Prevention of glucocorticoid-induced osteoporosis.

Abstract: Patients taking low-dose glucocorticoids for 3 months or more are at risk for rapid bone loss. The loss may be as high as 15% in the first 3 to 6 months of treatment, and can lead to osteoporotic fractures, with an increase in morbidity and mortality. This article discusses an evidence-based approach to the prevention of glucocorticoid-induced osteoporosis.

Key Words: glucocorticoid, osteoporosis, prevention

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Despite major new developments in pharmacotherapy for rheumatoid arthritis, asthma, and many other serious inflammatory diseases, glucocorticoids such as prednisone remain a mainstay of the physician's armamentarium for these chronic disorders. From population-based studies (1) it has been estimated that 0.2 to 0.5% of the general population is receiving glucocorticoid treatment for prolonged periods. It is estimated that more than 50% of these patients will eventually develop osteoporosis. (2)

Although the efficacy of glucocorticoids for treating a broad spectrum of inflammatory diseases is relatively well established, their proclivity for inducing potentially serious and even irreversible side effects, especially with long-term, high-dose treatment, continues to be documented. Although physicians attempt to place limits on the dose and duration of glucocorticoid therapy, these may not always be options. Many patients therefore face the risk of bone loss and fractures due to glucocorticoid-induced osteoporosis (GIOP).

Surveys suggest that, even when the risk of GIOP is recognized in individual patients, prevention and treatment measures may not be implemented. (3) Physicians need to become increasingly aware of the risk of GIOP in glucocorticoid-treated patients. To address this issue, the American College of Rheumatology (ACR) recently updated its 1996 recommendations on the prevention and treatment of GIOP. (4)

This review will focus on GIOP and the role in protecting the bone of patients taking glucocorticoids played by various agents including calcium and vitamin D, calcitonin, estrogen, raloxifene, the bisphosphonates, and the anabolic agent parathyroid hormone (PTH).

Prevention and Treatment of GIOP

The goal of prevention or treatment of GIOP is to reduce the risk of osteoporotic fracture. Numerous agents have been evaluated for this purpose, among them calcium and vitamin D supplements, calcitonin, estrogen, testosterone, PTH, and bisphosphonates. Despite accumulating evidence that bone mass can be successfully increased with these agents, particularly with the bisphosphonates, only about 5 to 30% of patients actually receive any agents for GIOP prevention. (3,5)

The current or anticipated chronic administration of an oral glucocorticoid should be accompanied by a plan to prevent or treat osteoporosis. The clinical utility of the various treatments is summarized here.

Calcium and vitamin D supplementation

Because calcium helps to stabilize bone resorption and is a critical building block of bone, calcium should be provided to reach a total of 1.5 g/d, achieved from both dietary and supplemental sources. It is also appropriate to administer doses of calciferol (200-800 IU/d) to glucocorticoid-treated patients. (6) In patients who are vitamin D deficient, a short course of higher potency ergocalciferol (50,000 IU twice weekly for 2 to 3 months) is justified. Ergocalciferol had similar efficacy to calcitriol but appeared inferior to alendronate in sustaining or improving bone mass for patients on glucocorticoids. (7)

Calcitonin

This synthetic hormonal agent inhibits bone resorption and has been studied to a limited extent in the treatment of GIOP. Although an injectable and an inhaled form of salmon calcitonin are available, the inhaled form administered as 200 IU in alternating nostrils is used almost exclusively. Calcitonin yields modest bone mineral density (BMD) benefits in GIOP, but there are no documented effects of calcitonin on fracture reduction in GIOP. (8,9) Given its modest efficacy, calcitonin is a second-line agent in patients receiving long-term glucocorticoid therapy with a low BMD, or for those unable to take a bisphosphonate. Injections of calcitonin can cause nausea and flushing, while the inhaled preparation can cause rhinitis (nasal congestion, discharge, or sneezing) and nasal dryness. (10)

