Glucocorticoid-Induced Osteoporosis: Treatment Update and Review

Abstract

Glucocorticoid-induced osteoporosis (GIO) is a serious consequence of glucocorticoid therapy leading to fractures in 30—50% of patients. A wide range of protective medications have been studied in this condition including calcium, vitamin D, vitamin D analogs, oral and intravenous bisphosphonates, sex hormones, anabolic agents and calcitonin. The mechanism of action, and evidence for these therapies, are reviewed — focusing on important trials and new evidence. Recently published guidelines are also reviewed and compared. Bisphosphonates are currently the recommended first-line therapy for the prevention and treatment of GIO. They have been shown to increase bone mineral density (BMD) at the spine and hip and to decrease the incidence of vertebral fractures (especially in postmenopausal women). Testosterone therapy and female hormone replacement therapy (HRT) have been found to increase lumbar spine BMD in hypogonadal patients on glucocorticoid therapy, but effects on hip BMD have not been consistent and there is no fracture data in the GIO population. Similarly, calcitonin increases lumbar spine BMD but has no proven fracture efficacy. The effect of selective estrogen receptor modulators, the oral contraceptive pill and strontium on GIO is relatively unknown. Parathyroid hormone (PTH 1–34) and zoledronic acid have emerged as exciting new options for the treatment of GIO. Both therapies have been found to result in gains in BMD at the spine and hip that are either noninferior or superior to those seen with oral bisphosphonate therapy. PTH 1–34 has also been found to decrease the incidence of new vertebral fractures and may be an option in high-risk patients established on long-term glucocorticoid therapy.

Introduction

Epidemiology

Glucocorticoids are important therapeutic agents that have been used for their potent anti-inflammatory and immunosuppressive properties for over 50 years. According to a study performed in the UK, 0.9% of the general adult population is taking oral steroids at any given time and this proportion increases with age to 2.5% by age 70—79 years [van Staa et al. 2000a]. Glucocorticoid-induced osteoporosis (GIO) is the most prevalent form of secondary osteoporosis [Mazziotti et al. 2006]. Of the multiple side effects that can occur with glucocorticoid therapy, osteoporotic fractures are one of the most devastating, affecting 30—50% of patients [Angeli et al. 2006; Feldstein et al. 2005; Shaker and Lukert, 2005].

Despite the prevalence of glucocorticoid therapy and GIO, many patients on chronic steroid therapy do not receive bone mineral density (BMD) assessment or the recommended preventative therapy for osteoporosis [Guzman-Clark et al. 2007; Feldstein et al. 2005]. In a recent study of a large managed care population in the United States, Saag and colleagues found low rates of preventative interventions in individuals on long-term glucocorticoid therapy. Postmenopausal women were the most likely to receive recommended interventions, yet only approximately 50% were treated with anti-osteoporotic medication. 10—19% of postmenopausal women underwent bone mass measurements. This number dropped to < 6% in women under 50 years of age and in men. The study also found that rheumatologists were three to four times more likely to initiate the above interventions than internists or family practitioners [Saag et al. 2006]. Interventions aimed at improving physician management of GIO have largely been unsuccessful. When physicians were randomized to receive a web-based GIO intervention (including a personalized performance-audit and feedback) versus control intervention, there was no significant increase in BMD testing (19 versus 21%) or prescription of antiosteoporotic medications (32 versus 29%) in the year following the intervention [Curtis et al. 2007].

Pathophysiology

Glucocorticoids have a detrimental effect on bone formation, turnover and integrity. The primary action is on osteoblasts, decreasing replication and impairing differentiation and maturation, leading to decreased bone formation [Canalis et al. 2007; Ito et al. 2007]. Osteocytes are also affected, with decreased cell function and increased apoptosis resulting in impairment of their ability to detect and repair bone microdamage. Decreased numbers of viable osteocytes are found in iliac crest biopsies of patients on glucocorticoid treatment [Sambrook et al. 2003]. GIO also involves an element of increased bone resorption. In the early phase of glucocorticoid treatment, decreased bone formation coupled with increased resorption leads to rapid loss of bone integrity and significant fracture risk. Later in the course of treatment, however, resorption slows resulting in a state of chronic decreased bone turnover [Canalis et al. 2004]. During the early phase of therapy, high-dose steroids increase osteoclast generation. Osteoblast signaling is affected, causing reduced osteoprote-gerin (OPG) release and increased receptor activator of NF-KB ligand (RANKL), resulting in osteoclastogenesis [Sivagurunathan et al. 2005]. Other actions of glucocorticoids that negatively affect bone include decreased calcium absorption by the gastrointestinal tract and renal calcium loss. Steroid myopathy results in muscle weakness and therefore increased risk of falls and fractures [Canalis et al. 2007].

