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Relevant BNF section: BNF 6.6
Abstract
Treatment with corticosteroids can adversely affect bone metabolism. In particular, it lowers bone mineral density (BMD) and increases the likelihood of fragility fractures, the hallmarks of osteoporosis, hence the term ‘corticosteroid-induced osteoporosis’.1 Since corticosteroids are used for a wide variety of inflammatory conditions, corticosteroid-induced osteoporosis represents a substantial disease burden. Here we aim to provide advice on prophylaxis and treatment for osteoporosis in adults receiving corticosteroid therapy.
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Relevant BNF section: BNF 6.6
About osteoporosis
Osteoporosis, a progressive, systemic skeletal disorder leads to an increased likelihood of bone fractures. These fractures occur most commonly in the vertebrae, hip and wrist, and are associated with substantial disability, pain, reduced quality of life and (in the case of vertebral and hip fractures) increased mortality rates.2 Traditionally, the diagnosis of osteoporosis has relied on the quantitative assessment of BMD, usually by central dual energy X-ray absorptiometry (DXA) scanning. On this measure, osteoporosis is defined as a BMD 2.5 standard deviations (SD) below the mean for a young adult population (i.e. a so-called T-score less than or equal to −2.5SD); osteopenia is defined as a T-score of −1.0 to −2.5SD; and a T-score above −1.0 is considered normal.2
The factors associated with an increased risk of fracture (some of which act through their association with low BMD) include the following: age; gender; low body mass index (≤19kg/m2); previous fragility fracture; parental history of hip fracture; smoking; alcohol intake of 3 or more units per day; secondary causes of osteoporosis (rheumatoid arthritis, type 1 diabetes mellitus, hyperthyroidism, untreated hypogonadism, prolonged immobility, gastrointestinal disease, chronic liver disease, chronic obstructive pulmonary disease); and current corticosteroid therapy.3
Due to the understanding that some risk factors operate through BMD and others not, there is not one single cut-off score for BMD indicating that a person requires treatment for osteoporosis. Nowadays, it is felt that the person’s overall risk of fracture should be evaluated,3 for example, using the World Health Organization fracture risk assessment tool FRAX (www.shef.ac.uk/FRAX), which calculates a 10-year probability of a fracture, using the risk factors listed above, for patients aged 40 or over. For the patient whose BMD has not been measured, the FRAX tool indicates whether or not they are at high risk, and therefore require treatment without needing a BMD scan; whether they are at intermediate risk at least and therefore should have their BMD measured; and whether at low risk and may be reassured and given lifestyle advice only without specific treatment for osteoporosis. Where a patient’s BMD is available, entering it into the FRAX tool indicates whether the person is above or below a threshold requiring intervention.
How corticosteroids affect bone
Corticosteroids decrease the number and activity of osteoblasts, leading to suppression of bone formation.1 They also prolong osteoclast survival, leading to increased bone resorption.1 Corticosteroids also decrease absorption of calcium from the intestine, and increase urinary calcium loss.1 There is a two- to threefold increase in the likelihood of fractures at the lumbar vertebrae and hip among users of corticosteroids compared with non-users.4
Dose and duration of corticosteroid therapy are the strongest risk factors for corticosteroid-induced osteoporosis. In particular, fracture risk rises steadily as dose and duration of prednisolone therapy increase beyond 5mg daily and 3 months, respectively.4 The risk of fracture rises from shortly after the start of treatment, but plateaus within 6 months and returns toward pre-treatment level within about 12 months of stopping corticosteroid therapy.4,5 Fracture risk also increases after several intermittent courses of high-dose oral corticosteroids (i.e. a daily dose of at least 15mg and cumulative exposure above 1g).5 However, there is no clear evidence that high doses of inhaled corticosteroids increase fracture risk.6 The increased fracture risk associated with corticosteroid therapy seems to be mostly independent of BMD, and corticosteroid users compared to non-users have a higher risk for vertebral fractures at a given BMD.7 Also, the likelihood of falling may be increased in corticosteroid users because of muscle weakness and frailty attributable to the underlying disease that requires such treatment.3
General advice
As the increased fracture risk develops within 3–6 months of the start of corticosteroid therapy,1,4 identification of patients at risk of corticosteroid-induced osteoporosis needs to be done as early as possible, ideally before starting planned corticosteroid therapy.
