Recommendations for the Prevention and Treatment of Glucocorticoid-Induced Osteoporosis

American College Of Rheumatology Ad Hoc Committee On Glucocorticoid-Induced Osteoporosis

Members of the American College of Rheumatology Ad Hoc Committee on Glucocorticoid-Induced Osteoporosis are as follows. Lenore Buckley, MD, MPH: Medical College of Virginia, Richmond; Maria Greenwald, MD: Palm Springs, California; Marc Hochberg, MD, MPH: University of Maryland School of Medicine, Baltimore; Nancy Lane, MD: University of California San Francisco School of Medicine; Stephen Lindsey, MD: Ochsner Clinic, Baton Rouge, Louisiana; Stephen Paget, MD: Cornell University School of Medicine, New York, New York; Ken Saag, MD, MSc: University of Alabama School of Medicine, Birmingham; Lee Simon, MD: Harvard University School of Medicine, Boston, Massachusetts.

The American College of Rheumatology is an independent professional, medical, and scientific society which does not guarantee, warrant, or endorse any commercial product or service.

Address correspondence and reprint requests to American College of Rheumatology, 2200 Lake Boulevard NE, Atlanta, GA 30319. Submitted for publication March 19, 1999; accepted in revised form April 11, 2001.

Funded by:
Merck & Co., Aventis Pharmaceuticals, Wyeth Ayerst, Bristol-Myers Squibb, Procter & Gamble, La Jolla Pharmaceuticals, Amgen, Novartis Pharmaceuticals, AstraZeneca Pharmaceuticals, Forest Pharmaceuticals,
Abgenix, Vertex, G. D. Searle & Co., Pharmacia

Glucocorticoid therapy is associated with a number of significant side effects, of which bone loss resulting in glucocorticoid-induced osteoporosis and an increase in fracture risk is the most serious (1-4). However, studies show that many patients treated with glucocorticoids do not receive treatment to prevent bone loss (5-7). This suggests that physician awareness of bone loss and the increase in fracture risk caused by glucocorticoid treatment is low, and that there is inadequate information about the effectiveness of preventive treatment strategies.

Glucocorticoids are used to treat a wide variety of allergic and inflammatory diseases and are prescribed by a wide variety of physicians, both specialists and generalists. A recent survey revealed significant variability in physicians' knowledge about glucocorticoid-induced osteoporosis, by specialty (8). While most physicians recognized that postmenopausal women have a high risk of fracture during glucocorticoid treatment, many reported that they did not routinely consider either hormone replacement therapy (HRT) or calcium and vitamin D supplementation. Physicians with the greatest experience with steroid therapy, such as rheumatologists and pulmonologists, were the most likely to report that they would prescribe preventive treatments, but the majority of other specialists reported taking no preventive measures. Even among rheumatologists, there is considerable variation in practice patterns regarding the use of pharmacologic agents for prevention and treatment (9). Also, many physicians are unaware that men and premenopausal women also are at great risk for glucocorticoid-induced osteoporosis, despite the existence of published studies demonstrating this (10, 11).

In 1996, the American College of Rheumatology (ACR) summarized available information about the pathophysiology, diagnosis, prevention, and treatment of glucocorticoid-induced osteoporosis and developed recommendations for clinical practice (12). Because of the recent publication and presentation of results of several randomized controlled trials of agents for the prevention and treatment of glucocorticoid-induced osteoporosis, as well as systematic reviews and meta-analyses of previously published trials (13-16), the ACR appointed an ad hoc committee, the ACR Ad Hoc Committee on Glucocorticoid-Induced Osteoporosis, to update these earlier recommendations. In addition, the Committee reviewed advances in the field of bone mass measurement and legislation that affects the availability of and reimbursement for this technology for patients receiving glucocorticoid therapy in the US.

These recommendations are intended to educate and update physicians on the prevention and treatment of glucocorticoid-induced osteoporosis. The Committee emphasizes that the recommendations are not fixed, rigid mandates and recognizes that the final decision concerning the treatment regimen for an individual patient results from an informed discussion between the patient and his or her health care provider.

Bone mass measurement
The US Congress passed the Bone Mass Measurement Act in 1997, and the Health Care Financing Administration published guidelines for its implementation in 1998 (17). Bone mass measurement is reimbursed by Medicare for 5 categories of persons at risk for osteoporosis in general; one category specifically includes patients receiving long-term glucocorticoid therapy at doses of 7.5 mg/day. Bone mass measurement is reimbursed for any procedure approved by the Food and Drug Administration (FDA) for detecting bone loss; the effect of this rule is that all forms of bone mass measurement, except dual-photon absorptiometry, are covered by Medicare.

