Bisphosphonates in the Prevention and Treatment of Glucocorticoid-Induced Osteoporosis

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

BMD Assessment and Preventive Measures

Although the risk of CIO and increased fracture risk is well cited, only 62% of surveyed physicians in one study¹² rated osteoporosis as one of the 3 most significant side effects discussed with patients taking high-dose steroids, and 2 cohort studies^13,14 found only a 5.6% and a 14% prescription rate for preventative medications when patients were prescribed glucocorticoids. Perhaps this mediocre reaction from primary care providers results from a shortage of clinical evidence to support preventive measures. Ideally, clinical decisions should be made using data concerning fracture risk reduction. Unfortunately, studies have not been sufficiently powered to assess fracture risk reduction, making it difficult to base therapeutic decisions on patient-oriented outcomes. The primary outcome assessed is the difference in percentage change from baseline in the BMD of the lumbar spine, femoral neck, and femoral trochanter between the treatment and placebo groups. It is important to recognize that the percentage change in BMD is a surrogate marker and has not been shown to directly correlate with decreased fracture risk. Other factors, such as bone strength and rate of turnover, may also contribute to fragility.

A BMD taken at one site, such as vertebrae or hip, correlates with risk of fracture at other sites; the best predictor of fracture, however, seems to be a BMD at the site in question.¹⁵ Patients at risk for CIO may have a comparatively higher risk of fracture at a given bone density than patients at risk for osteoporosis from other causes.¹⁶ A decrease in BMD of 1 SD below the mean of that of healthy adults aged 35 years will lead to a 1.5-fold to 3-fold increase in fracture risk,¹⁵ but this same bone density measure in the same woman taking corticosteroids may underestimate her risk of fracture.¹⁷

Presently the gold standard for BMD measurement is dual energy X-ray absorptiometry (DEXA). At this time, anteroposterior DEXA is recommended of both the lumbar spine and femoral neck for patients at risk for CIO.^17,18 If only one site can be obtained, the recommended site depends on the age of the patient. The lumbar spine is the site of choice for men and women younger than 60 years, while the femoral neck should be evaluated in men and women 60 years and older.¹⁸

Practice Guidelines

Two current sets of guidelines on the management of CIO are presently available: the recommendations of the 1998 United Kingdom (UK) Consensus Group¹⁷ and the 1996 American College of Rheumatology (ACR) Task Force on Osteoporosis Guidelines.¹⁸ Prevention and treatment options include risk factor modification (smoking cessation, fall prevention, and so forth) adequate calcium (1500 mg/day) and vitamin D3 intake (800 IU/day), hormone replacement when appropriate, bisphosphonates, and calcitonin (Figure). Other less-proven therapies such as thiazide diuretics, anabolic steroids, and fluoride are considered.

The ACR and UK guidelines differ considerably with respect to use of bisphosphonates in patients receiving long-term high-dose glucocorticoid therapy. The ACR task force recommends bisphosphonates only in patients with contraindications to hormone replacement therapy (HRT) or established osteoporosis.¹⁸ This class is not recommended in premenopausal women or men age younger than 50 years because of the lack of long-term safety data. The newer UK publication emphasizes that of all therapeutic options bisphosphonates have the most compelling BMD data and should be considered first-line treatment.¹⁷

Since the UK guidelines were published, 8 trials showing beneficial effects of bisphosphonates in the treatment of CIO have been published or presented at major medical meetings. Encouraging clinical data have resulted in alendronate and risedronate receiving United States Food and Drug Administration (FDA) approval for the indication of CIO. Our objective was to provide an evidence-based perspective of the use of bisphosphonates in corticosteroid-treated patients.

Methods

Literature searches were conducted independently by 2 authors using the MEDLINE, CURRENT CONTENTS, and HEALTHSTAR electronic databases to identify studies of bisphosphonates in the prevention or treatment of corticosteroid-induced osteoporosis. Medical subject headings and search terms included “bisphosphonates,” “diphosphonates,” “glucocorticoids,” “steroids,” and “osteoporosis.” We examined bibliographies of selected citations and review articles to obtain additional references. Unpublished information was obtained by hand-searching abstracts from recent meetings (1998) of the American Society for Bone and Mineral Research and the ACR. Studies were included if the design was randomized and controlled and if they evaluated the use of oral bisphosphonates in adults. Obtaining BMD results using the gold standard of measurement—central DEXA—was also necessary for study inclusion. Two authors assessed the methodologic quality of the trials using the 5-point criteria developed by Jadad and colleagues.¹⁹

Results

Bisphosphonates have been studied for use in CIO for more than a decade. Our search yielded a total of 34 citations of studies researching bisphosphonates for this indication. Twenty-one of these^20-40 were excluded for not meeting the specified inclusion criteria. The 13 studies included in our analysis^41-53 addressed the use of bisphosphonates in the prevention and treatment of corticosteroid-induced osteoporosis. Each bisphosphonate had the following number of citations and total number of patients in all studies combined: risedronate, 3 (n=638); etidronate, 8 (n=522); alendronate, 1 (n=477); and clodronate, 1 (n=74). The demographics pertaining to each study are summarized in [Table 1].

The methodologic quality of the trials was agreed on by the 2 reviewers. Scores ranged from 1 to 4 with 1 trial scoring 1,⁴¹ 2 trials scoring 2,^48,53 2 trials scoring 3,^45,47 and 8 trials scoring 4.^{42-44,46,49-52} All studies were reported as randomized; only 1 trial, however, described the randomization process.⁴⁴ Three of the 13 (23%) did not report using double-blind methodology.^41,48,53

The primary outcome assessed in all selected clinical trials is the difference in percentage change from baseline in the BMD of the lumbar spine, femoral neck, and femoral trochanter between the treatment and placebo groups. This complies with the ACR guidelines that recommend measurement at the lumbar spine and femoral neck. In regard to the studied primary outcomes, changes in BMD at the lumbar spine in treatment groups ranged from means of -0.137% to 4.9%; the control group values ranged from 3.7% to 0.98%. Three of 13 studies (23%) did not show a significant benefit at the lumbar spine when compared with the control group^41,47,48; however, 2 of these studies^41,48 used unusual doses of bisphosphonate. BMD changes at the femoral neck on treatment ranged from 1.28% to 3.6%; control group changes from baseline ranged from 3.6% to 3.64%. Nine of the 13 studies (69%) were not able to show statistical significance between the treatment and control groups at the femoral neck.^41-43,48-53 Changes in the treatment groups at the femoral trochanter ranged from -1.35% to 2.7%; placebo changes ranged from 3.06% to 1.5%. More than one half of studies reporting data at the femoral trochanter (6/10) showed that the treatment group was not significantly better than control group.^41,42,45,46 Specific BMD results from each trial are available in [Table 2]. Results varied based on the population, the bisphosphonate being investigated, the dosing regimen, and other distinctions in the study design.

