Cancer survivorship and bone health
Authors: Peter KK Wong, Weiwen Chen
Journal: The Lancet Healthy Longevity (2024)

Cancer is such a common condition. As health-care professionals, many of our patients have a history of cancer. Rapid advances in cancer treatment, including the advent of immunotherapy, have markedly improved cancer prognosis. However, improved cancer survivorship means these patients might experience chronic issues, such as poor bone health (osteoporosis or osteopenia) and fracture. As cancer tends to affect older individuals, this burden is compounded by age-related bone loss. Aside from fracture-related pain and incapacity, low trauma (equivalent to a fall from a standing height), fragility, and osteoporotic fractures are associated with increased mortality for up to 10 years after fracture.1Bliuc D Nguyen ND Milch VE Nguyen TV Eisman JA Center JR Mortality risk associated with low-trauma osteoporotic fracture and subsequent fracture in men and women.JAMA. 2009; 301: 513-521Crossref PubMed Scopus (1287) Google Scholar In The Lancet Healthy Longevity, Eva Buzasi and colleagues2Buzasi E Carreira H Funston G et al.Risk of fractures in half a million survivors of 20 cancers: a population-based matched cohort study using linked English electronic health records.Lancet Healthy Longev. 2024; (published online Feb 6.)https://doi.org/10.1016/S2666-7568(23)00285-4Google Scholar report findings from a large population-based matched cohort study using a rich dataset, the UK Clinical Practice Research Datalink. They found an increased risk of fractures in survivors of a range of cancers compared with controls without cancer. Although this large epidemiological study can only assess association and not causality, it provides a timely warning that bone health needs consideration in all cancer survivors. Specifically, after careful adjustment for multiple covariates, there was an increased risk of fracture in survivors of 15 of 20 cancers. Furthermore, there was an increased risk of major osteoporotic fractures (pelvic, hip, wrist, spine, or humerus) in cancer survivors of 17 of 20 cancers.2Buzasi E Carreira H Funston G et al.Risk of fractures in half a million survivors of 20 cancers: a population-based matched cohort study using linked English electronic health records.Lancet Healthy Longev. 2024; (published online Feb 6.)https://doi.org/10.1016/S2666-7568(23)00285-4Google Scholar One can debate the integrity of case ascertainment in the source data—how rigorous was the definition of an osteoporotic fracture (trauma equivalent to a fall from a standing height) and how potential pathological fractures from bone metastases were excluded. The association between poor bone health and cancer of the prostate,3Shahinian VB Kuo YF Freeman JL Goodwin JS Risk of fracture after androgen deprivation for prostate cancer.N Engl J Med. 2005; 352: 154-164Crossref PubMed Scopus (1154) Google Scholar breast,4Grossmann M Ramchand SK Milat F et al.Assessment and management of bone health in women with oestrogen receptor-positive breast cancer receiving endocrine therapy: Position statement of the Endocrine Society of Australia, the Australian and New Zealand Bone & Mineral Society, the Australasian Menopause Society and the Clinical Oncology Society of Australia.Clin Endocrinol (Oxf). 2018; 89: 280-296PubMed Google Scholar or haemopoietic system5Melton 3rd, LJ Kyle RA Achenbach SJ Oberg AL Rajkumar SV Fracture risk with multiple myeloma: a population-based study.J Bone Miner Res. 2005; 20: 487-493Crossref PubMed Scopus (234) Google Scholar is well recognised. However, surprisingly, fracture risk was also increased in cancers not often associated with osteoporotic fractures, such as CNS, gastrointestinal, cervix, and kidney cancers, with hazard ratios (HRs) ranging from 1·05 (95% CI 1·01–1·09) in colorectal cancer survivors to 1·94 (1·77–2·13) in multiple myeloma survivors. Does a fracture affect mortality? A population-based cohort study of 122 045 people with cancer from the Manitoba Cancer Registry (of whom 7120 [5·8%] had major fractures) found that during a median follow-up of 5·8 years after cancer diagnosis, all fracture sites, except for the forearm, were associated with increased risk of mortality.6Ye C Leslie WD Al-Azazi S et al.Fractures and long-term mortality in cancer patients: a population-based cohort study.Osteoporos Int. 2022; 33: 2629-2635Crossref PubMed Scopus (2) Google Scholar This increase was greatest in the first year after fracture, but persisted even after fractures that occurred more than 10 years after cancer diagnosis (HR 1·93, 95% CI 1·79–2·07).6Ye C Leslie WD Al-Azazi S et al.Fractures and long-term mortality in cancer patients: a population-based cohort study.Osteoporos Int. 2022; 33: 2629-2635Crossref PubMed Scopus (2) Google Scholar Although the use of large datasets has many strengths, there are limitations. Bone-active