The Committee recommends obtaining a baseline measurement of bone mineral density (BMD) at the lumbar spine and/or hip when initiating long-term (i.e., >6 months) glucocorticoid therapy. Longitudinal measurements may be repeated as often as every 6 months for monitoring glucocorticoid-treated patients to detect bone loss. In patients who are receiving therapy to prevent bone loss, annual followup measurements are probably sufficient. A review of the clinical considerations in bone mass measurement was recently published; this review discussed not only the interpretation of bone mass measurement with dual x-ray absorptiometry (DXA), but also the interpretation with other techniques including quantitative computed tomography (QCT), single x-ray absorptiometry, and quantitative ultrasound of bone (18).

Calcium and vitamin D
In 1996, Buckley and colleagues reported the results of a 2-year randomized controlled trial demonstrating that calcium and vitamin D supplementation prevented bone loss in the lumbar spine and greater trochanter in rheumatoid arthritis (RA) patients receiving long-term, low-dose glucocorticoid treatment (mean prednisone dosage 5.6 mg/day) (19). Patients who received placebo lost bone at a rate of 2% and 0.9% per year in the lumbar spine and greater trochanter, respectively, while patients who received 1,000 mg of calcium carbonate and 500 IU of vitamin D daily gained bone at a rate of 0.7% and 0.9% in the lumbar spine and greater trochanter, respectively.

Other data support the effectiveness of calcium and vitamin D supplementation in preserving bone mass in patients receiving regular glucocorticoid therapy. In a randomized placebo-controlled clinical trial of alendronate in the treatment of patients receiving glucocorticoids (median prednisone dosage 11 mg/day), bone mass at the lumbar spine was maintained in patients treated with placebo rather than alendronate who received supplementation with calcium at 800-1,000 mg/day and vitamin D at 250-500 mg/day (20). Similar results were noted in placebo-treated patients taking prednisone at a mean dosage of 15 mg/day who received 1,000 mg of calcium and 400 IU vitamin D daily during a randomized controlled trial of risedronate in patients receiving long-term glucocorticoid treatment (21). These patients had stable BMD at both the lumbar spine and the greater trochanter after 48 weeks of treatment. Furthermore, randomized controlled trials of the active vitamin D metabolites alfacalcidiol (1 [OH]-D3) at a dosage of 1 g/day and calcitriol (1,25[OH]2-D3) at 0.5-1 g/day in addition to calcium have demonstrated prevention of bone loss, compared with calcium and placebo, in patients starting glucocorticoid treatment (22,23). In addition, the results of meta-analyses of randomized controlled trials of calcium and vitamin D supplementation confirm the efficacy of this intervention (13,14), while a decision analysis suggested that supplementation with calcium and vitamin D would be cost effective for the prevention of glucocorticoid-induced osteoporosis in a patient with normal BMD (24).

Thus, supplementation with calcium and vitamin D, either plain or in an activated form, can preserve bone mass in patients receiving long-term treatment with glucocorticoids at an average dosage of 15 mg/day. However, calcium alone does not prevent bone loss in patients receiving glucocorticoid therapy (22,25,26). Therefore, supplementation with both calcium and vitamin D should be required for glucocorticoid-treated patients. It should be noted that if activated forms of vitamin D are used, especially in patients who are just beginning glucocorticoid therapy, these patients should be carefully monitored for the development of hypercalcemia and hypercalcuria; if these adverse events develop, the dosage of the activated vitamin D supplement should be reduced.

Antiresorptive agents
Glucocorticoids alter bone metabolism such that bone formation is reduced and resorption is increased, leading to rapid bone loss after initation of therapy. The mechanisms for the development of glucocorticoid-induced bone loss have been reviewed in detail in other recent publications (27-29). A number of antiresorptive agents are available to both prevent and treat glucocorticoid-induced bone loss.