Estrogen, Testosterone, and Raloxifene

Estrogen. An improved BMD has been noted in glucocorticoid-treated patients who were also being treated for sex hormone deficiency. Data from the only randomized, controlled clinical trial of estrogen replacement therapy in GIOP indicate that after 2 years of treatment with either transdermal estradiol, 50 [micro]g/d, or calcium, 400 mg/d, women with rheumatoid arthritis exhibited higher spinal bone densities with estradiol than with calcium administration. (11) Although hormonal treatment should be considered for hypogonadism in all glucocorticoid-treated patients, data from the Women's Health Initiative study (12) indicating an increased risk of cardiovascular disease and breast cancer with estrogen have significantly tempered enthusiasm for its bone benefit.

Testosterone and Raloxifene. The administration of testosterone to men receiving a glucocorticoid increased lumbar spine BMD by 5% after 12 months in a crossover trial. (13) The selective estrogen-receptor modulator (SERM) raloxifene mitigates osteoporotic bone loss and reduces spinal fracture in postmenopausal women. (14,15) However, no selective estrogenreceptor modulator has been sufficiently studied for use in GIOP.

Parathyroid hormone

In one controlled clinical trial (16,17) with PTH, 51 postmenopausal women receiving chronic glucocorticoid therapy (5-20 mg daily) were randomized to receive recombinant human PTH, 25 [micro]g, along with preexisting estrogen therapy, daily for 12 months. In the glucocorticoid-treated patients receiving the estrogen and PTH regimen, a statistically significant 11% increase in lumbar spine bone mass was observed on dual-energy x-ray absorptiometry, whereas women taking estrogen with the glucocorticoid, but no PTH, showed only a small change in lumbar spine BMD of 1.3% [+ or -] 0.8. Although this study did not determine whether the increases in spinal bone mass seen with estrogen in combination with PTH may be associated with a reduction in fracture risk, more recent data obtained in postmenopausal women with osteoporosis who were treated with PTH showed significant vertebral and nonvertebral fracture-risk reduction. (17) Further research evaluating recombinant PTH in GIOP is under way.

Bisphosphonates

The bisphosphonates are the most widely studied agents for GIOP. Due to their low bioavailability, oral bisphosphonates are taken with water while fasting, at least 30 minutes before eating. The outcomes of five analyses from double-blind, placebo-controlled clinical trials with bisphosphonates in GIOP are summarized in Table 1. (18-22) Calcium was administered concomitantly in four of these studies, usually with vitamin D.

Alendronate. Saag et al (18) reported the results of two 48-week, randomized placebo-controlled studies of treatment with two doses of alendronate (5 or 10 mg) in 477 men and women aged 17 to 83 years. Patients admitted to each study had a variety of diseases that required a daily dose of at least 7.5 mg of prednisone or its equivalent for a minimum of 1 year. The median daily dose was 10 mg prednisone equivalent for 48 weeks. Patients receiving alendronate (5 or 10 mg) showed a 2 to 3% improvement in spinal bone density over placebo. The incidence of vertebral fractures in patients receiving alendronate was proportionately lower than that of patients receiving placebo.

In a 12-month extension of the preceding 48-week alendronate clinical trial, Adachi et al (19) evaluated the continued efficacy and safety of alendronate in 208 patients who had completed the initial study. The BMD of the lumbar spine, total hip, trochanter, and total body were increased with alendronate therapy at 24 months relative to both the change with placebo and the values at baseline. There was a significant reduction in the number of patients with vertebral fractures, although the overall number of events was small.