Lifestyle advice may be useful in reducing the adverse skeletal effects of corticosteroids, although the evidence for this approach is weak.3,8 A daily calcium intake of around 1g, good nutrition and maintenance of a normal BMI should be encouraged, and excessive alcohol intake and smoking avoided. Physical activity within the limits imposed by the patient’s disease should be advocated, the patient’s risk of falling assessed and advice on preventing falls given where appropriate. Other measures include frequent review of corticosteroid dose, with reduction or cessation of this treatment where possible, and the use of alternative formulations (e.g. inhaled or topical corticosteroids) where appropriate.3
Calcium and vitamin D supplements
Supplemental calcium (1g daily) and vitamin D (800IU daily),3 should be used if there is any concern that the patient is unable to maintain an adequate dietary intake of these. Supplements are also needed by people with underlying disorders that can affect calcium and vitamin D absorption, such as inflammatory bowel disease. Hydroxylated forms of vitamin D (alfacalcidol and calcitriol) are unnecessary unless there is an underlying disorder associated with impaired vitamin D metabolism, such as severe renal impairment;9 they are associated with a higher likelihood of developing hypercalcaemia and hypercalciuria than with cholecalciferol.10,11, Vitamin D deficiency is common, and some consultants advocate routine measurement of vitamin D status by measuring baseline plasma 25-hydroxyvitamin D concentrations.
Drug treatment
Whether bone protective drug therapy is justified is determined by factors such as specific corticosteroid dose and clinical risk factors (including age, female gender, postmenopausal status, history of low-trauma fracture, parental history of hip fracture, smoking and excess alcohol intake). Guidelines published in 2002 by the UK Royal College of Physicians (which was before FRAX became available) recommend starting bone-protective drug therapy in patients for whom corticosteroid therapy is planned to last for at least 3 months, who are aged 65 years or above; and in younger patients with a history of low-trauma fracture.12 For other groups, a DXA scan is suggested, followed by drug treatment if the T-score is −1.5 or less. Compared with these guidelines, using FRAX has advantages as it allows different risk factors to be integrated to provide an overall risk score that can be used to assess the need for therapeutic intervention. However, as corticosteroid therapy is only entered into the FRAX alogorithm as a ‘yes’ or ‘no’ feature, the effect on fracture risk may be underestimated in patients receiving relatively high doses of corticosteroid.3
The American College of Rheumatologists has recently published recommendations on corticosteroid-induced osteoporosis based on the use of the FRAX tool.8 It recommends bone protective drug treatment for the following groups:
postmenopausal women and men aged over 50 years
at low risk of fracture and taking at least 7.5mg prednisolone daily (or equivalent) for 3 months or more;
at medium risk of fracture on any dose of corticosteroid for 3 months or more;
at high risk of fracture on any dose of corticosteroid for any duration;
women (not of childbearing potential) and men aged under 50 years with previous fragility fracture
on at least 5mg prednisolone daily for 1–3 months;
on any dose of corticosteroid for 3 months or more.
For women of childbearing potential, the College recommends treatment for those on at least 7.5mg prednisolone daily for 3 months or longer.
Treatment should be continued ideally for the duration of the corticosteroid therapy.
