Introduction

Osteoporosis is a highly prevalent disease, particularly in individuals over 50 years old, and represents a significant global healthcare burden. In countries such as the United Kingdom, osteoporosis-related hip fractures have alarmingly high mortality rates, reaching up to 30% within the first year after the injury. Despite advances in treatment and screening, population aging is expected to increase the incidence of these fractures, highlighting the urgency of implementing effective care models and evaluating new therapeutic strategies, particularly for preventable forms such as glucocorticoid-induced osteoporosis. This specific type of osteoporosis results from prolonged glucocorticoid use, which disrupts bone homeostasis, significantly increasing the risk of fractures in patients of all ages, regardless of other risk factors (1-2).

The management of glucocorticoid-induced osteoporosis involves both timely diagnosis and the implementation of effective pharmacological therapies. These include bisphosphonates such as alendronate and zoledronate, alternative therapies such as denosumab, and advanced options such as teriparatide for refractory cases (3). However, while systematic reviews exist for specific treatments, they are limited in scope, addressing only specific research questions and failing to comprehensively cover all aspects of the disease. Given this gap in the literature, a scoping review can map the available evidence, identify knowledge gaps, and provide a broader and more comprehensive perspective on the subject.

In this context, conducting a scoping review that integrates evidence on the effectiveness, safety, and adverse events associated with the available pharmacological therapies for glucocorticoid-induced osteoporosis is crucial. This review aims not only to describe the efficacy of these treatments but also to characterize the available evidence across different patient populations, therapies, and underlying causes of the disease. The findings of this review will provide a solid foundation for improving therapeutic decision-making and promoting the development of future research in this field.

Methodology

This review followed the recommendations provided in the Joanna Briggs Institute (JBI) protocol for scoping reviews (4).

• Population: Patients over 18 years old diagnosed with glucocorticoid-induced osteoporosis, with or without fractures, who received various pharmacological therapies for osteoporosis.

• Concept: Efficacy (positive outcomes under controlled conditions), effectiveness (positive outcomes in real-world conditions), and safety (adverse event profile) of therapies, including bisphosphonates, monoclonal antibodies and RANK ligand inhibitors, pyridine derivatives, estradiol derivatives and estrogen receptor antagonists, synthetic analogs of parathyroid hormone-related protein, and anti-sclerostin agents.

• Context: Patients in hospitalization, emergency, and outpatient settings worldwide, across diverse cultures and genders.

Results

The initial search across various databases and registries identified 4.590 studies. During the screening stage, 1.614 studies were removed as duplicates, leaving 2.976 studies. These were further assessed based on their title and abstract, resulting in the exclusion of 2.719 studies. Thus, 257 studies remained for full-text evaluation. Of these, 217 studies were excluded for the following reasons: 11 due to duplication, 15 for being case series, 11 for being narrative reviews, 83 for addressing primary osteoporosis, and 97 for addressing secondary osteoporosis caused by other conditions. Ultimately, 40 studies were included: 39 assessed efficacy, of which 12 also evaluated safety, and 1 focused on real-world effectiveness. For better clarity, the results of the search and selection process are presented in a PRISMA flow diagram (figure 1).

The data were then classified based on three key criteria: efficacy, effectiveness, and safety of treatments for glucocorticoid-induced osteoporosis (GIOP).

Of the 39 studies that assessed the efficacy of pharmacological therapies for glucocorticoid-induced osteoporosis, most were randomized controlled trials (RCTs) conducted under optimal conditions, controlling for external variables and using comparators such as placebo or standard treatment. Bisphosphonate therapy was found to be highly effective in this context. Reid et al. (6) reported that risedronate significantly increased bone mineral density (BMD) and reduced the incidence of vertebral fractures. However, Hoes et al. (7) found no significant differences between alendronate and alfacalcidol in fracture reduction, although 24% of patients developed new vertebral fractures.

On the other hand, Eastell et al. demonstrated that teriparatide was more effective than alendronate in promoting bone formation in these patients (8), a finding also supported by Payer et al. (9), who reported significant increases in BMD with teriparatide.