Replacement of gonadal sex hormones
Patients receiving prolonged glucocorticoid therapy may develop hypogonadism due to inhibition of secretion of luteinizing hormone and follicle-stimulating hormone from the pituitary gland, as well as direct effects on hormone production by the ovary and testes. All patients receiving long-term glucocorticoid treatment should be assessed for hypogonadism, and when present, this should be corrected if possible. In a trial of postmenopausal women with RA who were taking prednisone and were randomized to receive either HRT or placebo, those who received HRT had a significant (3-4%) increase in their lumbar spine BMD compared with controls, while there was no significant change in femoral neck BMD in either group (30). In a randomized controlled trial of injectable parathyroid hormone (1-34) (PTH (1-34), postmenopausal women receiving long-term low-dose glucocorticoid therapy and HRT in the control group showed no change in BMD at the lumbar spine, hip, or distal radius over the course of 1 year (31).

These data suggest that HRT is adequate therapy to prevent bone loss in postmenopausal women receiving prolonged low-to-moderate-dose glucocorticoid therapy. Currently, however, there are no published reports regarding the efficacy of HRT in preventing bone loss at the initiation of glucocorticoid treatment, or the degree of the protective effect of HRT when moderate-to-high doses of glucocorticoids are used for long-term treatment.

There is less information available regarding men with hypogonadism secondary to glucocorticoid treatment. A randomized crossover trial demonstrated the effectiveness of testosterone replacement therapy in 15 men with glucocorticoid-treated asthma (32). All of the men had low serum testosterone levels prior to therapy. Lumbar spine BMD, but not hip BMD, was significantly increased (nearly 4%) after 12 months of monthly intramuscular testosterone injections; in addition, there was an increase in lean body mass and a reduction in fat mass. Thus, men with low serum levels of testosterone who are receiving glucocorticoids should receive replacement therapy. Based on recommendations published by the American Association of Clinical Endocrinologists and the American College of Endocrinology, men with serum testosterone levels below the physiologic range (<300 ng/mL) should receive replacement therapy (33). Multiple different testosterone preparations are available, including short- and long-acting intramuscular injections and transdermal patches and gels. The goal of testosterone replacement therapy is to provide physiologic-range serum testosterone levels. It is important to emphasize that if testosterone replacement therapy is to be used in a hypogonadal man, the patient should be adequately assessed for the possibility of prostate cancer, with a digital rectal examination and measurement of prostate-specific antigen at baseline and annually thereafter. Prostate cancer is an absolute contraindication to testosterone replacement therapy.

Although no studies of HRT in premenopausal glucocorticoid-treated women have been performed, observational studies in premenopausal female athletes with menstrual irregularities suggest that women who receive oral contraceptives have higher adjusted bone mineral content and BMD than do women who do not take oral contraceptives (34,35). Therefore, premenopausal women who experience menstrual irregularities (oligo- or amenorrhea) while taking glucocorticoids should be offered oral contraceptives or cyclic estrogen and progesterone if contraindications are not present. At this time, no data are available on the efficacy of selective estrogen receptor modulators (SERMs) in the prevention or treatment of glucocorticoid-induced bone loss. The SERM raloxifene is approved by the FDA and is available for the prevention and treatment of postmenopausal osteoporosis (36,37). A SERM could theoretically be used to prevent glucocorticoid-induced bone loss in selected postmenopausal glucocorticoid-treated women who either have contraindications to or do not wish to take HRT or other antiresorptive medications.

Bisphosphonates
Results from 5 large randomized controlled clinical trials provide evidence that the bisphosphonates etidronate, alendronate, and risedronate are effective in both the prevention and the treatment of glucocorticoid-induced osteoporosis (20,21,25,26,38-40) (Table 1). Significant increases in BMD with bisphosphonate treatment, most consistently observed in the lumbar spine, were seen in patients with many different glucocorticoid-treated disorders, most often RA and polymyalgia rheumatica, and occurred generally irrespective of patient age, sex, and menopausal status in women. In addition, statistically significant reductions in the absolute risk and relative risk of incident radiographic vertebral fractures (11% and 70%, respectively) were demonstrated after 1 year of treatment with risedronate (40). A similar significant reduction in the risk of incident radiographic vertebral fractures (0.7% with alendronate versus 6.8% with placebo; P < 0.05) was seen in alendronate-treated patients who completed 2 years (1-year study and 1-year extension) of a study of alendronate in the prevention and treatment of glucocorticoid-induced osteoporosis (39). Serious drug toxicity was uncommon in all studies, with only a slight increase, compared with placebo, in nonserious upper gastrointestinal adverse events among patients receiving alendronate at 10 mg/day (20,39).