Six studies^{42,43,45,46,49,52} addressed the possible differences in treatment effect based on sex and menopausal status. The effect of bisphosphonate treatment on BMD in postmenopausal women was significant in 4 of the trials.^42,45,46,52 One study included postmenopausal women taking HRT and found alendronate 10 mg led to a higher increase in BMD in women not receiving estrogen.⁴⁵ Only one study, however, found a significant effect on BMD in premenopausal women receiving etidronate.⁴² Also, an increase in the BMD of men was found to be significantly increased in one study.⁴⁶

The percentage change from baseline of the BMD of the distal and midshaft radius was measured in 1 study of etidronate and 2 studies of risedronate^42,46,47; statistical significance was not obtained in any of the results. Other secondary outcomes measured in selected citations were: biochemical markers of bone resorption and formation including pyridinium crosslinks, osteocalcin, parathyroid hormone, ionized calcium, serum alkaline phosphatase, serum alanine aminotransferase, and bone-specific alkaline phosphatase. However, these are not discussed in detail because of the uncertainty of their relationship to fracture risk.

Fracture Risk

Although not a specified primary end point, the risk of fracture development was addressed in 9 of the studies.^{42,43,45-49,51-52} Since the rate of fractures was low in most studies and no studies were powered on the basis of fracture risk, some data were reported without statistical analysis. Six studies^{42,43,45-47,51} analyzed the difference between treatment and control groups with respect to fracture risk. Three of these studies reported at least a trend in reduced fracture rates^42,45,46; however, only 1 (in abstract) found a statistical difference in the overall population.⁴⁷ A 10.1% reduction in vertebral fractures was found in patients receiving risedronate (either 2.5 mg or 5 mg) at 12 months (P=.021).⁴⁷ According to an abstract, when these results were pooled with another trial⁴⁶ it was found that risedronate 5.0 mg statistically decreased the incidence of vertebral fractures at 1 year (16.2% vs 5.4%, P=.01).⁵⁴ Therefore, it would be necessary to treat 10 CIO patients for 1 year with risedronate 5 mg per day to prevent one vertebral fracture.

Although the fracture rate was not significant in most trials, the subpopulation of postmenopausal women experienced the greatest number of fractures and seemed to benefit the most from treatment. Two studies found borderline significance in the fracture rate when postmenopausal women were analyzed separately.^42,45 Etidronate and alendronate use led to an absolute risk reduction of 18.7% (P=.05) and 8.6% (P=.05), respectively. Men were the only other group to experience fractures in any of the studies. No fractures were reported in the premenopausal population.

When interpreting the results of these studies it is important to remember that trial results can vary according to a number of factors, including: definition of fracture, initial number of fractures, baseline BMD, and population differences. Therefore, the reported data should not be extrapolated to all populations. It should also be mentioned that all of the fracture data presented consisted of radiologically reported fractures, which does not necessarily correlate with clinical fractures.

Safety and Tolerability

The withdrawal rates of the included studies ranged from 0% to 62% ([Table 3]). Of the dropouts reported, 42% were secondary to protocol violations or administrative reasons, and 16% were because of noncompliance. Twenty percent of study withdrawals were because of adverse events, of which 78% (29/37) were deemed not related to the treatment regimen. No significant difference was reported in dropout rates between the treatment and control groups.

In most of the studies no statistical significance concerning adverse effects was found when the treatment group was compared with the control group. Nine studies^42-47,50,51 discussed the subgroup of gastrointestinal (GI) adverse events, since this has been the greatest historical concern about the use of bisphosphonates. Eight studies found no difference in overall GI effects, and one study⁴⁵ reported a statistical trend for increased GI side effects with dose escalation of alendronate. This trend was probably secondary to an increase in abdominal pain in the treatment group when compared with the placebo group. In one study,⁴⁶ diarrhea was more common in patients receiving 5 mg risedronate than those taking placebo (number needed to harm=15), although significance was not reported.

Discussion

The studies examining the use of bisphosphonates for the prevention or treatment of CIO are difficult to interpret because of the various bisphosphonates and regimens, the heterogenicity in populations, the effect of the underlying disease on bone, and concomitant therapeutic interventions. A review of the currently published literature suggests bisphosphonates effectively prevent vertebral bone loss in patients treated with long-term corticosteroids. Patients receiving steroids for more than 3 months (secondary prevention) gained bone mass when placed on a bisphosphonate, while patients naive to steroids (primary prevention) maintained more bone density than the control group.^{42-44,46,47,50,51,53} This reinforces the fact that patients taking steroids for more than 3 months have already lost bone that can be partially regained with bisphosphonate treatment. In contrast, patients given bisphosphonates who were naive to steroids did not have significant changes in BMD from baseline; this group, however, was able to maintain bone density while the control group lost bone density.

Data regarding the impact of bisphosphonates on the risk of CIO-induced fractures are sparse and inconclusive. This is not surprising since most of the trials have been of relatively short duration (<2 years), and have not been sufficiently powered to show fracture reduction. Postmenopausal women not taking estrogen seem to benefit most from using bisphosphonates for the prevention of bone loss and of vertebral fractures in CIO.

A meta-analysis of a similar set of data based on a Cochrane systematic review of published literature was reported in 1999.⁵⁵ The authors state that of the small number of controlled clinical trials examining the use of bone-sparing agents in patients at risk for CIO bisphosphonates have shown some of the best evidence for reducing bone loss, particularly at the lumbar spine. They also concluded that bone density changes correlate with fracture risk in patients with CIO, but there are insufficient data to make conclusions regarding fracture risk reduction and use of bisphosphonates.

