Steroids are used in oncology and palliative care for a range of indications1,2 (see Box 1). It is well recognised that patients on long-term oral steroids are at risk of osteoporotic fracture.3-7 The prevention of steroid-induced osteoporotic fracture has not always been a high priority in oncology and palliative care, particularly for patients with a limited prognosis.
Steroids reduce the lifespan and promote the apoptosis of osteoblasts and osteoclasts and decrease the recruitment of osteoblasts and osteoclasts from progenitor cells.3 The most marked effect on bone density occurs within the first two to three months of initiating steroid treatment. There is a rapid initial phase of 10-15 per cent bone loss during the first few months, then a slower phase of 2-5 per cent bone loss annually thereafter.3 About 25 per cent of patients taking steroids for three months or more at a dose of >7.5mg prednisolone a day will develop an osteoporotic fracture.6 Fracture risk declines towards baseline rapidly after cessation of oral corticosteroid treatment.4
Certain bones are more susceptible to steroid-induced osteoporosis, with the axial skeleton and proximal femur the most affected.3,4 The earliest changes of steroid-induced bone loss can be detected in the lumbar spine.3
Continue Reading
There is a dose-dependent relationship between steroids and risk of osteoporotic fracture.4,8 For example, on doses of <2.5mg prednisolone daily, the RR of hip fracture is 0.99 (CI 0.82-1.20) relative to control, rising to 1.77 (1.55-2.02) at a daily dose of up to 7.5mg daily, and 2.27 (1.94-2.66) at doses >7.5mg daily.4
Reducing osteoporotic fracture risk
More than 13 clinical trials have analysed the prevention of steroid-induced osteoporosis with bisphosphonates (etidronate, risedronate and alendronate), and these have been subjected to a meta-analysis and Cochrane review.5 The meta-analysis concluded that bisphosphonates are effective at preventing and treating corticosteroid-induced bone loss in patients taking a mean steroid dose of 7.5mg prednisolone a day or more. Some caution has to be observed in interpreting these results, because most of these trials used bone density as an outcome measure rather than incidence of fracture, but bone density changes have been shown to be directly correlated with fracture risk.5
Clinical trials have also investigated the efficacy of calcium and vitamin D in the prevention of bone loss in patients taking systemic corticosteroids.3,7,8-12 A meta-analysis and Cochrane review (including five randomised controlled trials) concluded that there was clinically and statistically significant prevention of bone loss at the lumbar spine and forearm with the use of vitamin D and calcium in corticosteroid treated patients. Outcomes on femoral neck bone density were not significantly different.10 It is recommended that all patients started on long-term corticosteroids should receive prophylactic therapy with calcium and vitamin D, although there are some inconsistencies in the evidence to support this.3,4,7,9-12 Clinical trials have typically measured outcomes at six and 12 months.9 It is therefore not clear what benefit is gained before six months and this has implications when considering osteoporosis prophylaxis in patients who have a shorter prognosis.
When to use osteoporosis prophylaxis
There are no specific guidelines on preventing steroid-induced osteoporotic fractures in oncology and palliative care. The guidance given here is based on several guidelines on the prevention and management of osteoporosis, which have been adapted to focus on oncology and palliative care patients requiring steroids.7,12,13
Whether a patient needs osteoporosis prophylaxis will depend on a number of factors, such as the length of steroid treatment. Prophylaxis should be considered if the patient is likely to have oral glucocorticoid treatment for more than three months at a dose equivalent to prednisolone 5mg daily or more. Note that 5mg prednisolone is approximately equivalent to 750 microgram dexamethasone, 4mg methylprednisolone, 20mg hydrocortisone or 750 microgram betamethasone.
The prognosis is relevant. Osteoporosis prophylaxis is unlikely to be appropriate in patients with a prognosis of days to weeks, but may be appropriate in those with a prognosis of several months or longer. This is because the greatest amount of bone is lost in the first two to three months of glucocorticoid use, so the risk of fracture at any given level of bone mineral density is greater in those on chronic glucocorticoid therapy compared to those who are not on a glucocorticoid.4,14 The presence of other risk factors in addition to steroid therapy should also be considered. These include previous fragility fracture (including vertebral fracture), parental history of hip fracture, current smoking, alcohol intake of three or more units daily and secondary causes of osteoporosis, such as rheumatoid arthritis, untreated hypogonadism, organ transplantation, type-1 diabetes, hyperthyroidism, chronic liver disease and COPD.