Fracture risk

Chronic glucocorticoid use therefore causes decreased bone remodeling and a state of low bone turnover. Trabecular bone loss, including vertebrae and the femoral neck, are usually the most significantly affected [Maricic and Gluck, 2004; van Staa et al. 2002]. There is a strong association between glucocorticoid dose, both daily and cumulative, and fracture risk; the greatest risk being during the first 3—6 months after steroids are initiated [van Staa et al. 2002]. Patients on oral glucocorticoid therapy have a relative rate of fracture, compared to matched controls, of 1.61 for hip fracture, 1.09 for forearm fracture and 2.6 for vertebral fracture [van Staa et al. 2002]. Fracture risk at a specific BMD is greater for patients on glucocorticoid therapy than the same BMD in a non-glucocor-ticoid-treated patient [Kanis et al. 2004], making it imperative that clinicians use different BMD thresholds for initiating osteoporosis treatments in these patients. The risk of fracture decreases after stopping glucocorticoid therapy. Similar to postmenopausal osteoporosis, vertebral fractures in GIO can be asymptomatic. One study found >37% of chronic glucocorticoid-treated patients had asymptomatic vertebral fractures with >14% having two or more [Angeli et al. 2006]. Although traditional risk factors for fracture (age, fall risk, BMI, gonadal status, physical activity, calcium intake and vitamin D levels [Johnell et al. 1995]) must be taken into consideration when assessing an individual patient for GIO, glucocorticoid use has been found to be an independent risk factor for fracture [van Staa et al. 2002].

Treatment studies

There are multiple challenges associated with treatment studies in the area of GIO. Most studies have been short term, using BMD as the primary endpoint. Fracture data and long-term outcomes are often lacking. The majority of studies have been performed predominantly in postmenopausal women, leaving the implications of treatments on men and premenopausal women less clear [Compston et al. 2008]. Studies are also complicated by the wide range of inflammatory conditions that lead to treatment with chronic glucocorticoid therapy. Many of these comorbid conditions themselves can lead to secondary osteoporosis, complicating the interpretation of study results further.

Despite these difficulties, treatment of this common and serious problem is of utmost importance. In this review, we discuss the various treatment options, focusing on new evidence and recent developments. We then discuss and compare selected recently published guidelines and recommend a treatment algorithm.

Treatment options

Vitamin D and calcium

Calcium and vitamin D are two nutrients essential for bone health [Gennari, 2001]. Adequate amounts of each nutrient are necessary to achieve optimal peak bone-mass and to decrease the rate of bone loss with age [Rodriguez-Martinez and Garcia-Cohen, 2002]. Vitamin D increases calcium absorption in the gastrointestinal tract as well as reabsorption in the distal renal tubules [Canalis et al. 2007]. Although sufficient calcium and vitamin D intake is a prerequisite for most current trials of osteoporosis medication, there have been multiple studies looking specifically at these agents used alone in GIO. Generally safe, patients receiving treatment with active vitamin D compounds should be monitored for hypercalcemia and hypercalcuria.

Calcium

Studies of calcium supplementation alone have had variable results. One study of 36 patients on steroids for chronic active hepatitis reported a decrease in loss of metacarpal bone with a microcrystalline hydroxyapatite compound given for 2 years versus placebo [Stellon et al. 1985], whereas other, more robust studies in premenopausal women with systemic lupus erythematosus (SLE) on glucocorticoid therapy have found that calcium (1200 mg/d and 500 mg twice daily) over 2 years preserves spine BMD, but does not increase it [Yeap et al. 2008; Lambrinoudaki et al. 2000]. There was a small decrease (0.93%, p < 0.001) in hip BMD over 2 years reported in one study [Yeap et al. 2008] but other studies have shown no significant change in hip BMD [Lambrinoudaki et al. 2000].

Vitamin D

Studies of calcium combined with vitamin D have also been variable. Trials including vitamin D 50 000IU given weekly with calcium 1000 mg/d [Adachi et al. 1996], and vitamin D 4000IU on alternative days with calcium 500 mg/d [Bijlsma et al. 1988] found no significant effect on BMD. However, a Cochrane database systematic review in 2000, that included 5 trials with 274 patients, found calcium combined with vitamin D improved vertebral and radial BMD in glucocorticoid patients with no significant effects on femoral BMD or fracture incidence [Homik et al. 2000b].

Vitamin D analogs

The literature suggests that vitamin D analogs [alfacalcidol 1-alpha(OH)D and calcitriol 1,25(OH)(2)D] may be more effective then native vitamin D in GIO [Richy et al. 2005]. In a 2004 meta-analysis, alfacalcidol and calcitriol were found to have the same efficacy in all outcomes. In five trials, when tested for maintaining spinal bone mass, they were found to have an effect size of 0.43 (p < 0.001). There was no significant reduction in fractures [Richy et al. 2004]. In a primary prevention study, 145 steroid-naïve patients about to start high-dose long-term steroid therapy were randomized to either 1 ug/day alfacalcidol or placebo. Alfacalcidol prevented bone loss at the lumbar spine at 12 months (increase in BMD of 0.39%, a decrease of 5.67% in the placebo group for a difference of 6.06% between groups, p = 0.02) [Reginster et al. 1999]. When used for secondary prevention in patients with established GIO alfacalcidol was found to be beneficial over native vitamin D 1000IU/d for lumbar spine BMD (increase of 2.0%, p < 0.0001) with no significant improvement in hip BMD or fractures [Ringe et al. 1999].