Overall, adverse effects of the bisphosphonates were minimal, and no statistical significance was found in studied populations when compared with control groups. However, the incidence of GI adverse events with alendronate may be as high as 15% in clinical practice, despite low incidence rates in phase III trials, possibly because of administration errors.⁵⁶ Directions for use are the same for all oral bisphosphonates, and include staying upright and not eating for at least 30 minutes after administration. Because oral bioavailability is usually less than 5% even on an empty stomach, bisphosphonates should be taken with a full glass of water in the morning after an overnight fast.^11,56,57

Implications for further research

Although current evidence supporting bisphosphonate use documents efficacy in BMD changes and trends toward reduced vertebral fracture risk in the treatment of CIO, more research is clearly desirable. The recent FDA approval of alendronate and risedronate has highlighted the need for aggressive measures to prevent and treat CIO. More research is needed in large studies to assess vertebral and nonvertebral fractures. Head-to-head comparative trials of bisphosphonates with other pharmacologic options, such as hormonal therapy or calcitonin are essential to establish evidence-based clinical guidelines. Studies addressing combination therapy with bisphosphonates and HRT in postmenopausal women would also be useful. Finally, comparative studies of the various bisphosphonates in relation to one another are needed. These synthetic pyrophosphate analogs possess a broad range of potencies, selectivity, and adverse effect profiles. Because each bisphosphonate has unique biological, chemical, and physiochemical properties, the results of one bisphosphonate study cannot be extrapolated to other compounds within the same drug class.^3,56,58,59 Differences in study design, patient populations, and other confounding variables also prevent the assumption of a class effect with certain research findings. This distinction becomes especially important with the new bisphosphonates on the horizon (clodronate, tiludronate, ibandronate, and zoledronate).

Although the relationship of BMD to fracture risk is well documented in postmenopausal osteoporosis, the correlation is not as well established in glucocorticoid-induced bone loss.^2,60 The present data suggest a trend in the reduction of fracture risk observed with the use of bisphosphonates in the treatment of glucocorticoid-induced osteoporosis. This information is promising but requires definitive confirmation in larger trials. Because of the prolonged skeletal retention of bisphosphonates, more extended trials are also needed to clearly establish the safety of long-term therapy in younger patients.

Recommendations for clinical practice

All patients beginning high-dose (Ž7.5 mg/day prednisone) long-term (>6 months) glucocorticoid therapy should be evaluated for pharmacologic prophylaxis against osteoporosis. Because the majority of bone loss occurs within the first 6 months of therapy, clinicians must vigilantly develop a preventative plan in advance, preferably before the glucocorticoid prescription is given to the patient. Current guidelines recommend a baseline BMD measurement of all patients with DEXA to determine the risk of osteoporosis and the monitor the efficacy of the chosen preventative measures throughout the course of therapy. Initial BMD measurements expressed as a T score are essential tools for constructing an individualized strategy. Critical T scores of less than or equal to 1.0 are indicative of high-risk patients.¹⁸ In addition to the risk imposed on patients secondary to their underlying disease state, other patients with strong predictive factors include those who are elderly and at greater risk of falling and those who have a previous history of fractures.

BMD measurements may be repeated in 6 to 12 months, depending on initial bone mass. If BMD has decreased by more than 5% from baseline, the initial choice of therapy should be changed or expanded.^18,61

Both glucocorticoid doses and the length of therapy require continuous reevaluation to decrease the total cumulative dose. If possible, dose maximization of inhaled and topical corticosteroids is recommended before progression to the oral form. More obvious preventive lifestyle modifications include smoking cessation, maintenance of healthy body weight, regular weight-bearing exercise, decreased alcohol consumption, sodium restriction, and increased dietary calcium intake. Most patients will require additional calcium supplementation to meet the ACR recommendation of 1500 mg per day, and patients at risk for vitamin D deficiency may also require supplementation.¹⁸

However, even with appropriate supplementation 1 in 6 corticosteroid-treated patients will experience a radiographically detected vertebral fracture within 12 months.^46,47,54 Therefore, alternative treatment regimens are needed. Bisphosphonate therapy looks promising in the prevention and treatment of CIO with respect to positively affecting BMD. As a result of this encouraging data, alendronate and risedronate have received FDA approval for the indication of CIO. However, it remains to be seen whether the use of these agents can lead to a reduction in fractures, both vertebral and nonvertebral. Subpopulations at highest risk (postmenopausal women and men) may benefit most with regard to fracture risk reduction, but more data are needed before bisphosphonates should be routinely recommended as first-line preventive therapy. Once osteoporosis is established (regardless of the pathogenesis), treatment should be aggressive to prevent further loss of bone density. In this population bisphosphonates are an appropriate therapeutic option, and further data will clarify their impact on the risk of fractures.

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

BMD Assessment and Preventive Measures

Although the risk of CIO and increased fracture risk is well cited, only 62% of surveyed physicians in one study¹² rated osteoporosis as one of the 3 most significant side effects discussed with patients taking high-dose steroids, and 2 cohort studies^13,14 found only a 5.6% and a 14% prescription rate for preventative medications when patients were prescribed glucocorticoids. Perhaps this mediocre reaction from primary care providers results from a shortage of clinical evidence to support preventive measures. Ideally, clinical decisions should be made using data concerning fracture risk reduction. Unfortunately, studies have not been sufficiently powered to assess fracture risk reduction, making it difficult to base therapeutic decisions on patient-oriented outcomes. The primary outcome assessed is the difference in percentage change from baseline in the BMD of the lumbar spine, femoral neck, and femoral trochanter between the treatment and placebo groups. It is important to recognize that the percentage change in BMD is a surrogate marker and has not been shown to directly correlate with decreased fracture risk. Other factors, such as bone strength and rate of turnover, may also contribute to fragility.

A BMD taken at one site, such as vertebrae or hip, correlates with risk of fracture at other sites; the best predictor of fracture, however, seems to be a BMD at the site in question.¹⁵ Patients at risk for CIO may have a comparatively higher risk of fracture at a given bone density than patients at risk for osteoporosis from other causes.¹⁶ A decrease in BMD of 1 SD below the mean of that of healthy adults aged 35 years will lead to a 1.5-fold to 3-fold increase in fracture risk,¹⁵ but this same bone density measure in the same woman taking corticosteroids may underestimate her risk of fracture.¹⁷

Presently the gold standard for BMD measurement is dual energy X-ray absorptiometry (DEXA). At this time, anteroposterior DEXA is recommended of both the lumbar spine and femoral neck for patients at risk for CIO.^17,18 If only one site can be obtained, the recommended site depends on the age of the patient. The lumbar spine is the site of choice for men and women younger than 60 years, while the femoral neck should be evaluated in men and women 60 years and older.¹⁸

Practice Guidelines

Two current sets of guidelines on the management of CIO are presently available: the recommendations of the 1998 United Kingdom (UK) Consensus Group¹⁷ and the 1996 American College of Rheumatology (ACR) Task Force on Osteoporosis Guidelines.¹⁸ Prevention and treatment options include risk factor modification (smoking cessation, fall prevention, and so forth) adequate calcium (1500 mg/day) and vitamin D3 intake (800 IU/day), hormone replacement when appropriate, bisphosphonates, and calcitonin (Figure). Other less-proven therapies such as thiazide diuretics, anabolic steroids, and fluoride are considered.

