Teaching old dogs new tricks? Combination therapy in osteoporosis

Dr Richard Keen Consultant in Metabolic Bone Disease

Royal National Orthopaedic Hospital, Stanmore

richard.keen@rnoh.nhs.uk

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