Both alendronate and risedronate are recommended for the prevention and treatment of glucocorticoid-induced bone loss. Glucocorticoid-treated premenopausal women, postmenopausal women receiving HRT, and men should be treated with either alendronate 5 mg/day or risedronate 5 mg/day. Postmenopausal women not receiving HRT should be treated with either alendronate 10 mg/day or risedronate 5 mg/day.
Based on these and other published data, bisphosphonates should be used in conjunction with calcium and vitamin D supplementation in the following groups of glucocorticoid-treated patients: 1) patients in whom glucocorticoid therapy is being newly initiated, to prevent bone loss; 2) patients receiving long-term glucocorticoid therapy, with documented osteoporosis based on BMD measurements or presence of an osteoporotic fracture; and 3) patients receiving long-term glucocorticoid therapy who have had fractures while receiving HRT or in whom HRT has not been well tolerated (41). The rationale for this is not only the prevention of bone loss and/or increase in BMD achieved with bisphosphonates, but also the prevention of apoptosis of osteocytes and osteoblasts (42) and the reduction in risk of radiographic vertebral fractures, the most common type of fracture in patients receiving glucocorticoids.

Calcitonin
Calcitonin, given via either subcutaneous injection or intranasal inhalation, has not been shown consistently to prevent bone loss compared with calcium and vitamin D supplementation alone, in patients starting glucocorticoid therapy (22,43-45). Calcitonin does increase BMD at the lumbar spine but not at the femoral neck in patients who have had prolonged glucocorticoid treatment (46-48). However, calcitonin does not reduce the risk of radiographic vertebral fractures: the pooled relative risk based on 5 studies was 0.71 (95% confidence interval 0.26-1.89) (16). Thus, calcitonin can be considered a second-line agent for treatment of patients with low BMD who are receiving long-term glucocorticoid therapy, and could be used in patients who have contraindications to, cannot tolerate, or do not wish to take bisphosphonates. Calcitonin is not recommended for prevention of bone loss in patients beginning glucocorticoid treatment.

Anabolic agents
Another class of bone-active drugs, anabolic agents, stimulates new bone formation beyond the filling in of the remodeling space. Fluoride, an anabolic agent, has been evaluated in glucocorticoid-induced osteoporosis. Lems and colleagues performed a randomized controlled trial in glucocorticoid-treated patients (range of prednisone dosage 15-22 mg/day). Sodium fluoride (50 mg/day) or placebo with elemental calcium and vitamin D supplementation was given. After 2 years, the lumbar spine bone mass in the sodium fluoride-treated group and the placebo-treated group, respectively, had increased by 2.2% and decreased by 3.0%, and the femoral neck bone mass had decreased by 3.8% and by 3.0%, respectively (49). No differences were seen between the sodium fluoride group and the placebo group in the number of peripheral or vertebral fractures. Another study compared the combination of intermittent etidronate treatment (400 mg/day for 2 weeks, followed by 11 weeks without this treatment) and sodium fluoride (50 mg/day) with placebo and cyclic etidronate with calcium supplementation. After 2 years, the lumbar spine bone mass had increased by 9.3% and 0.3%, and the femoral neck bone mass had decreased by 2.4% and 4.0% in the combination (etidronate plus sodium fluoride) group and the etidronate group, respectively (50). In the etidronate plus sodium fluoride group, the number of fractures was higher than in the etidronate group. However, in both studies the groups were small, so caution must be used in interpreting these data.

Thus, although fluoride increases BMD at the lumbar spine, it has no effect at the hip. Furthermore, there are not adequate data from these small randomized clinical trials in patients receiving glucocorticoids to warrant conclusions about the ability or lack thereof of fluoride to reduce the incidence of vertebral fracture.

Another anabolic agent, PTH (1-34), has been used to treat glucocorticoid-induced osteoporosis. Postmenopausal osteoporotic women receiving prolonged glucocorticoids and HRT were treated for 1 year, and lumbar spine bone mass increased by 11% as measured by DXA (31). One year after discontinuation of PTH, while the patients continued to receive HRT, lumbar spine bone mass remained stable while total hip bone mass increased 5% over baseline levels (51). Although PTH ([1-34]) treatment in postmenopausal osteoporotic women has been shown to reduce incident radiographic vertebral fractures, there are currently no fracture data available regarding PTH (1-34) in glucocorticoid-treated patients (52).