The ACR and UK guidelines differ considerably with respect to use of bisphosphonates in patients receiving long-term high-dose glucocorticoid therapy. The ACR task force recommends bisphosphonates only in patients with contraindications to hormone replacement therapy (HRT) or established osteoporosis.¹⁸ This class is not recommended in premenopausal women or men age younger than 50 years because of the lack of long-term safety data. The newer UK publication emphasizes that of all therapeutic options bisphosphonates have the most compelling BMD data and should be considered first-line treatment.¹⁷

Since the UK guidelines were published, 8 trials showing beneficial effects of bisphosphonates in the treatment of CIO have been published or presented at major medical meetings. Encouraging clinical data have resulted in alendronate and risedronate receiving United States Food and Drug Administration (FDA) approval for the indication of CIO. Our objective was to provide an evidence-based perspective of the use of bisphosphonates in corticosteroid-treated patients.

Methods

Literature searches were conducted independently by 2 authors using the MEDLINE, CURRENT CONTENTS, and HEALTHSTAR electronic databases to identify studies of bisphosphonates in the prevention or treatment of corticosteroid-induced osteoporosis. Medical subject headings and search terms included “bisphosphonates,” “diphosphonates,” “glucocorticoids,” “steroids,” and “osteoporosis.” We examined bibliographies of selected citations and review articles to obtain additional references. Unpublished information was obtained by hand-searching abstracts from recent meetings (1998) of the American Society for Bone and Mineral Research and the ACR. Studies were included if the design was randomized and controlled and if they evaluated the use of oral bisphosphonates in adults. Obtaining BMD results using the gold standard of measurement—central DEXA—was also necessary for study inclusion. Two authors assessed the methodologic quality of the trials using the 5-point criteria developed by Jadad and colleagues.¹⁹

Results

Bisphosphonates have been studied for use in CIO for more than a decade. Our search yielded a total of 34 citations of studies researching bisphosphonates for this indication. Twenty-one of these^20-40 were excluded for not meeting the specified inclusion criteria. The 13 studies included in our analysis^41-53 addressed the use of bisphosphonates in the prevention and treatment of corticosteroid-induced osteoporosis. Each bisphosphonate had the following number of citations and total number of patients in all studies combined: risedronate, 3 (n=638); etidronate, 8 (n=522); alendronate, 1 (n=477); and clodronate, 1 (n=74). The demographics pertaining to each study are summarized in [Table 1].

The methodologic quality of the trials was agreed on by the 2 reviewers. Scores ranged from 1 to 4 with 1 trial scoring 1,⁴¹ 2 trials scoring 2,^48,53 2 trials scoring 3,^45,47 and 8 trials scoring 4.^{42-44,46,49-52} All studies were reported as randomized; only 1 trial, however, described the randomization process.⁴⁴ Three of the 13 (23%) did not report using double-blind methodology.^41,48,53

The primary outcome assessed in all selected clinical trials is the difference in percentage change from baseline in the BMD of the lumbar spine, femoral neck, and femoral trochanter between the treatment and placebo groups. This complies with the ACR guidelines that recommend measurement at the lumbar spine and femoral neck. In regard to the studied primary outcomes, changes in BMD at the lumbar spine in treatment groups ranged from means of -0.137% to 4.9%; the control group values ranged from 3.7% to 0.98%. Three of 13 studies (23%) did not show a significant benefit at the lumbar spine when compared with the control group^41,47,48; however, 2 of these studies^41,48 used unusual doses of bisphosphonate. BMD changes at the femoral neck on treatment ranged from 1.28% to 3.6%; control group changes from baseline ranged from 3.6% to 3.64%. Nine of the 13 studies (69%) were not able to show statistical significance between the treatment and control groups at the femoral neck.^41-43,48-53 Changes in the treatment groups at the femoral trochanter ranged from -1.35% to 2.7%; placebo changes ranged from 3.06% to 1.5%. More than one half of studies reporting data at the femoral trochanter (6/10) showed that the treatment group was not significantly better than control group.^41,42,45,46 Specific BMD results from each trial are available in [Table 2]. Results varied based on the population, the bisphosphonate being investigated, the dosing regimen, and other distinctions in the study design.

Six studies^{42,43,45,46,49,52} addressed the possible differences in treatment effect based on sex and menopausal status. The effect of bisphosphonate treatment on BMD in postmenopausal women was significant in 4 of the trials.^42,45,46,52 One study included postmenopausal women taking HRT and found alendronate 10 mg led to a higher increase in BMD in women not receiving estrogen.⁴⁵ Only one study, however, found a significant effect on BMD in premenopausal women receiving etidronate.⁴² Also, an increase in the BMD of men was found to be significantly increased in one study.⁴⁶

The percentage change from baseline of the BMD of the distal and midshaft radius was measured in 1 study of etidronate and 2 studies of risedronate^42,46,47; statistical significance was not obtained in any of the results. Other secondary outcomes measured in selected citations were: biochemical markers of bone resorption and formation including pyridinium crosslinks, osteocalcin, parathyroid hormone, ionized calcium, serum alkaline phosphatase, serum alanine aminotransferase, and bone-specific alkaline phosphatase. However, these are not discussed in detail because of the uncertainty of their relationship to fracture risk.

Fracture Risk

Although not a specified primary end point, the risk of fracture development was addressed in 9 of the studies.^{42,43,45-49,51-52} Since the rate of fractures was low in most studies and no studies were powered on the basis of fracture risk, some data were reported without statistical analysis. Six studies^{42,43,45-47,51} analyzed the difference between treatment and control groups with respect to fracture risk. Three of these studies reported at least a trend in reduced fracture rates^42,45,46; however, only 1 (in abstract) found a statistical difference in the overall population.⁴⁷ A 10.1% reduction in vertebral fractures was found in patients receiving risedronate (either 2.5 mg or 5 mg) at 12 months (P=.021).⁴⁷ According to an abstract, when these results were pooled with another trial⁴⁶ it was found that risedronate 5.0 mg statistically decreased the incidence of vertebral fractures at 1 year (16.2% vs 5.4%, P=.01).⁵⁴ Therefore, it would be necessary to treat 10 CIO patients for 1 year with risedronate 5 mg per day to prevent one vertebral fracture.