Similarly, Struys et al. (10) and Ringe et al. (11) confirmed that etidronate and ibandronate, respectively, increased BMD compared to other treatments. In addition, Devogelaer et al. (12) reported that zoledronate led to greater reductions in bone turnover markers compared to risedronate, while Kasayama et al. (13) demonstrated that alendronate significantly improved BMD in asthmatic patients compared to alfacalcidol. In a combination therapy approach, Lems et al. (14) found that the co-administration of etidronate and sodium fluoride improved bone mineral density (BMD). Similarly, Fuji et al. (15) and Kikuchi et al. documented that risedronate and the combination of bisphosphonates with vitamin D3, respectively, increased BMD in patients with chronic kidney disease and glomerular diseases (16). Likewise, Lane et al. (17) and Farahmand et al. (18) reported that parathyroid hormone (PTH 1-34) improved BMD and vertebral strength, respectively, in patients receiving glucocorticoid treatment.

Additionally, Thomas et al. (19) observed significant reductions in vertebral and non-vertebral fractures with alendronate and risedronate, a finding supported by Li et al. (20), who reported improvements in BMD with ibandronate in women with systemic lupus erythematosus.

Figure 1. : PRISMA flow diagram of selected studies SC: CaseSeries; RN: Narrative Reviews; OP: Primary Osteoporosis; OS: Secondary Osteoporosis.

Source: Own elaboration.

Stoch et al. (21) and Buxton et al. reinforced these findings, demonstrating that alendronate increased BMD and that PTH therapy enhanced bone formation (22). However, Nordborg et al. found no significant differences between clodronate and calcium in BMD among patients with giant cell arteritis (23). In contrast, Losada et al. demonstrated that teriparatide was more effective than alendronate in increasing BMD in Hispanic patients with glucocorticoid-induced osteoporosis (24).

Switching from bisphosphonates to denosumab or teriparatide was beneficial for improving BMD, according to Ebina et al. (25). Meanwhile, Braith et al. demonstrated that the combination of alendronate and exercise restored BMD in post-transplant patients (26).

Sambrook et al. also indicated that alendronate was superior to calcitriol and vitamin D in preventing bone loss (27). Additionally, Saag et al. (2007) and Saag et al. (2019) confirmed that teriparatide and denosumab, respectively, were more effective than alendronate and risedronate in increasing BMD and reducing vertebral fractures (28-29).

In 2009, Saag et al. found that zoledronic acid was more effective than risedronate in preventing bone loss, while in 2016, they showed that teriparatide improved trabecular bone scores more than alendronate (30-31).

Finally, Roux et al., Rehman et al., Devogelaer et al., and Liu et al. concluded that zoledronate, parathyroid hormone, and teriparatide, respectively, were effective in improving BMD and reducing fracture risk in patients with glucocorticoid-induced osteoporosis (GIOP) (32-35). Hirooka et al. found that switching to teriparatide significantly increased BMD in the lumbar spine and femoral neck at 12 months (36-37).

On the other hand, Inoue et al. demonstrated that multidetector computed tomography (MDCT) enabled more precise detection of bisphosphonate efficacy in glucocorticoid-induced osteoporosis. This method showed significant improvements in bone volume fraction (BV/TV, p = 0.004) and trabecular separation (Tb.Sp, p = 0.015). In contrast, conventional methods such as DEXA and bone turnover markers failed to identify significant differences between treatments (p > 0.05), highlighting the advantage of MDCT in assessing bone microarchitecture (38).

Similarly, Soen et al. compared the efficacy of minodronate combined with alfacalcidol versus alfacalcidol alone for the treatment of glucocorticoid-induced osteoporosis. In this randomized study, after 24 months, patients who received the combination therapy showed a significant increase in lumbar spine BMD (4.0% vs. -0.2% in the alfacalcidol-only group, p = 0.0003) and total hip BMD (3.2% vs. -3.0%, p < 0.0001). Additionally, a significant reduction in bone turnover markers was observed in the combination group, with a 57% decrease in TRACP-5b at 3 months, which remained stable up to 24 months (39).

Similarly, Iseri et al. (40) conducted a randomized trial showing that, after 12 months, denosumab treatment significantly increased lumbar spine BMD by 5.3%, compared to a 2.0% increase in the alendronate group (p < 0.05). Moreover, denosumab reduced bone turnover markers more effectively than alendronate. While both treatments were effective in reducing these markers, denosumab resulted in greater suppression (40).

