OBJECTIVE: To summarize the literature concerning the use of bisphosphonates in the prevention and treatment of corticosteroid-induced osteoporosis and make recommendations concerning the proper use of these agents. search strategies We conducted a literature search to identify studies in the English language concerning the use of bisphosphonates in the prevention or treatment of corticosteroid-induced osteoporosis using the MEDLINE, CURRENT CONTENTS, and HEALTHSTAR electronic databases, bibliographies of selected citations, and recent meeting abstracts.
SELECTION CRITERIA: We included randomized controlled trials evaluating the use of oral bisphosphonates in adults by central dual X-ray absorptiometry.
DATA COLLECTION AND ANALYSIS: We assessed the methodologic quality of the trials using the Jadad criteria. Data were collected concerning bone mineral density (BMD) changes in multiple areas, fracture rates, safety, and tolerability.
MAIN RESULTS: Bisphosphonates generally increased BMD at the lumbar spine. Data were less clear concerning changes in the femoral area. Little information exists about the ability of bisphosphonates to reduce fracture risk in patients with corticosteroid-induced osteoporosis. Postmenopausal women seemed to receive the most benefit.
CONCLUSIONS: Bisphosphonates significantly increased BMD in patients at risk for corticosteroid-induced bone loss. However, there is a sparsity of data concerning the ability of these agents to affect the clinically important outcome of fracture rate reduction, especially among premenopausal women in whom fractures are rare within the first year or 2 of exposure to corticosteroids. Long-term studies powered to detect fracture risk reduction are needed as well as comparative trials with bisphosphonates and other agents.
CLINICAL QUESTION
What is the role of bisphosphonates in the prevention and treatment of glucocorticoid-induced osteoporosis in adults?
The detrimental effects of glucocorticoids on bone have long been recognized in the medical literature. An average of 5% of bone mass is lost during the first year of long-term therapy, and annualized rates of loss range from 0.3% to 3%.1,2 This bone reduction occurs most rapidly during the first 6 to 12 months of glucocorticoid therapy and is dose-dependent and time-dependant.3-5 Daily doses of oral prednisone greater than or equal to 7.5 mg or cumulative doses greater than 10 g produce the most significant effects, and alternate-day glucocorticoids do not decrease the risk.6 Although inhaled corticosteroids are generally considered safer, high inhaled doses can also reduce bone mass.1 An inverse relation between inhaled corticosteroid dose and bone mineral density (BMD) has been reported; doubling of the inhaled dose led to a decrease in lumbar bone mineral density of 0.16 standard deviations points (SDs).7 Menopausal status, sex, and age are other important contributing factors for the development of glucocorticosteroid-induced osteoporosis (CIO); surprisingly, men younger than 50 years may lose a higher percentage of bone than postmenopausal women.2,87,98
Of greater clinical significance is the increased incidence of fractures, which is 2 to 4 times higher than that of similar glucocorticoid-naive patients.1,11 Overall estimates of fractures during long-term steroid therapy range from 30% to 50%.1,4,5 Ultimately, all fracture types can result in skeletal deformities that cause extreme pain, exacerbate the primary autoimmune or inflammatory disease state, and represent a tremendous financial burden.6 Most alarming is the estimated incidence of mortality following a hip fracture in patients requiring long-term corticosteroids, which ranges from 5% to 9% in men older than 50 years and from 1% to 3% in age-matched women.1
Pathophysiology Of CIO
Glucocorticoids decrease bone formation and increase bone resorption through a number of different mechanisms that are beyond the scope of our article. However, a brief overview is warranted to better understand the role bisphosphonates have in the treatment of steroid-induced osteoporosis. On a cellular level, glucocorticoids directly inhibit osteoblast function at the glucocorticoid receptor. This inhibition results in decreased replication, differentiation, proliferation, and life span of the osteoblasts.2,4,11 Subsequently the total amount of bone restored during each remodeling cycle is decreased by 30%, leading to a reduced mean wall thickness.1,4,5 Also, glucocorticoids enhance the activity and increase the number of osteoclasts, leading to a greater number of active resorption surfaces.2,11
Additionally, steroid-treated patients demonstrate a dose-dependent malabsorption of calcium due to direct impairment of the intestinal cell calcium transport process.3,8 This decreased calcium absorption is often evident within the first 2 weeks of therapy.4,8 Then a secondary hyperparathyroidism ensues and urinary calcium excretion becomes double that of non-steroid-treated patients.3,4 Gonadal hormones—potent regulators of bone metabolism—are secreted to a much lower extent in patients treated with glucocorticoids.3 Treated men in particular have circulating testosterone concentrations of only 50% of those in a control group.4
Corticosteroids also reduce levels of prostaglandin E2, insulin-like growth factors, phosphate, type I collagen, and noncollagens including osteocalcin.4,5 Finally, muscle atrophy and subsequent wasting may be the most observable result of glucocorticoid treatment, resulting in less of the mechanical stimuli required to generate new bone formation.1,5,11