Calcitriol has also been shown to preserve or increase lumbar spine BMD when used as secondary prevention in premenopausal women with GIO over 2 years [Yeap et al. 2008; Lambrinoudaki et al. 2000]. As primary prevention, 0.5—1.0 μg/day of calcitriol plus calcium, with or without calcitonin, has been found to increase lumbar spine BMD by 4.3% versus calcium alone (p = 0.0035) [Sambrook et al. 1993]. However, in male and female asthma patients treated with regular inhaled and intermittent courses of oral steroids calcitriol was not found to be protective against bone loss [McDonald et al. 2006]. In a 2007 systemic review, no difference in vertebral fracture outcome was found for calcitriol versus other interventions or calcitriol versus placebo. Similarly, no significant decrease in nonvertebral fractures were found [Kanis et al. 2007].

Summary

Calcium and vitamin D have not been shown to protect against glucocorticoid-related fragility fractures. They are, however, important players when used as primary prevention to help prevent the bone loss seen with glucocorticoid use. As secondary prevention, they can maintain or increased lumbar spine and radial BMD, but they do not improve hip BMD.

Bisphosphonates

Bisphosphonates are potent inhibitors of bone resorption. The nitrogen-containing bisphosphonates (including alendronate, risedronate, ibandronate, and zoledronic acid) appear to work by inhibiting the osteoclast enzyme farnesyl pyrophosphate synthase (FPPS) which is important for osteoclast function [Russell et al. 2008]. A 2000 Cochrane database systemic review concluded that bisphosphonates are effective both for preventing and treating GIO; resulting in improved BMD at the lumbar spine and femoral neck. Although the review found a 24% reduction in the odds ratio for vertebral fracture, this result was not significant [Homik et al. 2000a]. A common side effect associated with bisphosphonate treatment, is gastrointestinal complaints although many studies find no increase in these complaints compared to the placebo group. A more serious (albeit very rare) complication is the association with osteonecrosis of the jaw [Ruggiero et al. 2009]. Bisphosphonates are retained in human bones for long periods and therefore their use in women of childbearing age is somewhat controversial. Animal studies have shown a negative effect on fetal skeleton, whereas the effect on the human fetus is relatively unknown. A recent literature review identified 51 cases of babies born to women using bisphos-phonates either before or during pregnancy, and found no reported fetal abnormalities [Djokanovic et al. 2008].

Etidronate

In 1997, the first randomized controlled trial (RCT) of bisphosphonate therapy in GIO was performed by Adachi and colleagues. There were 141 male and female patients who had recently begun high-dose glucocorticoid therapy, randomized to treatment with etidronate (400mg daily for 14 days followed by 500mg of calcium daily for 76 days; repeated for 4 cycles) versus placebo [Adachi et al. 1997]. Significant benefit was found in the etidronate group with a mean difference in BMD compared to the placebo group at 1 year of 3.72% at the lumbar spine (p = 0.02) and 4.14% at the trochanter (p = 0.02). No statistically significant differences in BMD were noted at the femoral neck or radius. Vertebral fracture benefit was evident in the etidronate group, especially in the subgroup of postmenopausal women in whom there was an 85% decrease in new vertebral fractures compared to the control group (p = 0.05); this group also had fewer vertebral fractures per patient (p = 0.04). A similar study in 1998 also found an increase of approximately 3% in lumbar spine BMD in etidronate-treated patients versus those receiving placebo [Roux et al. 1998].

However this study did not find a significant difference in hip BMD and was not adequately powered to comment on fracture incidence.

A 2000 review of pooled data found that etidronate, when used for prevention, produced an increased BMD at the spine of 3.7%, an increase at the femoral neck of 1.7% and an increase at the trochanter of 3.7%, compared with the BMD of placebo patients [Adachi et al. 2000]. A fracture benefit was present in postmenopausal women. When used as treatment, there was a pooled mean difference in lumbar spine BMD between etidronate-treated patients and placebo of 4.8% at the spine after one year and 5.4% after 2 years of therapy. A more recent 2007 systematic review identified 12 RCTs with reported fracture outcome in GIO etidronate studies [Kanis et al. 2007]. None of these studies showed significant vertebral or nonvertebral fracture outcomes; however, the review comments that none of the studies were adequately powered for fracture endpoints. The review did not look specifically at fracture outcomes in the subgroup of postmenopausal women in whom fracture benefit is described above.

Alendronate

Alendronate was studied in a 48-week RCT of 477 patients on glucocorticoid therapy for a variety of underlying conditions randomized to alendronate 5 or 10mg per day versus placebo [Saag et al. 1998]. All patients also received elemental calcium 800—1000 mg/d and vitamin D 250—500 IU/d. At 48 weeks, there were significant gains in spine BMD in the alendronate groups (increase of 2.1% in the 5mg group and 2.9% in the 10 mg group, p < 0.001) compared with the placebo group (BMD decrease 0.4%). Femoral neck BMD also improved (1.2 and 1%, respectively, versus a decrease of 1.2% in the placebo group, p < 0.01). There was no statistical difference in fracture rates but there was a trend toward fewer vertebral fractures in the alendronate groups. Gastrointestinal complaints, in particular abdominal pain, were the most commonly reported side effects. In a 12 month extension study, 208 patients (66 men and 142 women) from this trial were followed [Adachi et al. 2001]. Treatment advantages with alendronate were sustained with 2-year lumbar spine BMD increased by 2.8% (5 mg/d group) and 3.9% (10mg/d group) (p < 0.001) from baseline, versus a decrease of 0.8% in the placebo group. At 2 years, there was a significant increase in BMD at the trochanter (p < 0.05) but not at the femoral neck. Incidence of vertebral, but not nonvertebral, fractures did reach significance with vertebral fractures in 0.77% of the alendronate group versus 6.8% in placebo group (p = 0.026).