Similarly, Jinnouchi et al. evaluated a one-year of treatment regimen with etidronate and vitamin D3 in 25 patients. The results showed that the combination group had a significant improvement in bone mineral levels (YAM, p < 0.05) and a reduction in bone resorption compared to the group treated with vitamin D3 alone. Additionally, the combination group had a lower incidence of new vertebral compression fractures, suggesting that etidronate is effective in preventing bone loss and fractures in these patients (41).

Kanis et al. evaluated clinical studies and cost analyses for the treatment of glucocorticoid-induced osteoporosis, focusing primarily on the prevention of vertebral and non-vertebral fractures. This analysis highlighted that both risedronate and calcidiol showed significant efficacy in reducing vertebral fractures. Additionally, risedronate was assessed in terms of cost-effectiveness in patients with risk factors, such as advanced age and a history of fractures.

The study also proposed a treatment algorithm based on bone mineral density (BMD) and individual risk factors (42).

Finally, Langdahl et al. analyzed the efficacy of teriparatide versus alendronate in treating GIOP in patients of different genders and menopausal statuses. After 18 months, the results showed that teriparatide significantly increased lumbar spine BMD compared to alendronate in postmenopausal women (7.8% vs. 3.7%, p < 0.001), premenopausal women (7.0% vs. 0.7%, p < 0.001), and men (7.3% vs. 3.7%, p = 0.03). Additionally, a lower incidence of vertebral fractures was observed in the teriparatide group (1 case) compared to the alendronate group (10 cases), further emphasizing the superior efficacy of teriparatide in increasing BMD and reducing fractures in patients with glucocorticoid-induced osteoporosis (43).

Table 1 summarizes the articles related to the efficacy of therapies for glucocorticoid-induced osteoporosis

After reviewing the efficacy of pharmacological therapies in the treatment of glucocorticoid-induced osteoporosis, it is equally important to analyze their effectiveness in clinical practice.

Karras et al. conducted an observational study to evaluate the effectiveness of teriparatide in postmenopausal women with severe osteoporosis undergoing glucocorticoid treatment over a 36-month period. This prospective cohort study allowed for the observation of changes in fracture incidence and patient quality of life in a routine clinical setting. To analyze the results, the authors used a logistic regression model with repeated measures to examine changes in fracture risk over time. Compared to the first six months of treatment, fracture risk decreased by 81% between 24 and 30 months and by 89% between 30 and 36 months (p < 0.05). Additionally, reductions in lumbar pain were assessed using a mixed-effects repeated measures model, adjusted for variables such as baseline pain levels and fracture history. Throughout the study, patients reported an improvement in their health-related quality of life (HRQOL), measured using the EQ-5D scale (a standardized instrument for assessing five dimensions of health-related quality of life), with benefits persisting even after discontinuing teriparatide (44). The effectiveness findings are summarized in table 2.

Safety is also a fundamental aspect when evaluating pharmacological therapies used for the treatment of glucocorticoid-induced osteoporosis. Since these patients often require long-term treatment, it is crucial that medications are not only effective but also have a favorable safety profile. The studies we identified in this review assessed both efficacy and safety parameters. In total, five studies were reviewed. Below, we summarize the main findings, highlighting improvements in bone mineral density, reductions in fracture incidence, adverse effects, and treatment tolerability across different clinical contexts. Safety and efficacy outcomes of the included studies are summarized in table 3.

First, Cauza et al. evaluated intravenous pamidronate every three months in postmenopausal women and patients with GIOP. The treatment resulted in a significant increase in lumbar spine BMD in the postmenopausal group (p < 0.0001); however, in the GIOP group, no significant changes were observed in this region (p = 0.724). Nevertheless, an improvement in BMD at Ward’s triangle was recorded in the GIOP group (p = 0.0029). In terms of safety, pamidronate was well tolerated, with no serious adverse events. However, minor side effects such as abdominal pain, headache, and mild liver abnormalities were reported, suggesting a generally favorable safety profile, though caution is advised for patients with a history of gastrointestinal or liver conditions (45).