Anabolic steroids are potentially useful agents in glucocorticoid-treated patients. One study using nandrolone decanoate showed increases in forearm bone mass, but significant masculinizing side effects were noted (53). Medroxyprogesterone acetate, given as a 200-mg intramuscular injection every 6 weeks for 1 year, significantly increased lumbar spine bone mass as measured by QCT and reduced urinary calcium and hydroxyproline excretion in the treated men compared with controls (54). However, long-term studies with medroxyprogesterone acetate have not been performed.

Therefore, while anabolic agents can increase bone mass in the presence of glucocorticoids, sodium fluoride, which is currently available, appears only to increase bone mass at the spine without protecting the hip. Since fluoride has not been shown to prevent fractures in glucocorticoid-treated patients, the Committee does not recommend its use.

Summary
Glucocorticoid-induced bone loss should be prevented, and if present, should be treated (Table 2). Supplementation with calcium and vitamin D at a dosage of 800 IU/day, or an activated form of vitamin D (e.g., alfacalcidiol at 1 g/day or calcitriol at 0.5 g/day), should be offered to all patients receiving glucocorticoids, to restore normal calcium balance. This combination has been shown to maintain bone mass in patients receiving long-term low-to-medium-dose glucocorticoid therapy who have normal levels of gonadal hormones. However, while supplementation with calcium and vitamin D alone generally will not prevent bone loss in patients in whom medium-to-high-dose glucocorticoid therapy is being initiated, supplementation with calcium and an activated form of vitamin D will prevent bone loss. There are no data available to support any conclusion about the antifracture efficacy of the combination of calcium supplementation plus an activated form of vitamin D.

Table 2. Recommendations for the prevention and treatment of glucocorticoid-induced osteoporosis

Patient begining therapy with glucocorticoid (prednisone equivalent of 5 mg/day) with plans for treatment duration of 3 months:

Modify lifestyle risk factors for osteoporosis.
Smoking cessation or avoidance
Reduction of alcohol consumption if excessive
Instruct in weight-bearing physical exercise.
Initiate calcium supplementation.
Initiate supplementation with vitamin D (plain or activated form).
Prescribe bisphosphonate (use with caution in premenopausal women).

Patient receiving long-term glucocorticoid therapy (prednisone equivalent of 5 mg/day):

Modify lifestyle risk factors for osteoporosis.
Smoking cessation or avoidance
Reduction of alcohol consumption if excessive
Instruct in weight-bearing physical exercise.
Initiate calcium supplementation.
Initiate supplementation with vitamin D (plain or activated form).
Prescribe treatment to replace gonadal sex hormones if deficient or otherwise clinically indicated.
Measure bone mineral density (BMD) at lumbar spine and/or hip.
If BMD is not normal (i.e., T-score below -1), then
- Prescribe bisphosphonate (use with caution in premenopausal women).
- Consider calcitonin as second-line agent if patient has contraindication to or does not tolerate
bisphosphonate therapy.
If BMD is normal, follow up and repeat BMD measurement either annually or biannually.

Antiresorptive agents are effective in the treatment of glucocorticoid-induced bone loss. All of these agents either prevent bone loss or modestly increase lumbar spine bone mass and maintain hip bone mass. While there are no randomized controlled trials of prevention of glucocorticoid-induced bone loss or radiographic vertebral fracture outcomes with HRT or testosterone, patients receiving long-term glucocorticoid therapy who are hypogonadal should be offered HRT. The bisphosphonates are effective for both the prevention and the treatment of glucocorticoid-induced bone loss. Large studies have demonstrated that bisphosphonates also reduce the incidence of radiographic vertebral fractures in postmenopausal women with glucocorticoid-induced osteoporosis. Treatment with a bisphosphonate is recommended to prevent bone loss in all men and postmenopausal women in whom long-term glucocorticoid treatment at 5 mg/day is being initiated, as well as in men and postmenopausal women receiving long-term glucocorticoids in whom the BMD T-score at either the lumbar spine or the hip is below normal.

While there is little information on the prevention or treatment of bone loss in premenopausal women, these women, too, may lose bone mass if they are being treated with glucocorticoids, so prevention of bone loss with antiresorptive agents should be considered. If bisphosphonate therapy is being considered for a premenopausal woman, she must be counseled regarding use of appropriate contraception.
The therapies to prevent or treat glucocorticoid-induced bone loss should be continued as long as the patient is receiving glucocorticoids. Data from large studies of anabolic agents (e.g., PTH) and further studies of combination therapy in patients receiving glucocorticoids are eagerly awaited so additional options will be available for the prevention of this serious complication of glucocorticoid treatment.