Certain bisphosphonates and the parathyroid hormone analogue ▼teriparatide are licensed in the UK as prophylaxis and treatment for corticosteroid-induced osteoporosis. Bisphosphonates are the most widely evaluated treatments for this condition, and are generally regarded as first-line options.3
Interpretation of the results of drug trials in corticosteroid-induced osteoporosis is complicated by the heterogeneity of the trial populations in terms of age, gender, underlying disease, comorbidities, concurrent medications and the timing of intervention with respect to the start of corticosteroid therapy.3 Also, most of the studies have been short-term (lasting 1 year) and the number of men and premenopausal women in the studies has generally been low. Changes in BMD are usually used to assess the efficacy of drug treatment in osteoporosis. However, BMD is only a surrogate endpoint, and the true measure of clinical effectiveness of these drugs is their ability to prevent fractures in the context of corticosteroid-induced osteoporosis. There have been few trials of drug therapy for corticosteroid-induced osteoporosis in which fracture has been the primary endpoint. Of note, calcium and vitamin D supplementation has been routinely provided in most clinical trials of bone-protective therapy in corticosteroid-induced osteoporosis.3
Bisphosphonates
Oral bisphosphonates
Bisphosphonates bind avidly to bone, and inhibit bone resorption by osteoclasts. Three oral bisphosphonates are licensed in the UK as prophylaxis and treatment for corticosteroid-induced osteoporosis, namely alendronate (in postmenopausal women, at a dose of 10mg daily), risedronate (in postmenopausal women, at a dose of 5mg daily) and etidronate (in cycles of 400mg daily for 14 days followed by calcium 500mg for 76 days). A meta-analysis of 13 randomised controlled trials (involving a total of 842 patients) assessing bisphosphonates as prophylaxis or treatment for corticosteroid-induced osteoporosis found that the drugs were effective in reducing bone loss (weighted mean difference in BMD between treatment and placebo 4.3%, 95% CI 2.7% to 5.9% at the lumbar spine and 2.1%, 95% CI 0.01% to 3.8% at the femoral neck).13 The results of some trials assessing vertebral fracture rate as a secondary outcome measure suggest that these effects on BMD translate into a reduction in fracture rate. For example, in a double-blind randomised trial lasting 2 years and involving 208 men and women receiving prednisolone at a dose of at least 7.5mg daily (or equivalent), fewer of those on alendronate had vertebral fractures 0.7% vs. 6.8% with placebo, p=0.026).14 Also, in a double-blind placebo-controlled trial lasting 1 year and involving 290 men and women on oral corticosteroids for at least 6 months, fewer of those on risedronate 2.5mg or 5mg daily had vertebral fractures (15% vs. 5%, p=0.042), although the difference for each of the two doses analysed separately was not statistically significant.15
Intravenous bisphosphonates
▼Zoledronic acid 5mg, given by intravenous infusion once a year, is licensed as a treatment for corticosteroid-induced osteoporosis.16 A double-blind randomised controlled trial of intravenous zoledronic acid (a single 5mg infusion) involved 833 patients who were expected to take at least 7.5mg prednisolone daily (or equivalent) for at least 12 months.17 The drug was more effective than oral risedronate (5mg daily) in increasing spinal BMD (by 4.06% vs. 2.71%) when used as a treatment in patients who had been on corticosteroids for at least 3 months; it was also superior when used as prevention in those who had been on corticosteroids for under 3 months (BMD increased by 2.60% vs. 0.64%).
Contraindications and unwanted effects
There are few contraindications to bisphosphonates. Alendronate is contraindicated in patients with abnormalities of the oesophagus or other factors that delay oesophageal emptying; in patients unable to stand or sit upright for 30 minutes; and in those with hypocalcaemia. Risedronate is contraindicated in hypocalcaemia, severe renal impairment (creatinine clearance below 30mL/minute) and pregnancy and breastfeeding. Etidronate (which is presented together with calcium in a combination pack) is contraindicated in “severe renal impairment” (undefined in the drug’s summary of product characteristics [SPC]), clinically overt osteomalacia, hypercalcaemia or hypercalciuria and in pregnancy and breastfeeding. Zoledronic acid is contraindicated in hypocalcaemia and pregnancy and breastfeeding and patients with a creatinine clearance below 35mL/minute.
Alendronate and risedronate can cause upper gastrointestinal irritation. To prevent oesophageal injury, the SPCs recommend that they are taken with a full glass of water and that the patient remains upright for 30 minutes after swallowing the drug. Intravenous bisphosphonates provide a means of overcoming the problem of intolerance to oral bisphosphonates. However, in the trial comparing zolendronic acid with risedronate discussed above, the overall occurrence of unwanted effects was higher among those on zolendronic acid, mainly due to a higher frequency of symptoms (e.g. influenza-like illness, pyrexia) that were reported within 3 days of the infusion.17
Osteonecrosis of the jaw has been reported uncommonly in patients receiving bisphosphonates. Most cases have been related to the use of high-dose intravenous bisphosphonates in the treatment of malignant disorders.18 The risk with oral bisphosphonate therapy has been estimated at below 1 in 100,000 to 1 in 10,000 patient-treatment years.18 The Medicines and Healthcare products Regulatory Agency advises that during bisphosphonate therapy, patients should maintain good oral hygiene, receive routine dental check-ups and report any oral symptoms such as dental mobility, pain or swelling.19 As corticosteroid therapy is also a risk factor for jaw osteonecrosis, it may be prudent for patients on this treatment to undergo any planned dental procedures known to increase the likelihood of jaw osteonecrosis (e.g. dental extractions) before, rather than after, starting bisphosphonate therapy.