On the other hand, Tanaka et al., in the TOWER-GO study, compared weekly teriparatide with weekly alendronate in Japanese patients with GIOP. After 72 weeks, both treatments significantly increased lumbar spine BMD (teriparatide: 5.09% and alendronate: 4.04%; both p < 0.05), although teriparatide showed greater increases in bone formation markers. Regarding safety, both groups reported side effects such as nausea, muscle pain, and flu-like symptoms, but there were no significant differences in the frequency or severity of these events between the groups, indicating that both treatments were safe and well tolerated (46).

Fujieda et al., in the RISOTTO study, investigated risedronate in patients with GIOP and rheumatoid arthritis. The results showed a 3.49% increase in lumbar spine BMD in the risedronate group, compared to 0.12% in the placebo group (p < 0.0001). In terms of safety, 28 patients experienced adverse events, none of which were severe. The most common side effects were mild gastrointestinal discomfort and abdominal pain, which are characteristic of bisphosphonates. Additionally, 10 non-traumatic vertebral fractures were reported, highlighting the need for close monitoring of bone response in these patients (47).

Kitazaki et al. compared alendronate with alfacalcidol in patients with GIOP and ulcerative colitis. At the end of the study, alendronate showed a significant increase in lumbar spine BMD and a reduction in bone resorption markers, while both treatments were well tolerated. However, as a bisphosphonate, alendronate has a safety profile that requires particular attention in patients with a history of gastrointestinal conditions due to its potential to cause esophageal irritation. No serious adverse events were reported in this study, nor were treatments discontinued due to side effects, suggesting adequate safety in patients with comorbidities (48).

On the other hand, Glüer et al., in the EuroGIOPs study, compared daily teriparatide with weekly risedronate in men. Both treatments had comparable safety profiles, although 10.6% of patients in the risedronate group experienced new clinical fractures, while none of those in the teriparatide group experienced such events. Overall, no significant serious adverse events were reported, and both treatments were well tolerated (49).

Similarly, Allen et al. conducted a meta-analysis of 27 clinical trials with 3.075 participants, in which bisphosphonates showed no significant differences in the rate of serious adverse events compared to the control group. In the bisphosphonate group, the incidence of serious events was 14.7% (136 out of 892), compared to 16.2% (131 out of 811) in the control group, with an absolute risk difference of 0% (95% CI: -2% to +2%). The rate of treatment withdrawal due to adverse effects was 7.7% in the bisphosphonate group versus 7.3% in the control group, with a difference of +0.4% (95% CI: -1% to+3%). The most common adverse effects included gastrointestinal discomfort and flu-like symptoms, both considered mild (50).

Similarly, in the HORIZON study, Reid et al. compared zoledronic acid and risedronate over one year in 833 patients. Zoledronic acid caused a higher incidence of transient effects (fever and myalgia) within the first three days post-infusion, affecting 27.7% of patients (115 out of 416) compared to12% (50 out of 417) in the risedronate group. Serious events were rare in both groups, including worsening of rheumatoid arthritis in the treatment group and persistent fever in the prevention group. Regarding renal function, potential increases in creatinine were monitored in the zoledronic acid group, but no clinically significant changes were found (51).

In another study, Nanki et al. found that weekly teriparatide was superior to continuous bisphosphonates in patients with GIOP. Teriparatide significantly increased lumbar spine BMD by 4.7% versus 0.8% with bisphosphonates (p = 0.014) and also reduced the incidence of new fractures (17.6% vs. 22.7%). However, the teriparatide group reported more adverse effects (42.9% vs. 9.5%), including nausea, headache, and fatigue (52).

Ringe et al. evaluated ibandronate compared to alfacalcidol, highlighting that ibandronate was well tolerated and had a lower incidence of hypercalcemia or hypercalciuria (1.9% vs. 7.6%). Only one patient in the ibandronate group discontinued treatment due to a mild adverse event (11).

Meanwhile, Campbell et al. analyzed etidronate and calcium in asthmatic patients undergoing glucocorticoid treatment. Etidronate increased lumbar spine BMD by 4.1% (p = 0.001) and reduced fractures in postmenopausal women (OR 0.39, 95% CI 0.14-0.99). Regarding safety, the combination of etidronate with calcium increased gastrointestinal side effects (53). In another study in 2009, Campbell et al. compared hormone replacement therapy (HRT) with etidronate in postmenopausal women with asthma. Both treatments increased BMD by approximately 1% annually; however, 50% of patients with X-rays developed asymptomatic fractures, limiting their effectiveness in fracture prevention (54).