Although the fracture rate was not significant in most trials, the subpopulation of postmenopausal women experienced the greatest number of fractures and seemed to benefit the most from treatment. Two studies found borderline significance in the fracture rate when postmenopausal women were analyzed separately.^42,45 Etidronate and alendronate use led to an absolute risk reduction of 18.7% (P=.05) and 8.6% (P=.05), respectively. Men were the only other group to experience fractures in any of the studies. No fractures were reported in the premenopausal population.

When interpreting the results of these studies it is important to remember that trial results can vary according to a number of factors, including: definition of fracture, initial number of fractures, baseline BMD, and population differences. Therefore, the reported data should not be extrapolated to all populations. It should also be mentioned that all of the fracture data presented consisted of radiologically reported fractures, which does not necessarily correlate with clinical fractures.

Safety and Tolerability

The withdrawal rates of the included studies ranged from 0% to 62% ([Table 3]). Of the dropouts reported, 42% were secondary to protocol violations or administrative reasons, and 16% were because of noncompliance. Twenty percent of study withdrawals were because of adverse events, of which 78% (29/37) were deemed not related to the treatment regimen. No significant difference was reported in dropout rates between the treatment and control groups.

In most of the studies no statistical significance concerning adverse effects was found when the treatment group was compared with the control group. Nine studies^42-47,50,51 discussed the subgroup of gastrointestinal (GI) adverse events, since this has been the greatest historical concern about the use of bisphosphonates. Eight studies found no difference in overall GI effects, and one study⁴⁵ reported a statistical trend for increased GI side effects with dose escalation of alendronate. This trend was probably secondary to an increase in abdominal pain in the treatment group when compared with the placebo group. In one study,⁴⁶ diarrhea was more common in patients receiving 5 mg risedronate than those taking placebo (number needed to harm=15), although significance was not reported.

Discussion

The studies examining the use of bisphosphonates for the prevention or treatment of CIO are difficult to interpret because of the various bisphosphonates and regimens, the heterogenicity in populations, the effect of the underlying disease on bone, and concomitant therapeutic interventions. A review of the currently published literature suggests bisphosphonates effectively prevent vertebral bone loss in patients treated with long-term corticosteroids. Patients receiving steroids for more than 3 months (secondary prevention) gained bone mass when placed on a bisphosphonate, while patients naive to steroids (primary prevention) maintained more bone density than the control group.^{42-44,46,47,50,51,53} This reinforces the fact that patients taking steroids for more than 3 months have already lost bone that can be partially regained with bisphosphonate treatment. In contrast, patients given bisphosphonates who were naive to steroids did not have significant changes in BMD from baseline; this group, however, was able to maintain bone density while the control group lost bone density.

Data regarding the impact of bisphosphonates on the risk of CIO-induced fractures are sparse and inconclusive. This is not surprising since most of the trials have been of relatively short duration (<2 years), and have not been sufficiently powered to show fracture reduction. Postmenopausal women not taking estrogen seem to benefit most from using bisphosphonates for the prevention of bone loss and of vertebral fractures in CIO.

A meta-analysis of a similar set of data based on a Cochrane systematic review of published literature was reported in 1999.⁵⁵ The authors state that of the small number of controlled clinical trials examining the use of bone-sparing agents in patients at risk for CIO bisphosphonates have shown some of the best evidence for reducing bone loss, particularly at the lumbar spine. They also concluded that bone density changes correlate with fracture risk in patients with CIO, but there are insufficient data to make conclusions regarding fracture risk reduction and use of bisphosphonates.

Overall, adverse effects of the bisphosphonates were minimal, and no statistical significance was found in studied populations when compared with control groups. However, the incidence of GI adverse events with alendronate may be as high as 15% in clinical practice, despite low incidence rates in phase III trials, possibly because of administration errors.⁵⁶ Directions for use are the same for all oral bisphosphonates, and include staying upright and not eating for at least 30 minutes after administration. Because oral bioavailability is usually less than 5% even on an empty stomach, bisphosphonates should be taken with a full glass of water in the morning after an overnight fast.^11,56,57

Implications for further research

Although current evidence supporting bisphosphonate use documents efficacy in BMD changes and trends toward reduced vertebral fracture risk in the treatment of CIO, more research is clearly desirable. The recent FDA approval of alendronate and risedronate has highlighted the need for aggressive measures to prevent and treat CIO. More research is needed in large studies to assess vertebral and nonvertebral fractures. Head-to-head comparative trials of bisphosphonates with other pharmacologic options, such as hormonal therapy or calcitonin are essential to establish evidence-based clinical guidelines. Studies addressing combination therapy with bisphosphonates and HRT in postmenopausal women would also be useful. Finally, comparative studies of the various bisphosphonates in relation to one another are needed. These synthetic pyrophosphate analogs possess a broad range of potencies, selectivity, and adverse effect profiles. Because each bisphosphonate has unique biological, chemical, and physiochemical properties, the results of one bisphosphonate study cannot be extrapolated to other compounds within the same drug class.^3,56,58,59 Differences in study design, patient populations, and other confounding variables also prevent the assumption of a class effect with certain research findings. This distinction becomes especially important with the new bisphosphonates on the horizon (clodronate, tiludronate, ibandronate, and zoledronate).

Although the relationship of BMD to fracture risk is well documented in postmenopausal osteoporosis, the correlation is not as well established in glucocorticoid-induced bone loss.^2,60 The present data suggest a trend in the reduction of fracture risk observed with the use of bisphosphonates in the treatment of glucocorticoid-induced osteoporosis. This information is promising but requires definitive confirmation in larger trials. Because of the prolonged skeletal retention of bisphosphonates, more extended trials are also needed to clearly establish the safety of long-term therapy in younger patients.

