How to prevent glucocorticoid-induced osteoporosis

Who should receive a bisphosphonate?

In men and postmenopausal women, the ACR¹⁷ recommends a bisphosphonate for patients starting long-term glucocorticoid treatment (ie, expected to last 3 months or more) in doses of 5 mg or more per day of prednisone or its equivalent, irrespective of bone mineral density values.

In patients already taking glucocorticoids, a bisphosphonate should be started if the bone mineral density is below a certain threshold. The rationale for using bone mineral thresholds instead of giving bisphosphonates to all is that these drugs have potentially significant side effects and so should not be prescribed if not needed. The appropriate threshold at which intervention should be considered in glucocorticoid-treated patients is a matter of controversy. Based on evidence that fractures occur at a higher bone mineral density in glucocorticoid-treated patients than in postmenopausal women, the UK guidelines¹⁸ recommend starting a bisphosphonate if the T score is less than −1.5 at the spine or hip, but the ACR¹⁷ guidelines propose a T-score cutoff of −1.0. Whichever cutoff is chosen, its significance in terms of absolute fracture risk will differ according to the age of the patient. Therefore, use of T scores as an intervention threshold is not advisable.

The ACR and the UK guidelines both recommend measuring the bone mineral density by dual-energy x-ray absorptiometry at baseline (even though preventive therapy is not based on this value) and repeating it 6 months later and then yearly.

In premenopausal women, bisphosphonates should be used with caution, as they cross the placenta and are teratogenic in animals. Nevertheless, the ACR guidelines¹⁷ state they can be given after appropriate counseling and instruction about contraception.

The UK guidelines¹⁸ note that in the large clinical trials of alendronate and risedronate, the incidence of vertebral fractures was low in premenopausal women, indicating a very low fracture risk. Therefore, the UK guidelines state that bone-active drugs should be reserved for premenopausal women who have very low bone mineral density or who suffer fragility fractures or who have other strong risk factors for fracture.

In children and adolescents, the data are insufficient to produce evidence-based guidelines for the prevention and treatment of glucocorticoid-induced osteoporosis. General measures include using the lowest effective dose of glucocorticoids for the shortest period of time, and considering alternate therapies, calcium and vitamin D supplementation, weight-bearing exercise, and proper nutrition.

Bisphosphonates are recommended when bone mineral density is falling despite these general measures and when “high-dose” glucocorticoids are likely to be used for a “prolonged” time, or in patients who have already had a fracture.²¹

Weekly doses may improve compliance

Risedronate is approved by the US Food and Drug Administration (FDA) for the prevention of glucocorticoid-induced osteoporosis, and both risedronate and alendronate are approved for its treatment.

The ACR guidelines recommend the FDA-approved (ie, daily) doses of alendronate and risedronate for glucocorticoid-induced osteoporosis. Most patients, however, are pre-scribed weekly doses of these two agents, as compliance is much greater with this schedule of administration.

Estrogen is being used more selectively

The 2001 ACR guidelines said that, although there were no randomized controlled trials of hormone replacement (or testosterone) therapy to prevent glucocorticoid-induced bone loss, patients receiving long-term glucocorticoid therapy who are hypogonadal should be offered hormone replacement therapy.¹⁷

In 2002, the principal results of the Women’s Health Initiative²² showed that hormone replacement therapy with estrogen and progesterone was associated with a higher risk of breast cancer. Since then, the consensus has been that hormone replacement therapy should be restricted to women with menopausal symptoms or to older women who cannot tolerate other therapies or who express a strong preference for hormone replacement therapy despite being informed about potential adverse events.²³

A role for testosterone?

Since a daily dose of more than 5 to 7.5 mg of prednisone increases the risk of gonadotropin and testosterone suppression,²⁴ testosterone replacement therapy has been used to treat glucocorticoid-induced osteoporosis in men.

In two placebo-controlled trials in men receiving glucocorticoid therapy for bronchial asthma or chronic obstructive pulmonary disease, testosterone therapy was associated with a significant 4% increase (95% CI 2–7) in bone mineral density in the lumbar spine.^25,26

While these studies cannot be considered conclusive in view of their small size and the lack of fracture data, the Endocrine Society currently recommends that men with chronic obstructive pulmonary disease who are receiving glucocorticoids, are hypogonadal, and have no contraindications to androgen replacement therapy (eg, prostate cancer) be offered testosterone therapy to preserve lean body mass and bone mineral density.²⁷

Calcitonin is not a first-line therapy

Neither the ACR nor the UK guidelines recommended calcitonin as first-line therapy.

A Cochrane systematic review²⁸ evaluated the data on the use of calcitonin to prevent and treat glucocorticoid-induced osteoporosis. Nine trials met the inclusion criteria, and included 221 patients randomized to receive calcitonin and 220 patients who received placebo. Calcitonin was more effective than placebo in preserving bone density in the lumbar spine, with a weighted mean difference of 2.8% (95% CI 1.4–4.3) at 6 months and 3.2% (95% CI 0.3–6.1) at 12 months. However, at 24 months, the lumbar spine bone mineral density was not statistically different between groups, nor was the relative risk of fractures. Calcitonin was given subcutaneously in one trial, in which it showed a substantially greater degree of prevention of bone loss than in the other trials, in which it was given nasally.