Acknowledgements
The members of the Committee wish to thank Jim Moody, former Vice President for Socioeconomic Affairs, ACR, for his invaluable assistance in shepherding this project to its conclusion.

References
1. Saag K, Koehnke R, Caldwell J, Brasington R, Burmeister LD, Zimmerman B, et al. Low dose long-term corticosteroid therapy in RA: an analysis of serious adverse events. Am J Med 1994; 96: 115-23

2. McEvoy CE, Ensrud KE, Bender E, Genant HK, Yu W, Griffin JM, et al. Association between corticosteroid use and vertebral fractures in older men with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 1998; 157: 704-9.

3. Van Staa TP, Leufkens HG, Abenhaim L, Zhang B, Cooper C. Use of oral corticosteroids and risk of fractures. J Bone Miner Res 2000; 15: 993-1000

4. Van Staa TP, Leufkens HG, Abenhaim L, Zhang B, Cooper C. Oral corticosteroids and fracture risk: relationship to daily and cumulative doses. Rheumatology (Oxford) 2000; 39: 1383-9.

5. Peat ID, Healy S, Reid DM, Ralston SH. Steroid induced osteoporosis: an opportunity for prevention? Ann Rheum Dis 1995; 54: 66-8.

6. Walsh LJ, Wong CA, Pringle M, Tattersfield AE. Use of oral corticosteroids in the community and the prevention of secondary osteoporosis: a cross sectional study. BMJ 1996; 313: 344-6

7. Van Staa TP, Leufkens GH, Abenhaim L, Begaud B, Zhang B, Cooper C. Use of oral corticosteroids in the United Kingdom. QJM 2000; 93: 105-11.

8. Buckley LM, Marquez M, Hudson J, Downs RW, Vacek P, Small RE, et al. Variations in physicians' judgments about corticosteroid induced osteoporosis by physician specialty. J Rheumatol 1998; 25: 2195-202.

9. Soucy E, Bellamy N, Adachi JD, Pope JE, Flynn J, Sutton E, et al. A Canadian survey on the management of corticosteroid induced osteoporosis by rheumatologists. J Rheumatol 2000; 27: 1506-12.

10. Adinoff AD, Hollister JR. Steroid-induced fractures and bone loss in patients with asthma. N Engl J Med 1983; 309: 265-8.

11. Michel BA, Bloch DA, Wolfe F, Fries JF. Fractures in rheumatoid arthritis: an evaluation of associated risk factors. J Rheumatol 1993; 20: 1666-9.

12. American College of Rheumatology Task Force on Osteoporosis Guidelines. Recommendations for the prevention and treatment of glucocorticoid-induced osteoporosis. Arthritis Rheum 1996; 39: 1791-801.

13. Amin S, LaValley MP, Simms RW, Felson DT. The role of vitamin D in corticosteroid-induced osteoporosis: a meta-analytic approach. Arthritis Rheum 1999; 42: 1740-51.

14. Homik J, Suarez-Almazor ME, Shea B, Cranney A, Wells G, Tugwell P. Calcium and vitamin D for corticosteroid-induced osteoporosis Cochrane review. In: The Cochrane Library. Issue 2. Oxford (UK): Update Software; 2000.

15. Homik J, Cranney A, Shea B, Tugwell P, Wells G, Adachi R, et al. Bisphosphonates for steroid induced osteoporosis Cochrane review. In: The Cochrane Library. Issue 2. Oxford (UK): Update Software; 2000.

16. Cranney A, Welch V, Adachi JD, Homik J, Shea B, Suarez-Almazor ME, et al. Calcitonin for the treatment and prevention of corticosteroid-induced osteoporosis Cochrane review. In: The Cochrane Library. Issue 2. Oxford (UK): Update Software; 2000.

17. Health Care Finance Administration. Bone Mass Measurement Act. 63 Federal Register 34321 (1998, June 24).

18. Levis S, Altman R. Bone densitometry: clinical considerations. Arthritis Rheum 1998; 41: 577-87.

19. Buckley LM, Leib ES, Cartularo KS, Vacek PM, Cooper SM. Calcium and vitamin D supplementation prevents bone loss in the spine secondary to low dose corticosteroids in patients with rheumatoid arthritis: a randomized, double-blind, placebo controlled trial. Ann Intern Med 1996; 125: 961-86.