Assessing the risk
FRAX, the WHO fracture risk assessment tool, gives an estimate of the 10-year risk of osteoporotic fracture. Use of FRAX requires knowledge of the patient’s height and weight, as well as whether they have any of the above risk factors. It does not require knowledge of bone mineral density. The tool provides a probability of osteoporotic fracture and whether this represents a high, medium or low risk. The National Osteoporosis Group Guideline can be used to derive the same information. A tool that gave a six-month risk of fracture would be more appropriate, given that the greatest amount of bone loss is during the first few months of steroid treatment, but it remains a useful aid to help the clinician to quantify the risk for an indvidual patient.
Guidance on when to consider osteoporosis prophylaxis in oncology and palliative care is summarised in figure 1. Patients likely to have a prognosis of six months or more and to be on steroid doses equivalent to prednisolone 5mg for more than three months should be considered for general measures and daily calcium and vitamin D supplements.3,10,11
Patients defined to be at medium risk by FRAX should be referred for bone mineral density measurement to clarify whether a bisphosphonate is indicated. Lifestyle advice and calcium and vitamin D supplements should be offered.3,10,11,13 Patients at high risk may be treated empirically with a bisphosphonate and calcium and vitamin D without formal bone mineral density.3,10,11,13,14 These measures should be continued for as long as the patient remains on steroids.5
– Dr Dylan Harris is a specialist registrar in palliative medicine and Dr Nikki Pease is consultant in palliative medicine at Velindre Hospital, Cardiff.
Competing interests: None declared
References
1. Twycross R, Wilcock A, Charlesworth S et al. Palliative Care Formulary (second edition). Radcliffe Medical Press, Oxford, 2003.
2. Watson M, Lucas C, Hoy A et al. Oxford Handbook of Palliative Care. Oxford University Press, Oxford, 2005.
3. Jehle PM. Steroid-induced osteoporosis: how can it be avoided? Nephrol Dial Transplant 2003; 18: 861-4.
4. Van Staa TP, Leyfkens HGM, Abenhaim L et al. Use of oral corticosteroids and risk of fractures. J Bone Miner Res 2000; 15: 993-1000.
5. Homik J, Cranney A, Shea B et al. Bisphosphonates for steroid induced osteoporosis. Cochrane Database Syst Rev 1999, Issue 1. Art No: CD001347. DOI: 10.1002/14651858.CD001347.
6. Sambrook PN. How to prevent steroid induced osteoporosis. Ann Rheum Dis 2005; 64: 176-8.
7. Royal College of Physicians of London. Glucocorticoid-induced osteoporosis. RCP, London, 2002.
8. Bijlsma JWJ. Prevention of glucocorticoid induced osteoporosis. Ann Rheum Dis 1997; 56: 507-9.
9. Lips P. Prevention of corticosteroid induced osteoporosis. BMJ 1999; 318: 1366-7.
10. Homik J, Suarez-Almazor ME, Shea B et al. Calcium and vitamin D for corticosteroid-induced osteoporosis. Cochrane Database Syst Rev 1998, Issue 2. Art No: CD000952. DOI: 10.1002/14651858.CD000952.
11. Sambrook PN, Kotowicz M, Nash P et al. Prevention and treatment of glucocorticoid induced osteoporosis: a comparison of calcitriol, vitamin D plus calcium and alendronate plus calcium. J Bone Miner Res 2003; 18: 919-24.
12. American College of Rheumatology Task Force on Osteoporosis Guidelines. Recommendations for the prevention and treatment of glucocorticoid-induced osteoporosis (Update). Arthritis Rheum 2001; 44: 1496-1503.
13. National Osteoporosis Guideline Group. Guideline for the diagnosis and management of osteoporosis in postmenopausal women and men from the age of 50 years in the UK. NOGG, Sheffield, 2008.
14. Institute for Clinical Systems Improvement. Diagnosis and treatment of osteoporosis. Institute for Clinical Systems Improvement, Bloomington (MN), 2006.