Risedronate. Cohen et al (20) evaluated the effects of risedronate on prevention of bone loss in 224 men and women who had, within the past 3 months, been started on oral glucocorticoid. Significant improvements in BMD were noted at the lumbar spine (4.4%) and the femoral neck (5.1%) in the risedronate group versus the placebo group. The preservation of lumbar spine bone mass was associated with a trend toward a reduction in the vertebral fracture rate: 5.7% in the risedronate 5-mg group versus 17.3% in the placebo group. (19)

In a 1-year study, Reid et al (21) evaluated risedronate in men and postmenopausal women who were already receiving prednisone, at least 7.5 mg/d or the equivalent, for a minimum of 6 months. They were randomized to receive risedronate, 2.5 or 5 mg, or placebo daily for 12 months. Treatment with 5 mg risedronate increased BMD levels from 1.7 to 2.4% for women (versus baseline) and from 2.1 to 4.8% for men (versus baseline). At 12 months, there was a trend toward a 70% reduction in vertebral fracture rates for the 5-mg risedronate dose. (21)

Adverse effects of bisphosphonates. Gastrointestinal irritation is the adverse event most commonly associated with bisphosphonate treatment. Overall, study results in men and women indicate similar adverse event profiles for alendronate and risedronate compared with placebo, (18-20,23-26) indicating that these drugs are generally safe and well tolerated. More recently, in anecdotal reports, the weekly administration of both alendronate and risedronate has reduced patient reports of gastrointestinal adverse events.

Conclusion

The prevention and treatment of GIOP can be summarized in an algorithm (Figure) endorsed by the Southeast Osteoporosis Advisory Board and based in part on the revised 2001 American College of Rheumatology Guidelines for the Prevention of Glucocorticoid-Induced Osteoporosis, and which is very similar to the recent United Kingdom Bone and Tooth GIOP guidelines. (27) Patients who are current glucocorticoid users or who will have an anticipated duration of steroid therapy of more than 3 months should be considered for potential intervention. Aggressive therapy, including the use of a bisphosphonate, is indicated based on the accumulating scientific evidence for patients who have experienced fractures, are at high risk, have low-baseline bone mass (ie, beneath the National Osteoporosis Foundation intervention threshold), or are losing bone at a significant rate in follow-up measurements of bone mass. For low-risk patients with well-preserved bone mass, initial therapy is calcium, vitamin D, and risk factor modification. Abstinence from smoking, avoidance of excessive alcohol and caffeine use, and weight-bearing exercise, as well as other risk factor modifications, are recommended because of their benefits to bone. Given the rate at which bone may be lost, particularly during the first 2 years of glucocorticoid therapy, a repeat bone mass measurement within 6 to 12 months may be clinically justifiable. If these low-risk patients continue to maintain adequate bone mass and are not receiving excessive doses of glucocorticoids, it may be justifiable, based on the control group data from the large-scale randomized GIOP trials, to proceed conservatively. However, bone may still be lost at the femoral neck and there may still be a slight increase in fracture risk independent of changes in bone mass. There is considerably less debate over aggressively treating patients at high risk, those with a low bone mass, or those who have already experienced fractures: all such patients should ideally receive a bisphosphonate based on the strongest available current evidence. Other therapeutic options should be considered, if bisphosphonates are contra-indicated and as further data becomes available with newer agents.

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In summary, rapid bone loss and an increased risk of osteoporotic fractures are major clinical concerns in patients taking glucocorticoids, even at relatively low doses, if given for prolonged periods of time. In addition to the disability and the high cost of caring for fractures, the deleterious effects on the patient's quality of life must also be considered. Bone loss and fracture risk can be significantly attenuated with the use of existing pharmacotherapies, meriting the aggressive use of these effective therapies in all patients at increased risk.