20. Saag KG, Emkey R, Schnitzer TJ, Brown JP, Hawkins F, Goemaere S, et al. Alendronate for the treatment and prevention of glucocorticoid-induced osteoporosis. N Engl J Med 1998; 339: 292-9.

21. Reid DM, Hughes RA, Laan RF, Sacco-Gibson NA, Wenderoth DH, Adami S, et al. Efficacy and safety of daily risedronate in the treatment of corticosteroid-induced osteoporosis in men and women: a randomized trial. J Bone Miner Res 2000; 15: 1006-20.

22. Sambrook PN, Birmingham J, Kelly P, Kempler S, Pocock NA, Eisman JA. Prevention of corticosteroid osteoporosis: a comparison of calcium, calcitriol, and calcitonin. N Engl J Med 1993; 328: 1747-52.

23. Reginster JY, Kuntz D, Verdickt W, Wouters M, Guillevin L, Menkes CJ, et al. Prophylactic use of alfacalcidol in corticosteroid-induced osteoporosis. Osteoporos Int 1999; 9: 75-81.

24. Buckley LM, Hillner B. A cost-effectiveness analysis of calcium and vitamin D vs alendronate in the prevention of corticosteroid-induced osteoporos [abstract]. Arthritis Rheum 1997; 40 Suppl 9: S136.

25. Adachi JD, Bensen WG, Brown J, Hanley D, Hodsman A, Josse R, et al. Intermittent etidronate therapy to prevent corticosteroid-induced osteoporosis. N Engl J Med 1997; 337: 382-7.

26. Cohen S, Levy RM, Keller M, Boling E, Emkey RD, Greenwald M, et al. Risedronate therapy prevents corticosteroid-induced bone loss: a twelve-month, multicenter, randomized, double-blind, placebo-controlled, parallel-group study. Arthritis Rheum 1999; 42: 2309-18.

27. Manolagas SC, Weinstein RS. New developments in the pathogenesis and treatment of steroid-induced osteoporosis. J Bone Miner Res 1999; 14: 1061-6.

28. Canalis E. Glucocorticoid-induced osteoporosis. Curr Opin Endocrinol Diabetes 2000; 7: 320-4.

29. Weinstein RS. The pathogenesis of glucocorticoid-induced osteoporosis. Clin Exp Rheumatol 2000; 18 Suppl 21: S35-40.

30. Hall GM, Daniels M, Doyle DV, Spector TD. Effect of hormone replacement therapy on bone mass in rheumatoid arthritis patients treated with and without steroids. Arthritis Rheum 1994; 37: 1499-505.

31. Lane NE, Roe B, Genant HK, Arnaud C. Parathyroid hormone treatment reverses glucocorticoid-induced osteoporosis: results of a randomized controlled trial. J Clin Invest 1998; 102: 1627-33.

32. Reid IR, Wattie DJ, Evans MC, Stapleton JP. Testosterone therapy in glucocorticoid-treated men. Arch Intern Med 1996; 156: 1173-7.

33. Petak SM, Baskin HJ, Bergman DA, Dickey RA, Nankin HA. AACE clinical practice guidelines for the evaluation and treatment of hypogonadism in adult male patients. Accessed December 20, 2000. URL: (http://www.aace.com/clin/guides/hypogonadism.html).

34. Drinkwater BL, Nilson K, Ott S, Chesnut CH. Bone mineral density after resumption of menses in amenorrheic women. JAMA 1986; 256: 380-2.

35. Drinkwater BL, Nilson K, Chesnut CH, Brenner WJ, Shainholtz S, Southworth WB. Bone mineral content of amenorrheic and eumenorrheic athletes. N Engl J Med 1984; 311: 277-81.

36. Delmas PD, Bjarnason NH, Mitlak BH, Ravoux AC, Huster WJ, Draper M, et al. Effects of raloxifene on bone mineral density, serum cholesterol concentrations, and uterine endometrium in postmenopausal women. N Engl J Med 1997; 337: 1641-77.

37. Ettinger B, Black DM, Mitlak BH, Knickerbocker RK, Nickelsen T, Genant HK, et al, for the Multiple Outcomes of Raloxifene Evaluation (MORE) Investigators. Reduction of vertebral fracture risk in postmenopausal women with osteoporosis treated with raloxifene: results from a 3-year randomized clinical trial. JAMA 1999; 282: 637-45.

