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
Disclosures for 2016
• Lectures, consultancy or research support from:Alexion PharmaceuticalsClementia PharmaceuticalsInternis LillyRegeneronUCB
Outline of presentation• Combination treatment in chronic diseases
• Rationale for combined treatment in osteoporosis
• Anti-resorptive + anti-resorptive
• Teriparatide + anti-resorptive
Combination therapy in chronic diseases
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
Additive InteractionsDrug A →∆ADrug B → ∆BDrugs A+B → ∆ (A+B)
Synergistic InteractionsDrug A →∆ADrug B → ∆BDrugs A+B → ∆C
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
Drugs mode of action
Anti-resorptive Anabolic
- - Resorption ___ Formation
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
Anti-resorptive + Anti-resorptive
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
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
Bisphosphonates and SERMs(Johnell et al, JCEM 2002)
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
Anti-resorptive + Anabolic
HRT and Parathyroid Hormone(Ste- Marie, et al. JBMR 2005)
Lumbar spine BMD (n=247)
Alendronate + PTHBlunting of anabolic effect
Black et al, NEJM 2003
Finklestein et al, NEJM 2003P1NP CTx
Bone density effects of alendronate and PTH
Black et al, NEJM 2003
Changes in trabecular spine bone density
Finklestein et al, NEJM 2003
When starting Teriparatidedo you stop or continue Alendronate?
Cosman et al, JCEM 2009
N=102
N=96
Adding rather than switching has a positive effect on spine BMD
Adding rather than switching reduces early hip bone loss
Lumbar spine BMD (n=125)
Changes in total hip parameters
BMD QCT
12 months
0 3 6 9 12 15Months
N=43
N=40
N=43
PTH 1-34 25µg/day ALN 70mg/week
Biochemical markers changesSerum PINP
Bone density changesLumbar spine
Combination of PTH and Zoledronic acid(Cosman et al, JBMR 2010)
CTx P1NP
Combination of PTH and Zoledronate(Cosman et al, JBMR 2010)
Lumbar spine BMD Femoral neck BMD
Denosumab and Teriparatide(Leder et al, JCEM 2014)
Bone density changes
Bone density changes continue in year 2 of treatment
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
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
The Dream…Teaching old dogs new tricks