Alendronate (10mg/d) was found to be superior to alfacalcidol (1 μg/d) in a direct comparison RCT of female patients with rheumatic conditions starting glucocorticoid therapy [de Nijs et al. 2006]. At 18 months, there was a mean difference of change in lumbar spine BMD of 4% between the groups. There was also a trend towards fewer new vertebral deformities in the alendronate group, but these results were not statistically significant. Alendronate (10mg/day) was also studied versus alfacalcidol (1 (μg/day) in a RCT designed to assess changes in bone markers and associated changes in BMD in rheumatic patients recently initiated on glucocorticoid therapy [Jacobs et al. 2007]. After 18 months, markers of bone metabolism showed decreased bone resorption [measured by N-terminal telopeptide of type I collagen (NTx)] and decreased bone formation (measured by procollagen type IC-propeptide and osteocalcin) in the alendronate group. In contrast, the alfacalcidol group showed a decrease in markers of resorption and an increase in markers of formation. Despite the favorable bone metabolism picture suggested by these metabolic bone markers in the alfacalcidol group, lumbar spine BMD actually decreased in this group by 5.7% (p = 0.001), whereas it increased by 4.6% (p < 0.001) in the alendronate group. Changes in biochemical markers of bone turnover were not found to be correlated with changes in BMD, except for a negative correlation of total hip BMD with NTx. The study concluded that serial measures of bone turnover could not replace follow up with serial BMD as these measures did not correlate. Changes in serial BMD should be interpreted cautiously as both BMD and bone turnover markers are used as surrogates for fracture risk. Further study directly comparing changes in bone turnover markers with fracture outcomes in the setting of GIO are needed before firm conclusions can be made.

Alendronate has also been studied in patients with rheumatoid arthritis receiving chronic (≥3 months) low-dose (≤ 10 mg/d) prednisone. In this RCT, patients were randomized to receive placebo or alendronate (5 mg/day in premenopausal women and men or 10mg/d in postmenopausal women). At 12 months, BMD increased at the lumbar spine by 3.7% in the alendronate group, whereas the placebo group had a decrease in BMD of 1.07% (p < 0.0001). Bone turnover markers were also significantly lower in the alendronate group. There was no significant difference between the groups for changes in hip BMD or fracture rates. [Lems et al. 2006].

In premenopausal women with SLE, alendronate (70 mg qweekly) created an increase in lumbar spine BMD at 2 years of 2.69% (p < 0.001) and total hip BMD of 1.41% (p < 0.001) compared to similar patients on just calcium carbonate or calcium plus calcitriol [Yeap et al. 2008]. A recent study comparing alendronate (70 mg weekly) versus placebo in GIO found a difference in the mean per cent change from baseline BMD between the alendronate group and the placebo group to be 2.92% at the lumbar spine (p ≤ 0.001), 1.66% at the trochanter (p = 0.007), and 1.19% for total hip (p = 0.008) [Stoch et al. 2009]. The study was not powered to detect a difference in fragility fracture incidence.

Risedronate

A multicenter RCT of 224 men and women initiating long-term glucocorticoids was performed where patients were randomized to treatment with risedronate (2.5 or 5 mg) versus placebo. In this primary prevention study, all participants received 500 mg of elemental calcium per day. At 12 months the mean difference in BMD at the lumbar spine was 3.8% higher in the risedronate group versus placebo (p < 0.001) and 4.1% higher in the femoral neck (p < 0.001). Although there was no statistically significant reduction in fractures, there was a trend towards decreased vertebral fractures in the 5 mg risedronate group [Cohen et al. 1999]. In a study of secondary prevention, 290 men and women already on ≥ 6 months of high-dose steroid therapy were randomized to receive either risedronate 2.5 mg/d versus risedronate 5 mg/d versus placebo [Reid et al. 2000]. Everyone in the trial also received 1 g/day of calcium and 400 IU of vitamin D. After 12 months of therapy, overall, risedronate treatment significantly improved BMD at the spine (p < 0.001), femoral neck (p = 0.004) and trochanter (p = 0.010). In the risedronate 5 mg/d group, BMD increased by 2.9% at the lumbar spine, 1.8% at the femoral neck and 2.4% at the trochanter. The study found a 70% decreased risk of vertebral fractures in the combined risedronate group (p = 0.042). Similar results have been replicated in other studies [Wallach et al. 2000].

When studied specifically in men, risedronate has been found to be beneficial when used both as preventative therapy and in men on established glucocorticoid therapy of ≤ 6 months [Reid et al. 2001]. 5 mg/d of risedronate was shown to significantly prevent bone loss at all skeletal sights versus a placebo of calcium alone. 2.5 mg/d also had beneficial effects, but to a lesser degree than 5 mg/d. In men on established glucocorticoid therapy, 5 mg/d of risedronate increased BMD after 12 months in the spine (4.8%), femoral neck (2.1%) and trochanter (2.6%). An 82.4% decrease in vertebral fractures was found in men treated with risedronate (either dose) versus placebo.