medications, such as intravenous bisphosphonates (zoledronic acid and pamidronate), corticosteroids (prednisone and dexamethasone) and the RANKL inhibitor denosumab, are used in the treatment of osteoporosis and cancer, especially in the presence of bone metastases. Of note, much larger doses of these medications are used in the cancer setting than in benign bone disease, such as osteoporosis. These drugs reduce fracture risk, but the magnitude of their effect could not be determined from the UK Clinical Practice Research Datalink dataset.2Buzasi E Carreira H Funston G et al.Risk of fractures in half a million survivors of 20 cancers: a population-based matched cohort study using linked English electronic health records.Lancet Healthy Longev. 2024; (published online Feb 6.)https://doi.org/10.1016/S2666-7568(23)00285-4Google Scholar Stratification by stage or grade of cancer would have been helpful. Was it just the more extensive or aggressive lesions that were associated with increased fracture risk? We agree with the authors that different mechanisms might be responsible for varying patterns of fracture risk seen with different cancer types. First, therapies used to treat particular cancers are associated with increased risk of fracture. For example, androgen deprivation therapy (ADT) for prostate cancer reduces testosterone to castrate levels and is a strong risk factor for fracture,3Shahinian VB Kuo YF Freeman JL Goodwin JS Risk of fracture after androgen deprivation for prostate cancer.N Engl J Med. 2005; 352: 154-164Crossref PubMed Scopus (1154) Google Scholar while the use of tamoxifen and aromatase inhibitors in breast cancer has a similar effect.7Hadji P Asmar L van Nes JG et al.The effect of exemestane and tamoxifen on bone health within the Tamoxifen Exemestane Adjuvant Multinational (TEAM) trial: a meta-analysis of the US, German, Netherlands, and Belgium sub-studies.J Cancer Res Clin Oncol. 2011; 137: 1015-1025Crossref PubMed Scopus (0) Google Scholar The use of high dose potent corticosteroids, such as dexamethasone in CNS cancers, can have a deleterious effect on bone health. Second, the cancer itself, due to local cellular activation, can affect bone density—particularly in haematopoietic malignancies.8Bernstein ZS Kim EB Raje N Bone disease in multiple myeloma: biologic and clinical implications.Cells. 2022; 112308Crossref PubMed Scopus (6) Google Scholar Finally, the general effect of reduced mobility and lack of exercise resulting in sarcopenia and deconditioning afflicts many cancer survivors and increases falls and fracture risk.9Wildes TM Dua P Fowler SA et al.Systematic review of falls in older adults with cancer.J Geriatr Oncol. 2015; 6: 70-83Summary Full Text Full Text PDF PubMed Google Scholar Cancer combined with treatment-related generalised osteoporosis from drugs that adversely affect bone health, bone metastases, focal bone damage from radiotherapy, increased risk of falls, sarcopenia, malnutrition, and reduced physical activity is a potent combination leading to increased risk of fracture and mortality. Although timely cancer treatment is crucial, it is important that health-care professionals managing patients with cancer are aware of bone health issues. Depending on the type of cancer, early measures should be taken to optimise bone health. For example, many guidelines recommend a dual energy x-ray absorptiometry (DXA) scan to guide bone protection before starting ADT for prostate cancer. However, of 33 836 men with prostate cancer commencing ADT during 2017–20 in Australia, only 6683 (19·8%) underwent a DXA scan from 6 months before to 12 months after starting ADT.10Hamid MF Hayden A Moujaber T et al.Dual-energy x-ray absorptiometry assessment of bone health in Australian men with prostate cancer commencing androgen deprivation therapy.Med J Aust. 2023; 218: 126-130Crossref PubMed Scopus (0) Google Scholar Calcium and vitamin D status should be optimised according to local guidelines, while the role of weight-bearing exercise and progressive resistance (strength) training in increasing or maintaining bone density and reducing falls risk is important.11Kemmler W Shojaa M Kohl M von Stengel S Effects of different types of exercise on bone mineral density in postmenopausal women: a systematic review and meta-analysis.Calcif Tissue Int. 2020; 107: 409-439Crossref PubMed Scopus (48) Google Scholar PKKW is the Honorary Medical Director and Board Member of Healthy Bones Australia (formerly Osteoporosis Australia). WC declares no competing interests. Risk of fractures in half a million survivors of 20 cancers: a population-based matched cohort study using linked English electronic health recordsSurvivors of most types of cancer were at increased risk of bone fracture for several years after cancer, with variation by cancer type. These findings can help to inform mitigation and prevention strategies. Full-Text PDF Open Access