How to treat osteoporosis With what and for how long?

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1 How to treat osteoporosis With what and for how long? Professor Neil Gittoes Consultant Endocrinologist & Honorary Professor

2 Where will we be going? Drug therapies Current Indications Contraindications/unmet need Emerging Duration of therapy Drug pauses/holidays Longer term

3 Disclosures PI SCOOP Screening of Older Women for Prevention of Fracture Member National Osteoporosis Advisory Group (NOGG) Chair & Trustee, National Osteoporosis Society Clinical & Scientific Committee

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5 Osteoporosis - introduction Cost of osteoporosis in the UK new fragility fractures in hip fractures - Around 3.5 billion each year and rising 1:2 women 1:5 men NOS Facts & Figures, 2017

6 Major osteoporotic fractures

7 Secondary fracture prevention Case finding

8 What about screening for OP? UK 7 centre RCT women years Risk factor screening v standard care Is a community based screening programme effective and cost-effective in reducing fractures in older women in the UK?

9 Impact of screening NS 12 % % P=0.002 NS Screening Standard 2 0 All fractures Hip fractures Mortality Shepstone, Gittoes, et al, in press

10 Shepstone, Gittoes, et al, in press Conclusions from SCOOP A community based UK screening programme is feasible Evidence that hip fractures could be reduced No evidence that the overall rate of fractures or mortality could be significantly reduced Health economic data to follow

11 What are we trying to achieve with pharmacotherapy for osteoporosis? Improve bone strength Minimise fracture risk Minimise inconvenience to patients Safety and adverse events Acceptability Dosing frequency, route, palatability Improve bone quality Provide long-term solution for fracture risk reduction

12 The ideal osteoporosis drug Reverses pathology of osteoporosis * Reduces fracture risk to background Infrequently administered * Minimal side effects and inconvenience * Predictable response with reliable measures demonstrating anti-fracture efficacy Prolonged or pulsed exposure provides longterm safe care Acceptable to payers * * - not in same drug

13 Fracture reduction at all relevant sites Licensed indications for use (SPC) Drug Vertebral # Hip # GCIOP OP men Alendronate a a a a Risedronate a a a a Ibandronate a r r r Zoledronic acid a a a a Raloxifene a r r r (Strontium ranelate) a a r r Teriparatide a a a a Denosumab a a r a

14 Available therapies to reduce fracture risk What s good? Highly effective in high risk groups Fractures, older, low BMD (T<-2.5) 50%+ anti-fracture efficacy Sustained effect (10 yrs) Safe Rapid onset of anti-fracture effect 6-12 months Multiple treatment options Daily, weekly, monthly, 3/12, 6/12, 12/12 Oral, IV, s/c

15 Limitations of current drugs Side effects Uncertainty long-term Frequency/convenience/acceptability Best # risk reduction ~50% Cost Few reverse disease process Co-morbid mix Lack of reliable surrogates for efficacy Lack of evidence base for long-term care

16 Annual drug cost? v First year (health only) costs? 5,000 10,000 15,000 25,000 Leal et al, 2015; Davis, Gittoes et al, 2016

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18 Emerging therapies Abaloparatide PTHrP 1-34 PTH receptor 1 signalling s/c daily Romosozumab Sclerostin (Scl) inhibitor Scl is OB inhibitor s/c monthly Teriparatide (anabolic) Marcus et al, 2003

19 Abaloparatide change from baseline BMD Miller et al, 2016

20 Patients (%) Abaloparatide v placebo v TPTD RR 0.14 P<0.001 RR 0.57 P= % 43% AE hypercalcaemia ABAL (3.4%) v TPTD (6.4%)* Miller et al, 2016

21 Romosozumab and BMD Cosman et al, 2016

22 Romosozumab and fractures 73% Cosman et al, 2016

23 Patients (%) Romosozumab v alendronic acid RR 0.42 P< RR 0.81 P=0.04 RR 0.62 P= % 19% 38% Yr 1 CV AE 2.5% ROM v 1.9% ALN Saag et al, 2017

24 ow long to treat with bisphosphonates? Complications of bisphosphonates Established Upper GI with oral BP Array of alternatives (parenteral) Emerged Atypical femoral fractures (AFFs) <1:1,000 Prodromal pain Over egged Osteonecrosis of the jaw (ONJ) ~1:10, ,000

25 Bone strength Bone turnover link with fracture risk Bisphosphonates inhibit bone turnover? Physiological range Bone turnover Weinstein, 2000

26 Atypical femoral fractures (AFFs) Unique radiographic & clinical features Prodromal pain Prolonged BP use (3+ years, median 7) Particularly if initial BMD not low Glucocorticoids risk factor Absolute risk AFF small compared with beneficial effect ~100 per 100,000 in long term user Treatment of incomplete/in evolution AFFs Dell et al, 2010; Abrahamsen et al, 2010; Schilcher et al, 2011, Shane et al, 2013, Manolopoulos & Gittoes, 2013

27 How long to treat with bisphosphonates? NOGG, 2017

28 BTMs BMD Denosumab is not a bisphosphonate! Bone et al, 2011

29 Concerns withdrawing denosumab Popp et al, 2016; Lamy et al, 2017; Anastasilakis et al, 2017; Anastasilakis et al, 2017

30 Characteristics of rebound vertebral fractures in 24 cases Mean 4.7 (1-9) VFx per patient 92% multiple 8-16/12 after last DMAB Reasons for D/C Target achieved Duration complete AI treatment D/C 83% treatment naïve 1 SR, 1 RAL, 1 PTH, 2 BP 75% T<=-2.5 at DMAB D/C Vertebroplasty unhelpful DMAB <2 yrs 3.2 #/pt >2 yrs 5.2 #/pt Anastasilakis et al, 2017

31 Denosumab at 5 years Continue if fracture risk remains high and patient tolerating Document advice and warnings about long term antiresorptive therapy AFF and ONJ related Discontinuation without switching to an alternative treatment is not advised NOGG, 2017; Tsourdi et al, 2017

32 Denosumab at 5 years unanswered questions If target achieved, what to do? Role for zoledronic acid/other? What about patients with renal impairment? Intolerance to bisphosphonates? Timing of administration? With last dose?

33 Additional lessons Importance of timely administration of denosumab every 6/12 Importance of denosumab recall databases Primary care administration

34 Summary Osteoporotic fractures are common and have poor outcomes Secondary fracture prevention through FLS Potential role for osteoporosis screening Effective therapies reduce fracture risk ~50% Additional anabolic therapies emerging Caution with duration of therapy Bisphosphonates Active review (oral) at 5 years (IV 3 years) Denosumab Carefully consider switch/continuation not cessation

35 Conclusion Osteoporosis is not so silent (fractures) Considered use of growing array of drug therapies Awareness of absolute risk of fracture Retain holistic view Falls, frailty, lifestyle Not all patients should have bisphosphonates discontinued at 5 years Denosumab is different