Recommendations for clinical practice

All patients beginning high-dose (Ž7.5 mg/day prednisone) long-term (>6 months) glucocorticoid therapy should be evaluated for pharmacologic prophylaxis against osteoporosis. Because the majority of bone loss occurs within the first 6 months of therapy, clinicians must vigilantly develop a preventative plan in advance, preferably before the glucocorticoid prescription is given to the patient. Current guidelines recommend a baseline BMD measurement of all patients with DEXA to determine the risk of osteoporosis and the monitor the efficacy of the chosen preventative measures throughout the course of therapy. Initial BMD measurements expressed as a T score are essential tools for constructing an individualized strategy. Critical T scores of less than or equal to 1.0 are indicative of high-risk patients.¹⁸ In addition to the risk imposed on patients secondary to their underlying disease state, other patients with strong predictive factors include those who are elderly and at greater risk of falling and those who have a previous history of fractures.

BMD measurements may be repeated in 6 to 12 months, depending on initial bone mass. If BMD has decreased by more than 5% from baseline, the initial choice of therapy should be changed or expanded.^18,61

Both glucocorticoid doses and the length of therapy require continuous reevaluation to decrease the total cumulative dose. If possible, dose maximization of inhaled and topical corticosteroids is recommended before progression to the oral form. More obvious preventive lifestyle modifications include smoking cessation, maintenance of healthy body weight, regular weight-bearing exercise, decreased alcohol consumption, sodium restriction, and increased dietary calcium intake. Most patients will require additional calcium supplementation to meet the ACR recommendation of 1500 mg per day, and patients at risk for vitamin D deficiency may also require supplementation.¹⁸

However, even with appropriate supplementation 1 in 6 corticosteroid-treated patients will experience a radiographically detected vertebral fracture within 12 months.^46,47,54 Therefore, alternative treatment regimens are needed. Bisphosphonate therapy looks promising in the prevention and treatment of CIO with respect to positively affecting BMD. As a result of this encouraging data, alendronate and risedronate have received FDA approval for the indication of CIO. However, it remains to be seen whether the use of these agents can lead to a reduction in fractures, both vertebral and nonvertebral. Subpopulations at highest risk (postmenopausal women and men) may benefit most with regard to fracture risk reduction, but more data are needed before bisphosphonates should be routinely recommended as first-line preventive therapy. Once osteoporosis is established (regardless of the pathogenesis), treatment should be aggressive to prevent further loss of bone density. In this population bisphosphonates are an appropriate therapeutic option, and further data will clarify their impact on the risk of fractures.

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

BMD Assessment and Preventive Measures

Although the risk of CIO and increased fracture risk is well cited, only 62% of surveyed physicians in one study¹² rated osteoporosis as one of the 3 most significant side effects discussed with patients taking high-dose steroids, and 2 cohort studies^13,14 found only a 5.6% and a 14% prescription rate for preventative medications when patients were prescribed glucocorticoids. Perhaps this mediocre reaction from primary care providers results from a shortage of clinical evidence to support preventive measures. Ideally, clinical decisions should be made using data concerning fracture risk reduction. Unfortunately, studies have not been sufficiently powered to assess fracture risk reduction, making it difficult to base therapeutic decisions on patient-oriented outcomes. The primary outcome assessed is the difference in percentage change from baseline in the BMD of the lumbar spine, femoral neck, and femoral trochanter between the treatment and placebo groups. It is important to recognize that the percentage change in BMD is a surrogate marker and has not been shown to directly correlate with decreased fracture risk. Other factors, such as bone strength and rate of turnover, may also contribute to fragility.

A BMD taken at one site, such as vertebrae or hip, correlates with risk of fracture at other sites; the best predictor of fracture, however, seems to be a BMD at the site in question.¹⁵ Patients at risk for CIO may have a comparatively higher risk of fracture at a given bone density than patients at risk for osteoporosis from other causes.¹⁶ A decrease in BMD of 1 SD below the mean of that of healthy adults aged 35 years will lead to a 1.5-fold to 3-fold increase in fracture risk,¹⁵ but this same bone density measure in the same woman taking corticosteroids may underestimate her risk of fracture.¹⁷

Presently the gold standard for BMD measurement is dual energy X-ray absorptiometry (DEXA). At this time, anteroposterior DEXA is recommended of both the lumbar spine and femoral neck for patients at risk for CIO.^17,18 If only one site can be obtained, the recommended site depends on the age of the patient. The lumbar spine is the site of choice for men and women younger than 60 years, while the femoral neck should be evaluated in men and women 60 years and older.¹⁸

Practice Guidelines

Two current sets of guidelines on the management of CIO are presently available: the recommendations of the 1998 United Kingdom (UK) Consensus Group¹⁷ and the 1996 American College of Rheumatology (ACR) Task Force on Osteoporosis Guidelines.¹⁸ Prevention and treatment options include risk factor modification (smoking cessation, fall prevention, and so forth) adequate calcium (1500 mg/day) and vitamin D3 intake (800 IU/day), hormone replacement when appropriate, bisphosphonates, and calcitonin (Figure). Other less-proven therapies such as thiazide diuretics, anabolic steroids, and fluoride are considered.

The ACR and UK guidelines differ considerably with respect to use of bisphosphonates in patients receiving long-term high-dose glucocorticoid therapy. The ACR task force recommends bisphosphonates only in patients with contraindications to hormone replacement therapy (HRT) or established osteoporosis.¹⁸ This class is not recommended in premenopausal women or men age younger than 50 years because of the lack of long-term safety data. The newer UK publication emphasizes that of all therapeutic options bisphosphonates have the most compelling BMD data and should be considered first-line treatment.¹⁷

Since the UK guidelines were published, 8 trials showing beneficial effects of bisphosphonates in the treatment of CIO have been published or presented at major medical meetings. Encouraging clinical data have resulted in alendronate and risedronate receiving United States Food and Drug Administration (FDA) approval for the indication of CIO. Our objective was to provide an evidence-based perspective of the use of bisphosphonates in corticosteroid-treated patients.