Table. Recent controlled clinical trials using alendronate or
risedronate for the prevention or treatment of glucocorticoid-induced
osteoporosis (GIOP) (a)

                            Glucocorticoid     Bisphosphonate
Agent/indication (n) study  dose/d (b)         dose/d (c)

Alendronate/prevention and  10 mg (median)      5 mg
  treatment (n = 477) Saag   5-135 mg (range)  10 mg
  et al, 1998 (35)
                                               placebo
Alendronate/prevention and  17-21 mg (mean)     2.5/10 mg
  treatment (12-month                           5 mg
  extension of 1-year                          10 mg
  trial) (n = 208) Adachi
  et al, 2001 (36)
                                               placebo
Risedronate/prevention      20-22 mg (mean)     2.5 mg
  (n = 224) Cohen et al.                        5 mg
  1999 (37)
                                               placebo
Risedronate/treatment       15 mg (mean)        2.5 mg
  (n = 290) Reid et al,                         5 mg
  2000 (38)
                                               placebo
Risedronate/pooled results  17-18 mg (mean)     2.5 mg
  from above studies                            5 mg
  (n = 518) Wallach et al,
  2000 (39)
                                               placebo

                            Change in lumbar   Relative reduction in
                            spine BMD from     vertebral fracture risk
                            baseline mean      (d) (% reduction vs
Agent/indication (n) study  [+ or -] SD (%)    placebo)

Alendronate/prevention and   2.1 [+ or -] 0.3  38%; P > 0.05 (combined
  treatment (n = 477) Saag   2.9 [+ or -] 0.3     data from both dose
  et al, 1998 (35)                                groups)
                            -0.4 [+ or -] 0.3
Alendronate/prevention and   3.7 [+ or -] 0.6  90%; P = 0.03 (combined
  treatment (12-month        2.8 [+ or -] 0.6    data from all dose
  extension of 1-year        3.8 [+ or -] 0.7    groups)
  trial) (n = 208) Adachi
  et al, 2001 (36)
                            -0.8 [+ or -] 0.6
Risedronate/prevention      -0.1 [+ or -] 0.7  71%; P = 0.07 (5-mg dose)
  (n = 224) Cohen et al.     0.6 [+ or -] 0.5
  1999 (37)
                            -2.8 [+ or -] 0.5
Risedronate/treatment        1.9 [+ or -] 0.5  70%; P = 0.04 (combined
  (n = 290) Reid et al,      2.9 [+ or -] 0.5    data from both dose
  2000 (38)                                      groups)
                             0.4 [+ or -] 0.4
Risedronate/pooled results   1.3 [+ or -] 0.4  58%; P = 0.08
  from above studies         1.9 [+ or -] 0.4  70%; P = 0.01
  (n = 518) Wallach et al,
  2000 (39)
                            -1.0 [+ or -] 0.4

(a) BMD, bone mineral density.
(b) Glucocorticoid dose is reported as milligrams per day of prednisone
or its equivalent.
(c) Patients received calcium and vitamin D supplementation in four
trials (Saag et al. 1998 (35), Adachi et al. 2001 (36), Reid et al. 2000
(38), Wallach et al, 2000 (39)), and calcium alone in one trial (Cohen
et al. 1999 (37)).
(d) Percentages are reported for the number of evaluable patients, which
varied according to the study.

Copyright [c] 2004 by The Southern Medical Association

0038-4348/04/9706-0555

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RELATED ARTICLE: Key Points

* Osteoporsis is among the serious side effects associated with long-term glucocorticoid therapy, but available preventive and treatment options are currently underemployed.

* A range of agents of potential value in preventing or treating glucocorticoid-induced osteoporosis (GIOP) include calcium and vitamin D as well as bisphosphonates and other anti-resorptive agents.

* An algorithm is presented to guide the use of pharmacotherapies in patients at risk for GIOP.

Kenneth G. Saag, MD, MSC 

From the Division of Clinical Immunology and Rheumatology, Center for Education and Research on Therapeutics (CERTs) of Musculoskeletal Disorders, University of Alabama at Birmingham, Birmingham, AL.

Supported in part by an unrestricted educational grant from Aventis Pharmaceuticals, Inc.

Reprint requests to Kenneth G. Saag, MD, MSc, FOT 820, 1530 3rd Avenue South, Birmingham, AL 35294. Email: [e-mail]