Preventing Fractures in Cancer Patients: The Role of Diet, Exercise, and Medication

1. Dr Claire Higham 11.9.19 Can we prevent fractures in patients with cancer? Consultant Endocrinologist, The Christie Hospital NHS FT Honorary Senior Lecturer, University of Manchester

2. Dietary influences • BMI • calcium • vitamin D • magnesium anorexia and cachexia tumour cells hormone antagonists • Microenvironment • genetics • cellular processes • vascular supply • Hormonal influences • oestrogen • testosterone • growth hormone • glucocorticoids • Other Risk Factors • smoking • alcohol • FHx hip fracture • other conditions • (eg RA/DM/IBD/OI) radiotherapy chemotherapy • Macroenvironment • weight bearing exercise • muscle strength/torsion • falls risk

3. Dietary influences • BMI • calcium • vitamin D • magnesium anorexia/ cachexia anorexia and cachexia hormone antagonists tumour cells tumour cells hormone antagonists glucocorticoids • Microenvironment • genetics • cellular processes • vascular supply • Hormonal influences • oestrogen • testosterone • growth hormone • glucocorticoids radiotherapy chemotherapy • Macroenvironment • weight bearing exercise • muscle strength/torsion • falls risk radiotherapy chemotherapy

4. Bone Mineral Density • Bone Mineralisation • Skeletal Growth and Development • Fractures

5. Not all fractures are the same ! Osteoporotic Fragility Fracture Pathological Fracture Pelvic Insufficiency Fracture

6. Primary prevention • 20% of people suffering a hip fracture will die within 12 months • 50% of people suffering a hip fracture will not live independently • # in those >60 years account for 2 million hospital bed days in UK • Can we prevent a first fracture?

7. Secondary prevention • prior vertebral fracture leads to 5x increase in future fracture • prior fracture (any site) leads to 2x increase in future fracture • Can we prevent further fracture?

8. Primary and Secondary Prevention Osteoporotic Fragility Fracture Cummings et al JAMA 2002: 288: 1889-1897

9. Primary and Secondary Prevention Bisphosphonate therapy Risedronate VERT trial placebo bisphosphonate Zoledronate HORIZON trial % patients with VF 41% 47% 70% 62% Ibandronate BONE trial Alendronate FIT trial • Post menopausal females • Denosumab • Teriparatide Osteoporotic Fragility Fracture

10. Primary and Secondary Prevention Lifestyle : - exercise • Limitations of current data: • few studies have fracture as outcome • few studies in men, older frail, osteoporosis • is exercise safe in osteoporosis ? • is exercise safe following fracture? • does exercise prevent fracture ? Osteoporotic Fragility Fracture

11. Primary and Secondary Prevention Lifestyle : - exercise • Limitations of current data: • few studies have fracture as outcome • few studies in men, older frail, osteoporosis • is exercise safe in osteoporosis ? YES • is exercise safe following fracture? YES • does exercise prevent fracture ? POSSIBLY Osteoporotic Fragility Fracture

12. Exercise and Fracture STEADY STRONG • promoting bone strength • physical activity: • hip # risk • BMD loss • *Lack of evidence in elderly* Strong Steady Straight • exercise reduces falls risk • most NVF caused by falls *Don’t know if exercise reduces the falls that cause fractures!* STRAIGHT • reduce the risk and help symptoms of VF

13. Exercise, cancer and bone (8) Think about maximising bone health • BMD in ALL did not improve with 2 yr exercise program • - poor compliance (Hartman et al 2009; 53(1):64-71) • BMD in ALL improved with low magnitude high frequency • mechanical stimulation (Mogilet al 2016; 2(7): 908-914) • randomised, placebo controlled (n=48 completed) • > 5yrs from diagnosis of childhood ALL • Z-scores BMD <-1

14. Exercise, cancer and bone (8) Think about maximising bone health DXA lumbar spine • Adults with Osteopenia • Breast Cancer • all on AI/SERM’s • mean ages 46-62 yrs • Prostate Cancer • mean age 67-70 yrs • Exercise program 6- 24months • resistance and impact exercise • aerobic exercise • combination (football!) • 87% retention • “trend” for beneficial effect • (resistance/impact exercise) • FOOTBALL IS DANGEROUS (5 injuries) DXA femoral neck

