Glucocorticoids are widely used and are often required recurrently or for extended periods. A major side effect is osteoporosis with an increased fracture risk. The commonest reasons for the use of oral glucocorticoids in the community are asthma and chronic obstructive pulmonary disease (COPD), followed by skin and musculoskeletal conditions.
Glucocorticoids affect osteoblast function, increase bone resorption, calcium homeostasis, osteocyte apoptosis and affect sex hormone status. In addition, chronic use can lead to myopathy with increased risk of falls.
Bone Density & Fracture Risk
It is clear that there is a large, accelerated decline in bone mineral density (BMD) with oral glucocorticoid therapy. This effect is most pronounced in the first year, with trabecular bone more affected than cortical bone. Recent reports have shown markedly decreased BMD at the lumbar spine, femoral neck and whole body after only 2 months of initiating high-dose glucocorticoids (>40mg/day). The greatest loss is again seen at lumbar vertebrae, which consist of predominantly trabecular bone. In rheumatoid arthritis, more cortical bone loss is seen, and this may relate to the double effect of glucocorticoids and systemic inflammation.
Decreases in BMD correlate with cumulative glucocorticoid dose. In addition, there are randomized trials showing a low dose of Prednisone 7.5mg daily causing BMD reduction. Alternate day glucocorticoids do not appear to protect bone. It is likely that all patients on oral glucocorticoids at any dose lose bone density but the loss would be increased at the higher and more prolonged doses.
There is a rapid onset of BMD loss within the first few months of commencing therapy. This seems to slow down after 1 year. In part, this finding may relate to the fact that higher doses of glucocorticoids are used early, followed by a taper in the dose over time. This bone loss appears reversible to some extent, with an increase in BMD demonstrated following discontinuation of glucocorticoids.
The bone effect is not limited to oral preparations but the studies are less clear. Intramuscular steroid given monthly for rheumatoid arthritis over 2 years was associated with BMD loss in the order of 15%. In a cohort study of Chinese men over 65 years, inhaled steroids were shown to be negatively associated with lumbar and total hip BMD.
Fracture risk is higher than predicted by the bone density changes alone, with a higher fracture risk in glucocorticoid users for a similar level of BMD when compared with postmenopausal osteoporosis, particularly for vertebral fractures. About 20% of older men and postmenopausal women had vertebral fractures in the first year of steroid treatment.
Prevention & Treatment
Apart from the dose and duration of glucocorticoid therapy, other risk factors such as age, previous minimal-trauma fracture or maternal hip fracture, and the underlying disease, need to be considered. Bone densitometry is central with lower treatment thresholds recommended because not all the fracture risk appears to be mediated through BMD.
Ensuring adequate calcium and vitamin D intake is recommended but the evidence of benefit from this alone is variable. Activated vitamin D3 (eg Rocaltrol) has been shown to prevent bone loss and reduce vertebral fracture. Most therapeutic trials for steroid-induced osteoporosis have focused on the effectiveness of bisphosphonates, with risedronate and alendronate most studied. They are more effective agents than activated vitamin D3. Parenteral bisphosphonates such as ibandronate, pamidronate, and zolendronate are likely to be as effective but are less studied.
The promotion of bone formation with intermittent parathyroid hormone, given subcutaneously, dramatically increased vertebral bone density in postmenopausal women on prednisone. Lumbar spine BMD was increased by 11.8% after the first year compared to a non-treatment group. The increase in hip BMD was smaller but still significant. This agent is not currently available on the PBS.
Recommendations
Recommendations are based more on consensus that evidence due to studies being small and of short duration, and in general being underpowered to show effects on fracture. There is also much less evidence for prevention and treatment of glucocorticoid-induced osteoporosis in premenopausal women, younger men, children and adolescents.
Whether or not to intervene does depend on estimates of the probability of future fracture. This will be based on age, risk factors, BMD, dose and duration of glucocorticoid therapy. Duration of glucocorticoid therapy over 3-6 months, and a dose of prednisone of at least 5mg seems a reasonable threshold. If the patient is already osteopenic with a T-score less than –1.5, treatment is recommended. Most would use antiresorptive therapy with the bisphosphonates, as there is most evidence to support their use. These agents should be used early after commencement of glucocorticoid therapy if fracture risk is sufficiently high as most of the bone loss occurs in the first few months. Calcium and vitamin D deficiency should be corrected.
In children and adolescents where there is very little evidence for the different therapeutic options, emphasis is placed on adequate nutrition, calcium, vitamin D, exercise and the use of the lowest dose of glucocorticoid. Bisphosphonates are also used if prolonged high doses of glucocorticoids are to be used, if there are other major risk factors, or if bone density is falling despite general measures.
Clinicians often forget about the prevention and treatment of glucocorticoid-induced osteoporosis. Osteoporosis with increased risk of fracture is a serious complication of using glucocorticoids. While guidelines lack consistency and more evidence is required on the efficacy and cost-effectiveness of different interventions, this should not prevent clinicians being more aware of the problem and utilizing the currently available strategies.
Reference:
Woolf A, An update on glucocorticoid induced osteoporosis, Curr Opin Rheumatol 2007, 19:370-375
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