In the U.S., statistics indicate that about 1.2% of the population uses glucocorticoids for prolonged durations, with a notably low frequency of antiosteoporotic medication use (1). Glucocorticoid-induced osteoporosis (GIOP) is a notable side effect of prolonged glucocorticoid therapy (2). This condition is characterized by a significant risk of bone loss, predominantly within the first few months of treatment (3). Studies have indicated that even low doses of prednisone or its equivalents, ranging from 2.5 to 7.5 mg daily, are associated with an increased risk of fractures (4). Therefore, GIOP requires aggressive management, especially in patients who are already at a higher risk for fractures, such as older individuals or those with a history of fragility fractures (3).

According to the 2022 guidelines of the American College of Rheumatology, it is recommended to assess fracture risk in patients aged 40 and over as soon as possible after starting a treatment with ≥2.5 mg/day of glucocorticoids (GC) for more than 3 months. This assessment should be done using the FRAX (Fracture Risk Assessment Tool) and by performing BMD testing using dual-energy x-ray absorptiometry (DXA) with vertebral fracture assessment (VFA) testing or spinal x-rays. The guidelines advise that all adult patients with medium, high, or very high fracture risk should be considered for osteoporosis therapy.

Bisphosphonates (BPs), widely used for managing osteoporosis and other bone diseases, work by inhibiting osteoclast activity, which are cells responsible for bone tissue breakdown (5). While they are a standard treatment for GIOP, oral BPs sometimes cause gastrointestinal side effects, such as esophageal irritation and ulceration, and have absorption issues (5). Although intravenous formulations can reduce gastrointestinal complications, intravenous BPs may present different side effects, including flu-like symptoms, fevers, myalgias, arthralgias, headaches, and also carry potential risks of atypical femoral fractures and osteonecrosis of the jaw (ONJ) (6). In comparison, teriparatide, another medication used for GIOP, has demonstrated better BMD improvements than BPs (7). However, its usage is generally restricted to no more than two years in a patient’s lifetime and necessitates frequent daily or weekly injections.

The challenge in treating GIOP arises from the effects of GCs on bone health. GCs increase the apoptosis of mature osteoblasts and osteocytes, leading to decreased bone formation and an impaired ability to respond to bone damage (8). They also extend the lifespan of osteoclasts by upregulating receptor activator of nuclear factor kappa-B ligand (RANKL) while suppressing osteoprotegerin (OPG) (8). Furthermore, GCs inhibit the Wnt signaling pathway—crucial for osteoblastogenesis—by increasing the expression of inhibitors like dickkopf-1 (Dkk-1) and sclerostin. This suppression results in reduced osteogenesis and poor bone regeneration (8).

Denosumab, a human monoclonal antibody, offers a more convenient option with biannual administration. It is effective in treating osteoporosis, bone loss from other diseases, bone metastases, and giant cell tumors of the bone (5). It functions as a RANKL inhibitor, preventing bone resorption by hindering the development of osteoclasts (5). In contrast, BPs primarily work by binding to bone to inhibit osteoclasts, acting more indirectly and relying on accumulation within the bone. In a murine model of GIOP, denosumab inhibited cortical bone loss without compromising biomechanical strength (9). This demonstrates its efficacy in preserving bone integrity under conditions that typically lead to significant bone loss (9).

Based on recent studies and systematic reviews, there is a growing body of evidence regarding the use of denosumab treating GIOP (10, 11). A 2022 systematic review and meta-analysis found that denosumab outperformed BPs in increasing lumbar spine BMD at 6 and 12 months, but both treatments showed similar improvements in total hip and femoral neck BMD (11). Additionally, while denosumab more effectively suppressed bone turnover markers like serum CTx (C-terminal telopeptide) and P1NP (procollagen type 1 amino-terminal propeptide), no significant differences in side effects, infections, or fractures were noted between the two treatments (11).

Based on the current evidence, we conducted an updated meta-analysis to explore the efficacy and safety of denosumab compared to BPs for GIOP. Furthermore, our analysis will include groups that have started using glucocorticoids for less than 3 months. A key focus of our study will also be on safety concerns, particularly the risk of infections. This is especially crucial since research indicates a higher risk of infection in postmenopausal women using denosumab, a concern that is magnified in populations with prolonged use of glucocorticoids. To ensure that our updated meta-analysis is reliable and clinically relevant, we employed the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) framework (12). This approach enables a systematic evaluation of the quality of evidence, providing transparency in how conclusions are derived. The GRADE methodology was selected because it helps balance the benefits and risks of interventions, particularly in populations with complex health conditions such as GIOP. Additionally, it supports the prioritization of outcomes that matter most to patients and clinicians, such as fracture prevention and infection risk.