Ibandronate

Intravenous (IV) ibandronate significantly decreased vertebral fractures compared to alfacalcidol in a 3-year open label parallel group study. In the study 115 patients with established GIO (BMD ≥ 2.5 at baseline) on long-term high-dose glucocorticoids were paired (based on similar baseline characteristics) and then assigned to receive 500 mg of calcium and either IV ibandronate 2mg every 3 months or 1 μg of alfacalcidol daily. After 3 years, lumbar spine BMD increased 13.3% in the ibandronate group versus 2.6% in the alfacalcidol group (p < 0.001), and hip BMD increased 5.2 versus 1.9% (p < 0.001). There were 8.6% of patients in the ibandronate group who experienced a new vertebral fracture compared with 22.8% in the alfacalcidol group (p = 0.043). There were no significant differences in side effects between groups and the ibandronate group experienced less back pain (p < 0.001) and height loss (p = 0.001) [Ringe et al. 2003].

Pamidronate

IV pamidronate has been shown to be of benefit in glucocorticoid-treated patients in a primary prevention RCT [Boutsen et al. 1997]. In this study, 27 patients were randomized to an initial dose of 90 mg of IV pamidronate followed by 30 mg every 3 months versus standard therapy with 800 mg/d of elemental calcium. At 12 months, lumbar spine BMD increased by 3.6% and hip BMD by 2.2% in the pamidronate group compared with a decreased BMD of 5.3% in the spine and femoral neck in the placebo group. When the above pamidronate regimen was compared in a trial with a single IV dose of 90 mg, with no further treatments, there was no significant difference in BMD benefit found between the two modes of administration [Boutsen et al. 2001]. A 2007 systematic review identified four open-labeled RCTs that commented on fracture risk with pamidronate therapy in GIO [Kanis et al. 2007]. Few fractures were present in the trials, and no statistically significant fracture benefit was identified.

Zoledronic acid

Zoledronic acid, 5 mg IV given once per year, has been shown to be an effective treatment for postmenopausal osteoporosis significantly reducing the incidence of vertebral, hip and nonvertebral fractures while preserving bone structure and not causing problems with adynamic bone [Recker et al. 2008].

A recent noninferiority, multicenter, double-blind, double-dummy RCT including 833 patients examined a single zoledronic acid 5mg IV infusion versus oral risedronate 5 mg daily for 12 months in GIO. Prevention (patients on steroids less then 3 months) and treatment arms were included in each group. After 12 months, zoledronic acid was found to be noninferior and superior to risedronate for increase of lumbar spine BMD in both the treatment (least-squares mean 4.06% [standard error (SE) 0.28] versus 2.71% [SE 0.28], mean difference 1.36% [95% confidence interval (CI) 0.67—2.05], p = 0.0001) and prevention (2.60% [0.45] versus 0.64% [0.46], 1.96% [1.04—2.88], p < 0.0001) subgroups at 12 months. Zoledronic acid also significantly increased BMD at the femoral neck compared with risedronate, in both the treatment (1.45% [0.31] versus 0.39% [0.30], mean difference 1.06% [95% CI 0.32—1.79]) and prevention (1.30% [0.45] versus —0.03% [0.46], mean difference 1.33% [95% CI 0.41—2.25]) subgroups. This study was designed as a noninferiority trial and therefore the magnitude of the effect of zoledronic acid versus placebo is unknown. There was no significant difference in new fractures between the zoledronic acid and risedronate groups. Adverse events were greater in the zoledronic acid group consisting mostly of flu-like symptoms experienced within the first 3 days of treatment [Reid et al. 2009].

Summary

Bisphosphonates are therefore effective agents to increase BMD at the spine and hip when used as primary prevention or as treatment in both men and women on long-term glucocorticoids. They have proven efficacy in reducing the incidence of vertebral fractures (especially in postmenopausal women) and are considered first-line therapy for the prevention and treatment of GIO.

Sex hormones

Prolonged glucocorticoid therapy may lead to hypogonadism by altering hypothalamic gonadotropin-releasing-hormone release, inhibiting pituitary release of gonadotropins, suppressing adrenal androgen production, and directly affecting ovarian and testicular hormone production [ACR, 2001; Eastell et al. 1998]. Both estrogens and androgens prevent osteoblast apoptosis and decrease osteoclastogenesis and are thought to be important in maintaining bone health [Clark and Khosla, 2008].

Hormone replacement therapy

In postmenopausal women, whether in the context of glucocorticoid use or not, hormone replacement therapy (HRT) reduces bone resorption leading to a protective effect on bones [Hall et al. 1995]. There are not many studies looking specifically at HRT in the context of glucocorticoid-induced bone loss. An RCT of postmenopausal women with rheumatoid arthritis randomized to treatment with transdermal estradiol (50 μg daily) or calcium (400mg daily) for 2 years was performed. The study included 42 women on glucocorticoid therapy. The glucocorticoid-treated patients receiving HRT had an increase in their lumbar spine BMD by a mean of 3.75% (versus 0.85% in the calcium group). Changes in hip BMD were not significant [Hall et al. 1994]. In another study, 28 young (aged 37±6 years) hypogonadal women with SLE and GIO were randomized to HRT or calcitriol. After 2 years, spine BMD increased by 2.0% in the HRT group versus a decrease of 1.74% in the calcitriol group (p < 0.05) [Kung et al. 1999]. In Lane's 1998 study comparing parathyroid hormone (PTH) plus HRT versus HRT alone in postmenopausal GIO, the HRT group showed no change in BMD at the lumbar spine, femur, or distal radius [Lane et al. 1998]. Since the Women's Health Initiative study was stopped early in 2002 because of increased risk of breast cancer and cardiovascular disease associated with the use of HRT, it is no longer routinely used as a first-line treatment of osteoporosis in postmenopausal women [Rossouw et al. 2002].