Methods

Literature searches were conducted independently by 2 authors using the MEDLINE, CURRENT CONTENTS, and HEALTHSTAR electronic databases to identify studies of bisphosphonates in the prevention or treatment of corticosteroid-induced osteoporosis. Medical subject headings and search terms included “bisphosphonates,” “diphosphonates,” “glucocorticoids,” “steroids,” and “osteoporosis.” We examined bibliographies of selected citations and review articles to obtain additional references. Unpublished information was obtained by hand-searching abstracts from recent meetings (1998) of the American Society for Bone and Mineral Research and the ACR. Studies were included if the design was randomized and controlled and if they evaluated the use of oral bisphosphonates in adults. Obtaining BMD results using the gold standard of measurement—central DEXA—was also necessary for study inclusion. Two authors assessed the methodologic quality of the trials using the 5-point criteria developed by Jadad and colleagues.¹⁹

Results

Bisphosphonates have been studied for use in CIO for more than a decade. Our search yielded a total of 34 citations of studies researching bisphosphonates for this indication. Twenty-one of these^20-40 were excluded for not meeting the specified inclusion criteria. The 13 studies included in our analysis^41-53 addressed the use of bisphosphonates in the prevention and treatment of corticosteroid-induced osteoporosis. Each bisphosphonate had the following number of citations and total number of patients in all studies combined: risedronate, 3 (n=638); etidronate, 8 (n=522); alendronate, 1 (n=477); and clodronate, 1 (n=74). The demographics pertaining to each study are summarized in [Table 1].

The methodologic quality of the trials was agreed on by the 2 reviewers. Scores ranged from 1 to 4 with 1 trial scoring 1,⁴¹ 2 trials scoring 2,^48,53 2 trials scoring 3,^45,47 and 8 trials scoring 4.^{42-44,46,49-52} All studies were reported as randomized; only 1 trial, however, described the randomization process.⁴⁴ Three of the 13 (23%) did not report using double-blind methodology.^41,48,53

The primary outcome assessed in all selected clinical trials is the difference in percentage change from baseline in the BMD of the lumbar spine, femoral neck, and femoral trochanter between the treatment and placebo groups. This complies with the ACR guidelines that recommend measurement at the lumbar spine and femoral neck. In regard to the studied primary outcomes, changes in BMD at the lumbar spine in treatment groups ranged from means of -0.137% to 4.9%; the control group values ranged from 3.7% to 0.98%. Three of 13 studies (23%) did not show a significant benefit at the lumbar spine when compared with the control group^41,47,48; however, 2 of these studies^41,48 used unusual doses of bisphosphonate. BMD changes at the femoral neck on treatment ranged from 1.28% to 3.6%; control group changes from baseline ranged from 3.6% to 3.64%. Nine of the 13 studies (69%) were not able to show statistical significance between the treatment and control groups at the femoral neck.^41-43,48-53 Changes in the treatment groups at the femoral trochanter ranged from -1.35% to 2.7%; placebo changes ranged from 3.06% to 1.5%. More than one half of studies reporting data at the femoral trochanter (6/10) showed that the treatment group was not significantly better than control group.^41,42,45,46 Specific BMD results from each trial are available in [Table 2]. Results varied based on the population, the bisphosphonate being investigated, the dosing regimen, and other distinctions in the study design.

Six studies^{42,43,45,46,49,52} addressed the possible differences in treatment effect based on sex and menopausal status. The effect of bisphosphonate treatment on BMD in postmenopausal women was significant in 4 of the trials.^42,45,46,52 One study included postmenopausal women taking HRT and found alendronate 10 mg led to a higher increase in BMD in women not receiving estrogen.⁴⁵ Only one study, however, found a significant effect on BMD in premenopausal women receiving etidronate.⁴² Also, an increase in the BMD of men was found to be significantly increased in one study.⁴⁶

The percentage change from baseline of the BMD of the distal and midshaft radius was measured in 1 study of etidronate and 2 studies of risedronate^42,46,47; statistical significance was not obtained in any of the results. Other secondary outcomes measured in selected citations were: biochemical markers of bone resorption and formation including pyridinium crosslinks, osteocalcin, parathyroid hormone, ionized calcium, serum alkaline phosphatase, serum alanine aminotransferase, and bone-specific alkaline phosphatase. However, these are not discussed in detail because of the uncertainty of their relationship to fracture risk.

Fracture Risk

Although not a specified primary end point, the risk of fracture development was addressed in 9 of the studies.^{42,43,45-49,51-52} Since the rate of fractures was low in most studies and no studies were powered on the basis of fracture risk, some data were reported without statistical analysis. Six studies^{42,43,45-47,51} analyzed the difference between treatment and control groups with respect to fracture risk. Three of these studies reported at least a trend in reduced fracture rates^42,45,46; however, only 1 (in abstract) found a statistical difference in the overall population.⁴⁷ A 10.1% reduction in vertebral fractures was found in patients receiving risedronate (either 2.5 mg or 5 mg) at 12 months (P=.021).⁴⁷ According to an abstract, when these results were pooled with another trial⁴⁶ it was found that risedronate 5.0 mg statistically decreased the incidence of vertebral fractures at 1 year (16.2% vs 5.4%, P=.01).⁵⁴ Therefore, it would be necessary to treat 10 CIO patients for 1 year with risedronate 5 mg per day to prevent one vertebral fracture.

Although the fracture rate was not significant in most trials, the subpopulation of postmenopausal women experienced the greatest number of fractures and seemed to benefit the most from treatment. Two studies found borderline significance in the fracture rate when postmenopausal women were analyzed separately.^42,45 Etidronate and alendronate use led to an absolute risk reduction of 18.7% (P=.05) and 8.6% (P=.05), respectively. Men were the only other group to experience fractures in any of the studies. No fractures were reported in the premenopausal population.

When interpreting the results of these studies it is important to remember that trial results can vary according to a number of factors, including: definition of fracture, initial number of fractures, baseline BMD, and population differences. Therefore, the reported data should not be extrapolated to all populations. It should also be mentioned that all of the fracture data presented consisted of radiologically reported fractures, which does not necessarily correlate with clinical fractures.

Safety and Tolerability

The withdrawal rates of the included studies ranged from 0% to 62% ([Table 3]). Of the dropouts reported, 42% were secondary to protocol violations or administrative reasons, and 16% were because of noncompliance. Twenty percent of study withdrawals were because of adverse events, of which 78% (29/37) were deemed not related to the treatment regimen. No significant difference was reported in dropout rates between the treatment and control groups.

In most of the studies no statistical significance concerning adverse effects was found when the treatment group was compared with the control group. Nine studies^42-47,50,51 discussed the subgroup of gastrointestinal (GI) adverse events, since this has been the greatest historical concern about the use of bisphosphonates. Eight studies found no difference in overall GI effects, and one study⁴⁵ reported a statistical trend for increased GI side effects with dose escalation of alendronate. This trend was probably secondary to an increase in abdominal pain in the treatment group when compared with the placebo group. In one study,⁴⁶ diarrhea was more common in patients receiving 5 mg risedronate than those taking placebo (number needed to harm=15), although significance was not reported.