15. Exercise, cancer and bone (8) Think about maximising bone health • children and young adults poorly compliant to exercise studies • likely benefit to BMD from high frequency mechanical stimulation • prior to attainment of peak bone mass – ? benefit in older adults • resistance and impact exercise likely most beneficial in adults • - ? pre menopausal women benefit more • no fracture data (except that football increases the risk! - safety) • no data beyond 48 months • data needed outside ALL, breast and prostate cancer

16. Not all fractures are the same ! Osteoporotic Fragility Fracture Pathological Fracture Pelvic Insufficiency Fracture

17. Pelvic Insufficiency Fractures

18. Pelvic Insufficiency Fractures • Pain

19. Pelvic Insufficiency Fractures • Pain • Anxiety

20. Pelvic Insufficiency Fractures • Pain • Anxiety • Immobility

21. Pelvic Insufficiency Fractures are common following pelvic radiotherapy 100 • > 1020 PIF described 80 cervical/uterine all pelvic 60 rectal % PIF prostate chordoma 40 20 2015 2014 2017 2017 2017 2018 2018 2019 1992 1994 1996 2000 2000 2000 2002 2005 2006 2008 2008 2009 2010 2010 2011 2012 2012 2013 2014 Higham CE, Faithfull S. ClinOncol (R CollRadiol). 2015 Nov;27(11):668-78 – updated 2019

22. Pelvic Insufficiency Fractures : hypothetical mechanisms ? benefit of lifestyle intervention – exercise (prehabilitation)/nutrition/address risk factors

23. Prehabilitation clinical trials prior to surgery non-cancer n= 55 prior to surgery cancer n= 63

24. n= 3 radiotherapy n= 1 chemotherapy n= 3 HSCT prior to surgery non-cancer n= 55 prior to surgery cancer n= 63

25. n= 1 pelvic radiotherapy n= 3 radiotherapy n= 1 chemotherapy n= 3 HSCT prior to surgery non-cancer n= 55 prior to surgery cancer n= 63

26. n= 1 pelvic radiotherapy n= 3 radiotherapy n= 1 chemotherapy n= 3 HSCT prior to surgery non-cancer n= 55 prior to surgery cancer n= 63 recruiting unknown completed not yet recruiting active, not recruiting suspended/terminated

27. Exercise • Nutrition • Psychological Interventions

28. Exercise • Nutrition • Psychological Interventions • But : • acceptable : • burden of responsibility • burden of information • patient experience • equitable • cost- effective • safe

29. Clinical Academic Research Partnership Bone Toxicity following Pelvic Radiotherapy: understanding, predicting and preventing radiotherapy related insufficiency fractures • randomised • controlled • feasibility Study • Musculoskeletal Health Package • women • undergoing pelvic radiotherapy • cervical and uterine cancer

30. Clinical Academic Research Partnership Bone Toxicity following Pelvic Radiotherapy: understanding, predicting and preventing radiotherapy related insufficiency fractures • acceptability • safety • ePROMs and ePREMs • health economics • power for multicentre RCT

31. Clinical Academic Research Partnership Bone Toxicity following Pelvic Radiotherapy: understanding, predicting and preventing radiotherapy related insufficiency fractures • fracture incidence • BMD and body composition • 6 minute walk test • stability and grip strength • bone turnover

32. Summary • Multiple causes of poor bone health in cancer patients • Low BMD predisposes to fragility fracture • - post-menopausal women and older men • - increased morbidity and mortality • Not all fractures are the same • - osteoporotic fragility fractures vs radiotherapy PIF • Exercise can improve BMD, reduce falls risk, improve confidence • Prehabilitation studies mainly relate to surgery • - 1 study concerning pelvic radiotherapy • - no bone outcomes in any prehab study • Is a musculoskeletal bone health package feasible, acceptable, cost-effective ?