Testosterone

In men, hypogonadism is an important cause of secondary osteoporosis, and treatment with testosterone may lead to decreased bone resorption and an increase in bone mass [Kamel et al. 2001]. Hypogonadal men who are treated with testosterone to bring their serum testosterone level back into the normal range have increased BMD at the spine and hip [Snyder et al. 2000]. In a RCT where men on long-term glucocorticoid therapy were randomized to either testosterone (200 mg) versus nandrolone (200 mg) versus placebo given intramuscularly (IM) every 2 weeks for 12 months, the lumbar spine BMD increased significantly in the testosterone group (4.7%, p < 0.01). There was no significant change in BMD in the nandrolone group or in either group at the hip [Crawford et al. 2003]. In a smaller randomized crossover study, 15 men with low serum testosterone levels were given testosterone replacement or placebo. Lumbar spine BMD increased by 5% (p = 0.005) during the treatment phase [Reid et al. 1996]. Prostate cancer is a contraindication to testosterone use, and digital rectal exam as well as prostate-specific antigen must be followed regularly while on therapy.

Oral contraceptive pill

The effects of the oral contraceptive pill (OCP) on bone mass are controversial. One study found OCP use to be protective of BMD, with the duration of exposure being related to the degree of protection [Kleerekoper et al. 1991]. However, other studies have shown a negative relationship between a history of OCP use and BMD at both the spine and hip [Prior et al. 2001; Teegarden et al. 1995]. The effect of the OCP on GIO has not been studied.

Selective estrogen receptor modulators

Raloxifene, the selective estrogen receptor modulator (SERM) which has been best studied in postmenopausal osteoporosis, has been found, in that population, to increase BMD and decrease the rate of vertebral fractures while there has been no definitively demonstrated effect on nonvertebral fractures [Sambrook, 2005]. There have been no randomized trials to our knowledge looking at raloxifene in GIO. In a small study, 20 postmenopausal women with operable breast cancer were treated with glucocorticoid therapy as well as tamoxifen. At 24 months, these patients had BMD scores no different than a control group of similar cancer patients on tamoxifen with no steroid, indicating that tamoxifen may be beneficial in preserving BMD in the setting of glucocorticoids [Fentiman et al. 1992].

Summary

HRT and testosterone therapy have therefore been found to increase lumbar spine BMD in hypogonadal patients on glucocorticoid therapy. Effects on hip BMD have not been consistent and there is no fracture data in this population. The effect of SERMs or the OCP on GIO is relatively unknown.

Anabolic agents

Parathyroid hormone

Parathyroid hormone (PTH) works to increase bone mass and quality by directly stimulating osteoblastogenesis and prolonging osteoblast lifespan by inhibiting apoptosis [Jilka et al. 1999]. Glucocorticoid-treated rats show improved bone mineralization, mass, and increased bone formation when treated with PTH [Yao et al. 2008]. Teriparatide [recom-binant human PTH (1–34)] is the only anabolic agent currently approved by the FDA in the United States for treatment of osteoporosis in postmenopausal women and men with osteoporosis at high risk of fracture [Girotra et al. 2006]. In this population, it decreases the risk of both vertebral and nonvertebral fractures. There have been fewer studies in the GIO population, and no studies looking at PTH 1–84 in this population.

Teriparatide was studied in a 12-month RCT of 51 postmenopausal women on chronic steroid therapy who were also on HRT [Lane et al. 1998]. The women were randomized to subcutaneous PTH (25mg daily) plus estrogen versus estrogen alone. At 12 months, spinal BMD increased dramatically in the PTH group (11 versus 0% in the estrogen only group, p < 0.001). There was no significant difference in hip or forearm BMD changes between the two groups at 12 months, and no fracture data. In follow up, 12 months after PTH was discontinued, the BMD benefit at the spine on continued estrogen alone was maintained. In the group who had received PTH, there was a mean change in lumbar spine BMD, 24 months from baseline, of 12.6%. There was also improvement in total hip BMD (p<0.01) compared to the estrogen-only group noted at 24 months [Lane et al. 2000].

In 2007, Saag and colleagues published the first RCT directly comparing teriparatide to alendronate [Saag et al. 2007]. The study consisted of 428 patients, 80% women (the majority being postmenopausal) from 12 countries. After 18 months on either teriparatide 20 μg daily or alendronate 10mg daily, the teriparatide group had a greater increase in lumbar spine BMD (7.2 versus 3.4%, p< 0.001), and total hip BMD (3.8 versus 2.4%, p = 0.005). New vertebral fractures were less frequent in the teripara-tide group (0.6 versus 6.1%, p = 0.004) whereas there was no significant difference in nonverteb-ral fracture rate. There were no significant differences in reported adverse events between the two groups in this study, but side effects experienced in the teriparatide group included injection site reactions, gastrointestinal complaints, arthralgias, musculoskeletal complaints and high serum measurements of urate and calcium. The patients included in this study all had established osteoporosis with lower BMD and higher fracture rate than in many other trials looking at the GIO population. The results therefore cannot be generalized to a primary prevention population. However, this study shows, as secondary prevention in high-risk patients, teriparatide is more effective then alendronate.