38. Roux C, Oriente P, Laan R, Hughes RA, Ittner J, Goemaere S, et al. Randomized trial of effect of cyclical etidronate in the prevention of corticosteroid-induced bone loss. J Clin Endocrinol Metab 1998; 83: 1128-33.

39. Adachi JD, Saag KG, Delmas PD, Liberman UA, Emkey RD, Seeman E, et al. Two-year effects of alendronate on bone mineral density and vertebral fracture in patients receiving glucocorticoids: a randomized, double-blind, placebo-controlled extension trial. Arthritis Rheum 2001; 44: 202-11.

40. Wallach S, Cohen S, Reid DM, Hughes RA, Hosking DJ, Laan RF, et al. Effects of risedronate treatment on bone density and vertebral fracture in patients on corticosteroid therapy. Calcif Tissue Int 2000; 67: 277-85.

41. Sambrook PN. Corticosteroid osteoporosis: practical implications of recent trials. J Bone Miner Res 2000; 15: 1645-9.

42. Plotkin LI, Weinstein RS, Parfitt AM, Roberson PK, Manolagas SC, Bellido T. Prevention of osteocyte and osteoblast apoptosis by bisphosphonates and calcitonin. J Clin Invest 1999; 104: 1363-74.

43. Kotaniemi A, Piirainen H, Paimela L, Leirisalo-Repo M, Uoti-Reilama K, Lahdentausta P, et al. Is continuous intranasal salmon calcitonin effective in treating axial bone loss in patients with active RA receiving low-dose glucocorticoid? J Rheumatol 1996; 23: 1875-9.

44. Healey JH, Paget SA, Williams-Russo P, Szatrowski TP, Schneider R, Spiera H, et al. A randomized controlled trial of salmon calcitonin to prevent bone loss in corticosteroid-treated temporal arteritis and polymyalgia rheumatica. Calcif Tissue Int 1996; 58: 73-80.

45. Adachi JD, Bensen WG, Bell MJ, Bianchi FA, Cividino AA, Craig GL, et al. Salmon calcitonin nasal spray and the prevention of corticosteroid-induced osteoporosis. Br J Rheumatol 1997; 36: 255-9.

46. Ringe JD, Welzel D. Salmon calcitonin in the therapy of corticosteroid-induced osteoporosis. Eur J Clin Pharmacol 1987; 33: 35-9.

47. Luengo M, Picado C, Del Rio L, Guanabens N, Montserrat JM, Setoain J. Treatment of steroid-induced osteopenia with calcitonin in corticosteroid-dependent asthma. Am Rev Respir Dis 1990; 142: 104-7.

48. Luengo M, Pons F, Martinez de Osaba JM, Picado C. Prevention of further bone mass loss by nasal calcitonin in patients on long term glucocorticoid therapy for asthma: a two year follow up study. Thorax 1994; 49: 1099-102.

49. Lems WF, Jacobs WG, Bijlsma JW, Croone A, Haanen HC, Houben HH, et al. Effect of sodium fluoride on the prevention of corticosteroid-induced osteoporosis. Osteoporos Int 1997; 7: 575-82.

50. Lems WF, Jacobs JW, Bijlsma JW, van Veen GJ, Houben HH, Haanen HC, et al. Is the addition of sodium fluoride to cyclical etidronate beneficial in the treatment of corticosteroid-induced osteoporosis? Ann Rheum Dis 1997; 56: 357-63.

51. Lane NE, Sanchez S, Modin G, Genant HK, Pierini E, Arnaud CD. Bone mass continues to increase at the hip after parathyroid hormone treatment is discontinued in glucocorticoid-induced osteoporosis: results of a randomized controlled clinical trial. J Bone Miner Res 2000; 15: 944-51.

52. Lindsay R, Nieves J, Formica C, Hennerman E, Woelfert L, Shen V, et al. Randomized controlled study of effect of parathyroid hormone on vertebral bone mass among postmenopausal women with osteoporosis. Lancet 1997; 350: 550-5.

53. Adami S, Fossaluzza V, Rossini M, Bertaldo F, Gatti D, Zamberlan N, et al. The prevention of corticosteroid-induced osteoporosis with nandroline deconoate. Bone Miner 1991; 15: 72-81.

54. Greco EO, Weinshelbaum A, Simmons R. Effective therapy of glucocorticoid-induced osteoporosis with medroxyprogesterone acetate. Calcif Tissue Int 1990; 46: 294-9.