Discussion

The studies examining the use of bisphosphonates for the prevention or treatment of CIO are difficult to interpret because of the various bisphosphonates and regimens, the heterogenicity in populations, the effect of the underlying disease on bone, and concomitant therapeutic interventions. A review of the currently published literature suggests bisphosphonates effectively prevent vertebral bone loss in patients treated with long-term corticosteroids. Patients receiving steroids for more than 3 months (secondary prevention) gained bone mass when placed on a bisphosphonate, while patients naive to steroids (primary prevention) maintained more bone density than the control group.^{42-44,46,47,50,51,53} This reinforces the fact that patients taking steroids for more than 3 months have already lost bone that can be partially regained with bisphosphonate treatment. In contrast, patients given bisphosphonates who were naive to steroids did not have significant changes in BMD from baseline; this group, however, was able to maintain bone density while the control group lost bone density.

Data regarding the impact of bisphosphonates on the risk of CIO-induced fractures are sparse and inconclusive. This is not surprising since most of the trials have been of relatively short duration (<2 years), and have not been sufficiently powered to show fracture reduction. Postmenopausal women not taking estrogen seem to benefit most from using bisphosphonates for the prevention of bone loss and of vertebral fractures in CIO.

A meta-analysis of a similar set of data based on a Cochrane systematic review of published literature was reported in 1999.⁵⁵ The authors state that of the small number of controlled clinical trials examining the use of bone-sparing agents in patients at risk for CIO bisphosphonates have shown some of the best evidence for reducing bone loss, particularly at the lumbar spine. They also concluded that bone density changes correlate with fracture risk in patients with CIO, but there are insufficient data to make conclusions regarding fracture risk reduction and use of bisphosphonates.

Overall, adverse effects of the bisphosphonates were minimal, and no statistical significance was found in studied populations when compared with control groups. However, the incidence of GI adverse events with alendronate may be as high as 15% in clinical practice, despite low incidence rates in phase III trials, possibly because of administration errors.⁵⁶ Directions for use are the same for all oral bisphosphonates, and include staying upright and not eating for at least 30 minutes after administration. Because oral bioavailability is usually less than 5% even on an empty stomach, bisphosphonates should be taken with a full glass of water in the morning after an overnight fast.^11,56,57

Implications for further research

Although current evidence supporting bisphosphonate use documents efficacy in BMD changes and trends toward reduced vertebral fracture risk in the treatment of CIO, more research is clearly desirable. The recent FDA approval of alendronate and risedronate has highlighted the need for aggressive measures to prevent and treat CIO. More research is needed in large studies to assess vertebral and nonvertebral fractures. Head-to-head comparative trials of bisphosphonates with other pharmacologic options, such as hormonal therapy or calcitonin are essential to establish evidence-based clinical guidelines. Studies addressing combination therapy with bisphosphonates and HRT in postmenopausal women would also be useful. Finally, comparative studies of the various bisphosphonates in relation to one another are needed. These synthetic pyrophosphate analogs possess a broad range of potencies, selectivity, and adverse effect profiles. Because each bisphosphonate has unique biological, chemical, and physiochemical properties, the results of one bisphosphonate study cannot be extrapolated to other compounds within the same drug class.^3,56,58,59 Differences in study design, patient populations, and other confounding variables also prevent the assumption of a class effect with certain research findings. This distinction becomes especially important with the new bisphosphonates on the horizon (clodronate, tiludronate, ibandronate, and zoledronate).

Although the relationship of BMD to fracture risk is well documented in postmenopausal osteoporosis, the correlation is not as well established in glucocorticoid-induced bone loss.^2,60 The present data suggest a trend in the reduction of fracture risk observed with the use of bisphosphonates in the treatment of glucocorticoid-induced osteoporosis. This information is promising but requires definitive confirmation in larger trials. Because of the prolonged skeletal retention of bisphosphonates, more extended trials are also needed to clearly establish the safety of long-term therapy in younger patients.

Recommendations for clinical practice

All patients beginning high-dose (Ž7.5 mg/day prednisone) long-term (>6 months) glucocorticoid therapy should be evaluated for pharmacologic prophylaxis against osteoporosis. Because the majority of bone loss occurs within the first 6 months of therapy, clinicians must vigilantly develop a preventative plan in advance, preferably before the glucocorticoid prescription is given to the patient. Current guidelines recommend a baseline BMD measurement of all patients with DEXA to determine the risk of osteoporosis and the monitor the efficacy of the chosen preventative measures throughout the course of therapy. Initial BMD measurements expressed as a T score are essential tools for constructing an individualized strategy. Critical T scores of less than or equal to 1.0 are indicative of high-risk patients.¹⁸ In addition to the risk imposed on patients secondary to their underlying disease state, other patients with strong predictive factors include those who are elderly and at greater risk of falling and those who have a previous history of fractures.

BMD measurements may be repeated in 6 to 12 months, depending on initial bone mass. If BMD has decreased by more than 5% from baseline, the initial choice of therapy should be changed or expanded.^18,61

Both glucocorticoid doses and the length of therapy require continuous reevaluation to decrease the total cumulative dose. If possible, dose maximization of inhaled and topical corticosteroids is recommended before progression to the oral form. More obvious preventive lifestyle modifications include smoking cessation, maintenance of healthy body weight, regular weight-bearing exercise, decreased alcohol consumption, sodium restriction, and increased dietary calcium intake. Most patients will require additional calcium supplementation to meet the ACR recommendation of 1500 mg per day, and patients at risk for vitamin D deficiency may also require supplementation.¹⁸

However, even with appropriate supplementation 1 in 6 corticosteroid-treated patients will experience a radiographically detected vertebral fracture within 12 months.^46,47,54 Therefore, alternative treatment regimens are needed. Bisphosphonate therapy looks promising in the prevention and treatment of CIO with respect to positively affecting BMD. As a result of this encouraging data, alendronate and risedronate have received FDA approval for the indication of CIO. However, it remains to be seen whether the use of these agents can lead to a reduction in fractures, both vertebral and nonvertebral. Subpopulations at highest risk (postmenopausal women and men) may benefit most with regard to fracture risk reduction, but more data are needed before bisphosphonates should be routinely recommended as first-line preventive therapy. Once osteoporosis is established (regardless of the pathogenesis), treatment should be aggressive to prevent further loss of bone density. In this population bisphosphonates are an appropriate therapeutic option, and further data will clarify their impact on the risk of fractures.