In the non-GIO population, PTH 1–34 is recommended for 18 months of therapy followed by bisphosphonate therapy to maintain gains in BMD [Cosman, 2006]. The optimal duration of treatment with PTH 1–34in GIO is unknown.

Fluoride

Fluoride increases BMD by increasing bone mineral apposition with no creation of new trabeculae [Balena et al. 1998; Zerwekh et al. 1994]. Bone volume is increased but trabecular thickness is not, especially when fluoride is used in higher doses. At high doses it has been shown to impair osteoblast function [Balena et al. 1998].

Several small RCTs have been performed demonstrating favorable BMD results in patients with GIO. Increased BMD has been reported when fluoride is used as primary prevention alone versus placebo [Lems et al. 1997a], when it is used together with calcium and 25-hydroxy-vitamin D [Lippuner et al. 1996], and when it is used in combination with etidronate in patients with established GIO [Lems et al. 1997b]. Fluoride use is controversial and is not currently an approved osteoporosis treatment. There is concern that, despite increasing BMD, fluoride does not recreate normal boney architecture and quality and may result in increased skeletal fragility and fracture risk [Riggs et al. 1990]. A recent meta-analysis, not specifically looking at GIO, showed a lack of effect of fluoride on vertebral and nonvertebral fractures; with a trend towards increased fracture risk with increased dose of fluoride [Vestergaard et al. 2008]. Interestingly, in subgroup analysis, it was found that, at low doses (≤20 mg fluoride equivalents), fluoride is associated with a reduction in fracture risk [odds ratio (OR) = 0.28, 95% CI 0.09—0.87 for vertebral fractures and OR = 0.52, 95% CI 0.28—0.76 for nonvertebral fractures]. This association has not been looked at specifically in the GIO population.

Strontium

Strontium ranelate (SR) has proven efficacy in postmenopausal osteoporosis and is approved for its treatment. SR increases the replication of pre-osteoblast cells stimulating bone formation while decreasing osteoclast differentiation and activity [Tournis, 2007]. It has been shown to cause an increase in BMD that is associated with reduced fracture risk in postmenopausal osteoporosis [Bruyere et al. 2007]. Currently, there are no published studies that we know of examining SR specifically in the GIO population.

Summary

PTH is an exciting emerging therapy for GIO resulting in gains in BMD at the spine and hip that are superior to those seen with bisphosphonates. PTH also decreases the incidence of vertebral fractures in this population but has not yet been shown to decrease the incidence of nonvertebral fractures. Fluoride is not currently used because of concerns of increased fracture risk and strontium has not yet been studied in the GIO population.

Calcitonin

Calcitonin targets the most active osteoclasts and decreases their action, resulting in decreased bone resorption [Karsdal et al. 2008]. Multiple studies have assessed the effect of calcitonin, both intranasal and subcutaneous preparations, on GIO. A 2000 Cochrane database systemic review using 9 trials found calcitonin to be 3.2% more effective than placebo at increasing lumbar spine BMD during the first 12 months of treatment; however, this benefit was lost by 24 months. The improvement seemed to be most prominent when calcitonin was used in patients with established glucocorticoid use, rather than as primary prevention, and when administered subcutaneously. There was no improvement in femoral neck BMD or in the relative risk of vertebral or nonvertebral fractures [Cranney et al. 2000]. Another, more recent, systemic review found similar results with no effect on fracture risk for both vertebral and nonvertebral fractures [Kanis et al. 2007]. Side effects reported in trials include nausea and facial flushing.

Guidelines

Six recent clinical guidelines and recommendation summaries are presented in Table 1. Most of these recommendations were formulated based on systematic review of the literature. All of the guidelines, unless not specified, recommend BMD testing in patients on chronic glucocorticoid therapy. Most also recommend a screening BMD measurement in patients initiating glucocorticoid therapy that is expected to be long term. Whereas the Osteoporosis Society of Canada recommends adequate age-specific calcium and vitamin D to all individuals (not just those on glucocorticoid) for osteoporosis prevention, the American College of Rheumatology (ACR) and European League against Rheumatism make specific recommendations based on dose and duration of long-term glucocorticoid treatment. The ACR and Japanese Society for Bone and Mineral Research (JSBMR) recommend active vitamin D compounds as an alternative to native vitamin D (ACR) or as a second-line or adjunctive treatment for GIO (JSBMR). Bisphosphonates are consistently considered the first-line treatment for GIO, but the guidelines differ significantly with respect to who should be treated. Four of the six guidelines specifically recommend bisphosphonates as preventative therapy at the initiation of glucocorticoid treatment in certain groups including those with prior fragility fractures, older age [>65 years (Royal College of Physicians[RCP]) versus > 75yrs (National health Service, UK[NHS])], low BMD [< —1.5 (RCP) versus <—2.0 (NHS)] and treatment with ≥5 mg/d of prednisone-equivalent for ≥ 3 months (ACR). Recommendations for sex hormone replacement vary. The two guidelines that specifically address monitoring frequency in patients not on treatment with a bisphosphonate, recommend follow up of BMD every 6—12 months (JSBMR also recommends spinal X-rays). It is recommended that patients started on therapy have repeat BMD testing performed in 1—2 years.