Finally, Sato et al. evaluated etidronate in Japanese patients with connective tissue diseases, showing a 4.8% increase in lumbar spine BMD at 144 weeks (p < 0.005), with no new vertebral fractures and minimal adverse effects, highlighting its safety profile (55).

In summary, the reviewed studies indicate that bisphosphonates, teriparatide, and etidronate are effective and generally well-tolerated treatments for glucocorticoid-induced osteoporosis, with acceptable safety profiles. Each treatment has specific adverse effects, with gastrointestinal symptoms being more common with bisphosphonates, while transient effects such as fever and flu-like symptoms are observed with teriparatide and zoledronic acid. Although some treatments, such as teriparatide, may be associated with transient side effects, including post-infusion fever or hypercalcemia, most adverse events are not severe. This reinforces the long-term safety of these treatments for managing GIOP.

In summary, bisphosphonates (risedronate, alendronate, and zoledronate), teriparatide, and denosumab are effective treatments for increasing bone mineral density and reducing fracture risk in patients with glucocorticoid-induced osteoporosis. Teriparatide stands out for its superior ability to promote bone formation and reduce vertebral fractures, while bisphosphonates and denosumab significantly lower the risk of non-vertebral fractures. The reviewed therapies have an acceptable safety profile, with mostly mild adverse events. However, it is crucial to consider each patient's individual profile to optimize treatment and minimize risks.

Discussion

Glucocorticoid-induced osteoporosis (GIOP) is a common complication in patients undergoing long-term corticosteroid treatment, typically at doses of ≥5 mg/day for more than 3 months. This condition is associated with a significant loss of bone mineral density (BMD) and an increased risk of fractures, particularly vertebral and hip fractures, which are the most prevalent fracture types in this form of secondary osteoporosis.

This scoping review evaluated the efficacy, effectiveness, and safety of the different available therapies for the treatment of glucocorticoid-induced osteoporosis. Among the most effective treatments are bisphosphonates (risedronate and alendronate) and anabolic agents such as teriparatide, which have demonstrated a significant increase in BMD and a reduction in the risk of both vertebral and non-vertebral fractures.

The reviewed evidence shows a consensus on the use of bisphosphonates as a first-line therapy for fracture prevention in patients with GIOP. In the study by Reid et al., risedronate (5 mg/day) increased lumbar spine BMD by 4.8% and femoral neck BMD by 2.1%, with an 82.4% reduction in the risk of vertebral fractures (6). However, while bisphosphonates remain a cornerstone as a drug class, the clinical use of risedronate has declined in several countries in recent years. In contrast, alendronate and intravenous zoledronic acid continue to be widely used due to their efficacy, dosing convenience, and improved treatment adherence, particularly in patients with contraindications to oral therapy.

This finding is consistent with other studies, such as that by Sambrook et al., which reported a significant increase in lumbar spine BMD with alendronate. Both studies agree that bisphosphonates are effective in preventing vertebral fractures and, to a lesser extent, non-vertebral fractures (including hip and trochanteric fractures) (56).

However, in the clinical trial by Hoes et al., no significant differences were observed in the reduction of new fractures between alendronate and alfacalcidol, suggesting that treatment response may vary depending on the patient's risk profile (7).

Regarding anabolic agents, studies such as Eastell et al. showed that teriparatide (20 μg/day) was superior to alendronate in improving BMD and restoring bone formation, particularly in patients with GIOP, who experience greater suppression of bone-forming activity (8). In addition, zoledronic acid deserves specific mention, as evidence from randomized trials (e.g., HORIZON) demonstrates superior or non-inferior improvements in BMD compared with those achieved by oral bisphosphonates, with an acceptable safety profile, making it a valuable option in routine clinical practice.

