How to prevent glucocorticoid-induced osteoporosis
ABSTRACTWhen prescribing glucocorticoids for long-term treatment, physicians should take steps to prevent osteoporosis, a common and serious side effect of these drugs.
KEY POINTS
- Glucocorticoids have both direct and indirect effects on bone cells, and they both suppress bone formation and promote resorption.
- Patients who need glucocorticoids should receive the lowest effective dose for the shortest possible time. They should also be advised to undertake general health measures, including stopping smoking, reducing alcohol intake, exercising daily, and taking in adequate amounts of calcium and vitamin D.
- Bisphosphonates and teriparatide (Forteo) are approved for treating glucocorticoid-induced osteoporosis, but adherence to guidelines for managing this condition is far from optimal.
NEWLY APPROVED AND INVESTIGATIONAL AGENTS
Zoledronic acid once a year
Zoledronic acid (Reclast), a bisphosphonate given intravenously once a year, was approved for glucocorticoid-induced osteoporosis after the ACR and UK guidelines were published.
Zoledronic acid underwent a randomized multicenter, double-blind, active control trial29 in 833 men and women, age range 18 to 85 years, who had glucocorticoid-induced osteoporosis (they had been treated with 7.5 mg per day or more of prednisone or its equivalent). Of these patients, 416 received a single infusion of 5 mg of zoledronic acid and daily oral placebo, and 417 received a single placebo infusion and daily oral risedronate 5 mg as an active control. All patients also received 1,000 mg of calcium and 400 to 1,000 IU of vitamin D per day. The study duration was 1 year.
Of those who had received a glucocorticoid for more than 3 months, those who received zoledronic acid had a significantly greater mean increase in lumbar spine bone mineral density compared with those in the oral risedronate group: 4.1% vs 2.7%, an absolute difference of 1.4% (P < .0001).
In those who had received a glucocorticoid for 3 months or less, those who received zoledronic acid also had a significantly greater mean increase in lumbar spine bone mineral density compared with those in the risedronate group at 1 year: 2.6% vs 0.6%, a treatment difference of 2% (P < .0001).
Bone biopsy specimens were obtained from 23 patients, 12 in the zoledronic acid group and 11 in the risedronate group.30 Qualitative assessment showed normal bone architecture and quality without mineralization defects. Apparent reductions in activation frequency and remodeling rates were seen when compared with the histomorphometric results in the zoledronic acid postmenopausal osteoporosis population.31 The long-term consequences of this degree of suppression of bone remodeling in the glucocorticoid-treated patients are unknown.
The overall safety and tolerability of zoledronic acid in the glucocorticoid-induced osteoporosis population was similar to that in the postmenopausal osteoporosis clinical trial.29,31 Adverse reactions reported in at least 2% of patients that were either not reported in the postmenopausal osteoporosis trial or were reported more frequently in the glucocorticoid-induced trial included the following: abdominal pain, musculoskeletal pain, nausea, and dyspepsia. The incidence of serious adverse events was similar in the zoledronic acid and the active control groups. In the zoledronic acid group, 2.2% of the patients withdrew from the study due to adverse events vs 1.4% in the active control group.
Teriparatide, a parathyroid hormone drug
Teriparatide (Forteo) consists of a fragment of the human parathyroid hormone molecule. It is given once daily by subcutaneous injection. It was also approved for treating glucocorticoid-induced osteoporosis after the current guidelines were written.
Teriparatide was compared with alendronate in a randomized, double-blind trial in patients with glucocorticoid-induced osteoporosis. 32 Entry criteria were treatment with at least 5 mg of prednisone per day for at least 3 months before screening and a T score of −2.0 or less in the lumbar spine, total hip, or femoral neck, or −1.0 or less plus one or more fragility fractures.
Eighty-three men and 345 women ages 21 or older were enrolled and randomized to receive injectable teriparatide 20 μg per day plus oral placebo or oral alendronate 10 mg per day plus injectable placebo. All of them also received calcium 1,000 mg per day and vitamin D 800 IU per day.
At 18 months, the bone mineral density had increased significantly more in the teriparatide group than in the alendronate group in the lumbar spine (P < .001) and in the total hip (P < .01). As expected, markers of bone turnover were suppressed in the alendronate group but were increased in the teriparatide group.
New vertebral fractures were found on radiography in 10 of 165 patients in the alendronate group vs 1 of 171 patients in the teriparatide group (P = .004). Clinical vertebral fractures occurred in 3 of 165 patients treated with alendronate but in none of the teriparatide-treated patients (P = .07). Nonvertebral fractures occurred in 8 of 214 patients treated with alendronate and 12 of 214 patients treated with teriparatide (P = .362). Three of 214 patients treated with alendronate suffered nonvertebral fragility fractures, compared with 5 of 214 patients treated with teriparatide (P = .455).
Denosumab, an antibody to RANK ligand
Denosumab (Prolia) is a fully human monoclonal antibody to RANK ligand. (Recall that glucocorticoids are associated with increases in RANK ligand and decreases in osteoprotegerin.) Denosumab is given subcutaneously in a dosage of 60 mg every 6 months. It was recently approved for the treatment of postmenopausal osteoporosis.
In a phase 2 study of denosumab33 in men and women with rheumatoid arthritis (an independent risk factor for bone loss), the bone mineral density of the lumbar spine increased irrespective of whether the patients were treated with bisphosphonates and glucocorticoids.
ADHERENCE TO GUIDELINES IS POOR
Unfortunately, prevention and treatment in actual clinical practice still lag behind what is recommended in the current guidelines, even though multiple therapies are available.
In 2005, Blalock et al34 expressed concerns about patients’ knowledge, beliefs, and behavior and the prevention and treatment of glucocorticoid-induced osteoporosis. They found that most patients taking oral glucocorticoids are not adequately educated about the prevention of osteoporosis, stating that “patients either are not being counseled or they are being counseled in a manner that is not sufficient to promote subsequent recall and behavior change.”34 They concluded that research is needed to develop effective ways to educate patients about how to prevent glucocorticoid-induced osteoporosis.
Also in 2005, Curtis et al35 reviewed the records of managed-care patients taking glucocorticoids, comparing the prescription of antiresorptive therapy and the use of over-the-counter calcium or vitamin D or both in the periods 2001 to 2003 vs 1995 to 1998. The frequency of bone mineral density measurement in 2001 to 2003 had increased threefold compared with 1995 to 1998, and the use of a prescription antiresorptive drug had increased approximately twofold. However, only 42% of the patients underwent bone mineral density testing or were prescribed bone-protective medicine. The rates were lowest for men, at 25%.
A CALL TO ACTION
Evidenced-based guidelines exist to guide the clinician in an attempt to prevent the deleterious effects of glucocorticoids on bone. Physicians, physician assistants, nurse practitioners, and pharmacists need to coordinate their effects to ensure that adherence to these guidelines improves. Only then will the bone health of patients treated with glucocorticoids improve.