Teriparatide
Teriparatide is a recombinant peptide comprising the first 34 amino acids of parathyroid hormone (the primary regulator of calcium and phosphate metabolism in bone and the kidney).20 Parathyroid hormone stimulates bone formation by direct effects on osteoblasts and indirectly by increasing the intestinal absorption of calcium and increasing the tubular reabsorption of calcium and excretion of phosphate by the kidney. Teriparatide is licensed as treatment for osteoporosis associated with sustained corticosteroid therapy in women and men at increased risk for fracture. It is given as a daily self-administered subcutaneous injection of 20µg for up to 24 months. Unlike bisphosphonates, which act to suppress bone remodelling, teriparatide is an anabolic drug, which stimulates new bone formation by osteoblasts.21 As such, it could, in theory, be more effective than bisphosphonates as a treatment for corticosteroid-induced osteoporosis, given that suppression of osteoblast function is thought to underlie the pathogenesis of the condition.21 Evidence supporting this possible advantage comes from a double-blind randomised controlled trial (involving 428 patients who had received 5mg prednisolone daily or equivalent for at least 3 months).21 In this study, teriparatide increased spinal BMD (the primary outcome measure) to a greater extent than alendronate (mean increase in lumbar spine BMD 7.2% vs. 3.4%, p<0.001), and was associated with fewer vertebral fractures (a secondary outcome measure, 0.6% vs. 6.1%, p=0.004).
Contraindications and unwanted effects
Contraindications to teriparatide include hypercalcaemia, “severe renal impairment” (undefined in the SPC), pregnancy and breastfeeding, metabolic bone disease, and unexplained elevations of alkaline phosphatase. Nausea, limb pain, headache and dizziness are the most commonly reported unwanted effects. Other common effects (each occurring in 1–10% of patients) include palpitations, anaemia, dyspnoea, increased sweating, muscle cramps and hypercholesterolaemia and hypotension.20
Other drugs
In theory, other drugs that could be beneficial in corticosteroid-induced osteoporosis include the bisphosphonate ibandronate (which can be used orally or intravenously), strontium ranelate, raloxifene, hormone replacement therapy and calcitonin. However, there is little evidence supporting their use in this setting.3 There have been randomised controlled trials of calcitonin as prophylaxis or treatment for corticosteroid-induced osteoporosis but a meta-analysis of the results did not show a clear benefit with regards to fracture risk.22
Who needs referral?
Most patients at risk of corticosteroid-induced osteoporosis can be managed in primary care. A few need referral to a specialist service, for example because of intolerance of oral bisphosphonates and for consideration of drugs such as teriparatide and intravenous zoledronic acid.
Conclusion
Patients receiving systemic corticosteroid therapy are at increased risk of bone loss and fractures, particularly at doses and durations above 5mg prednisolone daily (or equivalent) for 3 months. To minimise this added risk, the lowest dose of corticosteroid should be used for the shortest time. Patients taking corticosteroids should be counselled about lifestyle measures, including good nutrition, adequate calcium and vitamin D intake, appropriate physical activity, avoidance of smoking and excessive alcohol intake, and risk assessment for falling. The individual patient’s risk of corticosteroid-induced osteoporosis should also be considered, taking into account the corticosteroid dose, the likely duration of treatment and clinical risk factors such as postmenopausal status or any history of low-trauma fracture.
Much of the evidence on the efficacy of drug treatments in preventing fracture is extrapolated from that in post-menopausal osteoporosis, which has a different pathogenesis from that in corticosteroid-induced osteoporosis. More research is therefore needed to determine the most effective preventive and treatment strategy in people at risk of corticosteroid-induced osteoporosis.
In patients needing bone protective therapy, treatment with a bisphosphonate (alendronate is the cheapest) together with calcium and vitamin D supplements should be offered (with discussion of potential benefits and harms) as close as possible to the start of corticosteroid therapy, and continued for its duration. Patients might need to be referred to specialist services, for example because of intolerance of oral bisphosphonates.
References
[R=randomised controlled trial; M=meta-analysis]