor and risk/benefit balance unfavourable A number of alternative therapeutic options are available for such women that are effective, safe and well tolerated HRT is not the first-line prevention for osteoporosis in postmenopausal women

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