This study reported a 9.8% increase in lumbar spine BMD and a greater reduction in vertebral fractures. Devogelaer et al. also supported the efficacy of teriparatide; however, their analysis found that the glucocorticoid dose influenced treatment response, suggesting that higher corticosteroid doses (>15 mg/day of prednisone) could reduce the effectiveness of BMD improvement. Additionally, safety concerns regarding teriparatide have been raised due to a higher incidence of mild adverse events, such as nausea and fatigue, although serious adverse effects are generally not reported (12).

Limitations and strengths

Although anti-sclerostin agents such as romosozumab were considered within the conceptual framework of this scoping review, no studies meeting the inclusion criteria were identified specifically for glucocorticoid-induced osteoporosis. This highlights an important evidence gap and the need for future clinical research in this area.

Several limitations were identified in this review, including the heterogeneity of studies in terms of glucocorticoid dose and treatment duration, as well as variability in the studied populations. Differences in inclusion criteria may have influenced comparisons of efficacy and effectiveness outcomes across treatments. Moreover, some studies were not specifically designed to assess fracture prevention, which limits the interpretation of data related to this key clinical outcome. On the other hand, one of the main strengths of this review is the inclusion of recent studies that analyze not only changes in BMD but also bone turnover markers as predictors of therapeutic response, allowing for a more comprehensive approach to evaluating treatment efficacy and safety.

The findings of this review suggest that bisphosphonates, particularly risedronate and alendronate, remain the first-line therapies for preventing vertebral and non-vertebral fractures (mainly hip and trochanteric fractures) in patients with GIOP. However, in patients at higher fracture risk or those with greater suppression of bone formation, teriparatide should be considered a superior therapeutic option. In terms of effectiveness, anabolic agents have been shown to be more effective in improving bone quality, although their use must be weighed against potential adverse effects and the high cost of treatment. Future research should focus on the long-term evaluation of the safety of these treatments, as well as cost-effectiveness studies to assess the incorporation of anabolic agents into the standard treatment of GIOP, given their high cost.

In our review, we identified a notable limitation in the available studies regarding adverse events associated with different drugs used in GIOP. Although some studies mention adverse effects, few delve into the most significant ones or assess their impact on overall patient health. This is concerning, as adverse events can not only limit treatment adherence but also increase the burden of comorbidities in an already vulnerable population.

Conclusion

Glucocorticoid-induced osteoporosis (GIOP) is a treatable complication. Bisphosphonates as a class remain effective options for preventing vertebral and non-vertebral fractures; however, in current clinical practice, alendronate and intravenous zoledronic acid are more commonly used than risedronate in many settings. Anabolic agents, such as teriparatide, represent a valuable alternative for patients at higher fracture risk or with severe suppression of bone formation. Evidence regarding anti-sclerostin therapies (e.g., romosozumab) in GIOP is limited, underscoring the need for future studies to clarify their role. An individualized approach that balances efficacy, safety, availability, and cost-effectiveness is essential.

Author’s contribution

Gloria Ibis Tirado Romero: Conceptualization, methodology, investigation, data curation, formal analysis, writing - original draft, and project administration; Juan Felipe Alvarado: Screening, data extraction, validation, and writing - review & editing; Stefany Daniela Mesa Orduz: Investigation and writing - review & editing; Syndi Katherine Guarín Rivera: Data curation, visualization, and resources; Zeyany Vanessa Guerrero Flórez: Supervision, validation, and writing - review & editing.

Ethical statement

The authors declare that this study is a scoping review based exclusively on previously published literature. Therefore, no procedures involving humans or animals were conducted, and no identifiable personal data were used. Accordingly, neither ethics committee approval nor informed consent was required. All studies included in this review had already obtained the corresponding ethical approvals in their original publications.

Conflict of interest

The authors declare no conflicts of interest.

Funding statement

This research received no specific funding from agencies in the public, commercial, or not-for-profit sectors.

Use of artificial intelligence (AI)

Artificial intelligence tools were used solely to support language improvement and English style revision during the writing and editing process of the manuscript. The authors were responsible for the conception of the study, literature search and analysis, interpretation of results, and final drafting of the manuscript. Artificial intelligence did not participate in data analysis or in the generation of scientific results.

Data statement

This study is a scoping review based on previously published literature; therefore, no new datasets were generated. The data used were sourced from studies available in scientific databases and can be accessed through the references cited in the manuscript.