Our meta-analysis offers critical insights into the efficacy and safety of denosumab in comparison to bisphosphonates, particularly in the context of pr GC therapy and long-term GC treatment. This analysis is especially pertinent given the diversity of patient groups, including those with prior bisphosphonate treatment, treatment-naive individuals. The marked improvement in BMD at the LS and TH with denosumab underscores its potential superiority over bisphosphonates, demonstrating notable effectiveness for both newly initiated and long-term GC users. This is of significant interest for patients initiating GC therapy, where early intervention is crucial for preventing GIOP. Although changes in BMD at the FN was less pronounced, they align with the trend favoring denosumab. Complementing our findings, the study by Geusens P et al. (24), although not included in our analysis, reveals similar trends in patients initiating GC therapy or on long-term GC therapy. Their study employed high-resolution peripheral quantitative computed tomography scans and found that denosumab was superior to risedronate in preventing failure load loss at the distal radius and tibia (24).

In terms of bone turnover markers, notably P1NP, CTx, and TRACP-5b, denosumab demonstrated a significant reduction compared to bisphosphonates. These findings are indicative of denosumab’s potent antiresorptive properties, essential in the early stages of GC therapy where bone turnover may be rapidly affected. In addition, changes BAP levels with denosumab versus BPs were not significant, contrasting with findings in postmenopausal women studies (25, 26). This warrants further investigation to understand these differing responses.

Regarding safety profiles, some studies have indicated that denosumab may increase the risk of infections (20, 27, 28). In populations undergoing long-term immunosuppressive therapy, the risk of infection is always a significant concern. Our study demonstrates that, in the GIOP population, denosumab has a similar safety profile to bisphosphonates, without increasing the risks of infection or fractures.

While our study confirms the efficacy and safety of denosumab, there are several limitations. Firstly, inherent methodological constraints, particularly non-uniform blinding protocols across included studies, necessitate a guarded interpretation of our outcomes. This lack of blinding introduces a potential for systematic bias, which is a common limitation in clinical trials, as noted in the literature. Secondly, the analysis revealed significant heterogeneity among the included studies, which may be attributed to variations in methodological designs. Differences in the types of BPs used, study durations, and patient demographics, such as comorbidities and the duration of GCs use, likely contributed to the observed inconsistencies. Although our leave-one-out sensitivity analysis underscored the stability of our results, the limited and selective pool of studies, particularly those of larger scale such as Saag KG et al., may skew the meta-analytical outcomes (19). Thirdly, the potential for publication bias remains a concern. The small number of included studies inherently limits the scope of our analysis and precludes comprehensive subgroup evaluations. This limitation constrains the extent to which our findings can be generalized across diverse clinical scenarios.

Fourthly, while our study included research with a maximum duration of 24 months, it’s important to consider the long-term implications of denosumab therapy. Research in postmenopausal women has demonstrated the efficacy and safety of denosumab over a 10-year period. This highlights a need for extended-duration studies to explore the long-term therapeutic outcomes and safety in patients with GIOP, including fracture risk. Moreover, the issue of discontinuation is crucial. As shown in the study by Saag KG et al., the focus was on rheumatoid arthritis patients receiving glucocorticoid treatment (29). The research found that upon discontinuation of denosumab, bone turnover markers and bone mineral density returned to baseline levels within a year (29). This emphasizes the need for ongoing bone health management in this specific patient group after stopping denosumab therapy. Lastly, although not directly addressed in this study, recent systematic reviews on cost-effectiveness analyses have indicated that most studies suggested denosumab is a cost-effective or superior option compared to oral bisphosphonates. This aspect is particularly important for future research in GIOP populations, especially regarding long-term use.

In conclusion, our findings suggest denosumab may be a more effective option than BPs for patients on long-term glucocorticoid therapy, with a comparable safety profile. However, given the limitations observed, further studies, particularly larger and more diverse clinical trials, are necessary to fully understand denosumab’s role in this patient population. Future research should also focus on the long-term implications of denosumab use, including strategies for safe discontinuation and cost-effectiveness analysis.