osteoporosis 2016 | teaching old dogs new tricks? combination therapy in osteoporosis: prof. richard...
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Teaching old dogs new tricks? Combination therapy in osteoporosis
Dr Richard Keen Consultant in Metabolic Bone Disease
Royal National Orthopaedic Hospital, Stanmore
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Disclosures for 2016
• Lectures, consultancy or research support from:Alexion PharmaceuticalsClementia PharmaceuticalsInternis LillyRegeneronUCB
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Outline of presentation• Combination treatment in chronic diseases
• Rationale for combined treatment in osteoporosis
• Anti-resorptive + anti-resorptive
• Teriparatide + anti-resorptive
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Combination therapy in chronic diseases
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Why use combination therapy ?
• Better efficacy when compared to mono-therapy– Additive effects– Synergistic effects
• Reduced side effects when compared to high dose monotherapy
• Less chance of resistance• Costs
– should be lower overall
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Additive InteractionsDrug A →∆ADrug B → ∆BDrugs A+B → ∆ (A+B)
Synergistic InteractionsDrug A →∆ADrug B → ∆BDrugs A+B → ∆C
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Anti-fracture efficacy of interventions in postmenopausal osteoporotic women
Spine Non-vertebral Hip
Abaloparatide A A -Alendronate A A ACalcitriol A A -Calcium A B BCalcium + vit D - A ADeosumab A A AHRT A A AIbandronate A - -Raloxifene A - -Risedronate A A ARomosozumab A - -Strontium ranelate A A ATeriparatide (PTH) A A -Vitamin D - B BZoledronate A A A
Adapted from RCP Guidelines 2000
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Drugs mode of action
Anti-resorptive Anabolic
- - Resorption ___ Formation
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Limitations to combination studies
• Relatively small subject numbers• Pre-treatment drug status• Study duration 1-2 years• No fracture data• Surrogate markers
– aDXA, markers, QCT, HRpQCT• Low power to detect rare side-effects
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Anti-resorptive + Anti-resorptive
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Bisphosphonates and HRT(Lindsay et al, JCEM 1999)
428 postmenopausal women
On HRT for > 12 months
Rx-ALN 10mg/day or PBO
F/U-1 year
Lumbar spine BMD
NTx
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Bisphosphonates and SERMs(Johnell et al, JCEM 2002)
331 postmenopausal womenAged < 75 yearsFN T-score < -2
Randomised to RLX 60mg/dayALN 10 mg/dayALN + RLXPBO
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Bisphosphonates and SERMs(Johnell et al, JCEM 2002)
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Combined treatment to reduce side-effects
HRT and Bazedoxifene
Moderate-Severe Hot Flushes at 12 weeks Adjusted annual change in spine BMD over 12-24 months
Lindsay et al, Fertil Steril 2009Pinkerton et al, Menopause 2009
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Anti-resorptive + Anabolic
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HRT and Parathyroid Hormone(Ste- Marie, et al. JBMR 2005)
Lumbar spine BMD (n=247)
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Alendronate + PTHBlunting of anabolic effect
Black et al, NEJM 2003
Finklestein et al, NEJM 2003P1NP CTx
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Bone density effects of alendronate and PTH
Black et al, NEJM 2003
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Changes in trabecular spine bone density
Finklestein et al, NEJM 2003
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When starting Teriparatidedo you stop or continue Alendronate?
Cosman et al, JCEM 2009
N=102
N=96
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Adding rather than switching has a positive effect on spine BMD
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Adding rather than switching reduces early hip bone loss
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Lumbar spine BMD (n=125)
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Changes in total hip parameters
BMD QCT
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12 months
0 3 6 9 12 15Months
N=43
N=40
N=43
PTH 1-34 25µg/day ALN 70mg/week
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Biochemical markers changesSerum PINP
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Bone density changesLumbar spine
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Combination of PTH and Zoledronic acid(Cosman et al, JBMR 2010)
CTx P1NP
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Combination of PTH and Zoledronate(Cosman et al, JBMR 2010)
Lumbar spine BMD Femoral neck BMD
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Denosumab and Teriparatide(Leder et al, JCEM 2014)
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Bone density changes
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Bone density changes continue in year 2 of treatment
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Improvement in HR-pQCT parameters at radius with combined PTH and DMab
(Tsai et al, JBMR 2015)
• P < 0.05 vs baselineBar line: P < 0.05 between groups
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SummaryCombination treatments
• Limited role for anti-resorptive + anti-resorptive combinations• Marginal increases in BMD• Potential increase risk of side-effects
• Anti-resorptive and anabolic combinations may be effective• Combination of Denosumab and Teriparatide appears the most
promising at present• When starting Teriparatide, consider continuation of anti-resorptive
treatment in those at high risk of fracture, particularly at hip. • Combination treatment also useful when you want rapid onset of
effect
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The Dream…Teaching old dogs new tricks