Table 1.

Guidelines for glucocorticoid-induced osteoporosis.

Organization	American College of Rheumatology (ACR) [ACR, 2001]	Royal College of Physicians, UK (RCP) [RCP, 2002]	Osteoporosis Society of Canada [Brown and Josse, 2002]	Japanese Society for Bone and Mineral Research (JSBMR) [Nawata et al. 2005]	National Health Service, UK (NHS) [Kanis et al. 2007]	European League Against Rheumatism (EULAR) [Hoes et al. 2007]
Publication date	2001	2002	2002	2004	2007	2007
Evidence	Expert committee review of the literature	Systematic review with evidence grading	Systematic review with evidence grading	Based on two studies by the sub-committee and evidence from the literature	Systematic review and cost-effectiveness analysis	Systematic review with evidence grading and expert consensus
BMD testing	If GC planned for > 6 months. All patients on long-term GC	Not required for those starting on bisphosphonate, but everyone else should be tested	All patients on > 2.5 mg/d prednisone for > 3 months	If GC planned for ≥ 3 months and no prior fragility fractures	All patients < 75 years and with no prior fragility fracture	Not specified
Vitamin D and calcium	All patients initiating therapy [≥ 5 mg/d prednisone equivalent for ≥ 3 months]. All patients on longterm GC. Use 800 IU/d Vitamin D or active vitamin D	Adequate dietary calcium recommended. Use as adjunct with bisphosphonate therapy	All patients: 400 IU/d vitamin D if < 50 years, 800 IU/d if > 50 years. 1000 mg/d calcium for women < 50 years or men, 1500 mg/d for women > 50 years	Active vitamin D as second-line treatment agent. Active vitamin D with bisphosphonate in high-risk patients	Not specified	If on ≥7.5mg/d prednisone equivalent for > 3 months
Bisphosphonates: -patients warranting treatment	All patients at initiation of GC theraphy [≥ 5 mg/d prednisone equivalent for ≥3 months], and patients on longterm GC if T-score < −1.0. Alendronate or risedronate as first-line agents. Use caution in premepausal women	At initiation of GC theraphy if > 65 years, with prior fragility fracture, or BMD ≤ −1.5	Patients on > 7.5mg/d prednisone-equivalent for > 3 months, or 2.5mg/d−7.5mg/d for > 3 months and BMD ≤ 1.5. Alendronate, risedronate or etidronate for prevention or treatment	All patients with prior fragility fracture. All patients on ≥ 5 mg/d of prednisone-equivalent for ≥3 months for BMD <80% young adult mean	Patients with prior fragility fracture. All patients > 75 years. Patients withy BMD ≤ −2.0. Less stringent BMD cut-off if on higher-than-average dose of GC	Based on risk factors: low BMD female gender, older age, postmenopausal
Sex hormones	Replace if deficient or clinically indicated	Offer to hypogonadal patients	Not specified	Consider raloxifene in postmenopausal women if cannot tolerate bisphosphonate	Not specified	Not specified
Monitoring frequency	As often as every 6 months to follow if not on therapy. Annually if on therapy	No specific recommendation, may see effects of therapy in 1–2 years after starting	1–2 years after starting treatment	BMD and spinal X-rays every 6–12 mo to follow if not on therapy	Not specified	Not specified
Duration of treatment	Continue as long as receiving GC	Not specified	Not specified	Not specified	Not specified	Not specified

BMD, bone mineral density; GC, glucocorticoid.

Summary and recommendations

GIO and associated fractures remain an important consequence of glucocorticoid therapy. Although specific treatment guidelines vary, prevention should be considered and discussed in all patients when glucocorticoid treatment is initiated. For premenopausal women and men under the age of 50 years, fracture risk should be determined and treatment decisions based on this assessment. In postmenopausal women and older men, the risk of GIO and fractures is greater and the evidence demonstrating the benefit of preventative therapy is clear. In our opinion, these patients should be initiated on preventative therapy. Currently, guidelines recommend oral bisphosphonate therapy as first-line treatment, with adjuvant calcium and vitamin D. New evidence suggests greater BMD gains with zoledronic acid and PTH 1–34 and these therapies may therefore provide important options particularly in high-risk patients with established GIO. The studies of PTH 1–34 and zoledronic acid in GIO were not yet available when current treatment guidelines were created; therefore, future guidelines may recommend a more prominent role of these therapies. Given the potential for rapid bone loss with glucocorti-coid therapy, frequent monitoring is warranted while bearing in mind that BMD is a surrogate marker for fracture risk and patients on glucocor-ticoids fracture at higher BMD than other patients [Maricic and Gluck, 2004]. Once treatment is initiated, BMD should be monitored annually (expert opinion) to ensure compliance and efficacy. Further research is needed to define in an evidence-based manner the most efficient frequency of BMD monitoring and the optimal duration of treatment with bisphosphonates.