boxed-textde Nijs RNJ et al. (2006) Alendronate or alfacalcidol in glucocorticoid-induced osteoporosis. N Eng J Med 355: 675–684
Patients with rheumatic diseases often receive treatment with glucocorticoids, and treatment with these agents has been associated with an increased risk of bone loss and fracture.
The objective of this study was to determine whether alendronate or alfacalcidol is more effective in the prevention of glucocorticoid-induced bone loss and fracture.
Design and intervention
This was a randomized, double-blind, double-placebo trial of patients treated with either the vitamin D3 analogue alfacalcidol or the bisphosphonate alendronate over 18 months. Patients included in this trial were aged 18–90 years, were diagnosed with rheumatic disease and were either about to receive therapy with glucocorticoids or had begun glucocorticoid treatment at a daily dose of at least 7.5 mg of prednisone within 12 weeks of the beginning of the trial. Patients receiving treatment with hormone-replacement agents, anabolic steroids, calcitonin, active vitamin D3 analogues, or bisphosphonates in the 12 months before the trial, as well as patients with hypocalcemia, hypercalciuria, or metabolic bone disease, were excluded from this study. Participants were assessed 3 weeks before the study, at baseline, and every 3 months until the end of the trial. Changes in glucocorticoid dose, incidence of nonvertebral fractures, and back pain were recorded at each patient visit.
The primary outcome measure of this study was the percentage change in bone mineral density (BMD) of the lumbar spine after 18 months of treatment. The secondary outcome measures included the percentage change in BMD of the femoral neck and hip, the incidence of nonvertebral fractures or symptomatic vertebral fractures, and morphometric vertebral deformities.
In total, 201 patients participated in this trial and were randomly assigned to treatment with 1 μg alfacalcidol and a placebo capsule of alendronate daily (n = 101), or 10 mg alendronate and a placebo capsule of alfacalcidol daily (n = 100). Adherence to treatment was 79% and 83% in each group, respectively. There was a 2.1% increase in BMD of the lumbar spine in the alendronate group after 18 months (95% CI 1.1–3.1%). BMD of the lumbar spine was decreased by 1.9% in the alfacalcidol group after 18 months (95% CI −3.1% to −0.7%), resulting in an absolute difference of 4.0% between the two groups (95% CI 2.4–5.5%). Similarly, BMD of the femoral neck was increased in the alendronate group (1.4%) and decreased in the alfacalcidol group (2.0%). New vertebral deformities were observed in three patients in the alendronate group, and in eight patients in the alfacalcidol group, three of which were symptomatic vertebral fractures (hazard ratio 0.4, 95% CI 0.1–1.4).
The authors conclude that the bisphosphonate alendronate is more effective in the prevention of glucocorticoid-induced bone loss than the vitamin D3 analogue alfacalcidol is.
This study by de Nijs and colleagues is an important advance in the prevention of corticosteroid-induced osteoporosis in patients with rheumatic disease. Treatment with a bisphosphonate was shown to be superior to treatment with a vitamin D3 analog in preventing bone loss and the incidence of bone fractures. The study design is impressive, although some details are missing, such as the definition of the 'metabolic bone disease' that patients were excluded on the basis of. As several subjects had experienced vertebral fractures at study entry, it is likely that 'ordinary' postmenopausal osteoporosis or aging or rheumatic diseases were not excluded, and that 'metabolic bone disease' meant primary or secondary hyperparathyroidism or osteomalacia, and not osteoporosis.
The specific treatments compared were a bisphosphonate (alendronate) and a hydroxylated analog of vitamin D3 (1alpha-OH-vitamin D3, or alfacalcidol). Alfacalcidol is converted in the liver to 1,25-dihydroxyvitamin D3 (1,25-(OH)2D3, or calcitriol). Use of vitamin D3 analogs, particularly alfacalcidol, has been advocated because it is more effective than vitamin D3 in promoting bone formation and reducing osteoclast activity. In fact, both alfacalcidol and calcitriol are superior to vitamin D3 in preventing bone loss and spinal fractures in primary osteoporosis.1 Alfacalcidol is not currently available in the US, but is available in several countries in Europe and in South Africa. Calcitriol, however, is widely available, although it is advisable to monitor serum and urine calcium levels regularly in patients receiving vitamin D3 analogs, in order to detect hypercalcemia and hypercalciuria.
In the de Nijs study, the dosing of alendronate was 10 mg daily. This approach is inconvenient for patients because of the necessity of taking bisphosphonates on an empty stomach (for 6–8 h before and for 30–60 min after each dose, to maximize intestinal absorption) and to avoid lying down afterwards (to protect against esophagitis). It is, therefore, common to administer alendronate in single, weekly doses, which were not studied in this trial. Alendronate 35 mg weekly is equivalent to alendronate 5 mg daily in the maintenance of bone mass in primary osteoporosis and in the frequency of adverse effects.2 Alendronate should be started soon after the clinical recommendation of systemic corticosteroid therapy.
As the de Nijs et al. study did not include a placebo group, the role of vitamin D3 replacement in prevention of steroid-induced bone loss is not clear. Although patients in the alfacalcidol group had decreased bone density compared with the patients in the alendronate group, this could have been worse without vitamin D3 replacement therapy. Since the original observation that supplementation with vitamin D metabolites reduces bone loss in patients with rheumatic disease who are receiving corticosteroids,3 substantial evidence has shown that such supplementation also helps maintain bone mass in these patients.4
If clinicians adhere to the recommendations supported by this study and prescribe alendronate to maintain bone density, they should also recommend supplemental calcium intake (usually 1,000–1,500 mg/day), and should maintain serum vitamin 25OHD levels at 30–60 mg/ml to optimize calcium absorption. The latter suggestion might require supplementation with vitamin D3 400–2,000 units daily, or 50,000 units monthly, especially in older patients.4 The optimal duration of regimens such as this and the optimal doses of bisphosphonates and vitamin D are not yet known; further high-quality studies are needed to address these issues.
Richy F et al. (2005) Vitamin D analogs versus native vitamin D in preventing bone loss and osteoporosis-related fractures: a comparative meta-analysis. Calcif Tissue Int 76: 176–186
Lucky MM et al.(2003) Therapeutic equivalence of alendronate 35 milligrams once weekly and 5 milligrams daily in the prevention of postmenopausal osteoporosis. Obstet Gynecol 101: 711–721
Hahn, TJ et al. (1979) Altered mineral metabolism in glucocorticoid-induced osteopenia. Effect of 25 hydroxy vitamin D administration. J Clin Invest 63: 655–663
Holick MF (2006) The role of vitamin D in bone health and fracture prevention. Curr Osteoporosis Rep 4: 96–102
The synopsis was written by Jasmine Farsarakis, Associate Editor, Nature Clinical Practice.
The authors declare no competing financial interests.
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Hahn, B., Hahn, T. Alendronate versus alfacalcidol in the prevention of glucocorticoid-induced bone loss. Nat Rev Rheumatol 3, 10–11 (2007). https://doi.org/10.1038/ncprheum0370