Osteoporosis (OP) is a common chronic metabolic osteopathy associated with multiple factors, including menopause and aging (Ni et al., 2024; Zhang et al., 2020; Wu et al., 2022; Jiang et al., 2021). Its clinical features include reduced bone density, altered bone quality, and abnormalities in microstructure and biomechanics (Tao et al., 2022; Guo et al., 2022; Yang et al., 2024; Kong et al., 2023).

Given that the patient population has historically shown a significant female-to-male ratio, the core target population for research is postmenopausal women, and some of the developed drugs (such as raloxifene) are even restricted to use in women. Treatment options for elderly male patients are extremely limited, particularly due to the need for further clarification of BMD response differences across different anatomical sites and the lack of comprehensive safety data. However, with further research in recent years, in June 2020, the National Medical Products Administration approved denosumab for therapeutic interventions for osteoporosis in aged male population with significant fracture risk (SJ20200020). Osteoporosis is one of the most common skeletal diseases among elderly men (Gao et al., 2022; Zhang et al., 2023; Chen et al., 2024; Bandeira et al., 2022; Johnston and Dagar, 2020). Pharmacotherapy is indispensable for fracture prevention in osteoporotic geriatric males. Denosumab and zoledronic acid (ZA), as the two most commonly used therapeutic drugs at present, have attracted considerable attention in clinical application (Lin et al., 2024). Denosumab binds receptor activator of nuclear factor-κB ligand (RANKL) with high specificity, suppressing osteoclast development and viability to decrease bone resorption and elevate bone mineral density (Kawahara et al., 2021; Hanley et al., 2012). ZA is a potent bisphosphonate drug used in clinical practice. It suppresses osteoclast activity, lowers bone turnover, and consequently elevates bone density (Wang et al., 2020). In traditional treatment, ZA is widely used, and its effectiveness in improving bone density has been clinically validated to a certain extent (Sølling et al., 2021). However, ZA may cause some adverse reactions during use, such as flu-like symptoms, muscle pain, and back pain (Jin et al., 2024). In elderly men, whose physical functions are relatively weak, this may affect their tolerance to treatment. Denosumab, as a relatively new drug, has shown good efficacy in increasing bone density (McConnell et al., 2022). However, the long-term efficacy of denosumab and its effects on different skeletal sites in elderly males require further research and discussion. Efficacy comparisons between denosumab and ZA for geriatric male osteoporosis lack consensus. Some studies suggest that denosumab is superior to ZA in improving spinal BMD (McConnell et al., 2022); however, other studies indicate that when considering drug safety, long-term efficacy, and effects on the entire skeleton, it is difficult to simply compare the advantages and disadvantages of them (Yassin et al., 2020). Therefore, how to precisely select the most appropriate treatment drug based on the individual differences of elderly male osteoporosis patients has become an important challenge for clinicians.

A comparison of the efficacy and safety of denosumab and ZA in elderly male patients with osteoporosis during knee arthroplasty revealed significant differences in the improvement of bone mineral density (BMD) at different sites between the two drugs. The results of this study showed that denosumab was significantly superior to ZA in improving lumbar spine BMD (P = 0.037). This finding is consistent with the conclusions of several recent clinical studies (Tsourdi et al., 2020), as it specifically inhibits the RANKL signaling pathway, blocking osteoclast differentiation and activation. Its effects encompass both cortical and trabecular bone, particularly demonstrating significant inhibitory effects on bone resorption in the highly metabolically active spinal column. The notable effect of ZA on femoral neck BMD (P = 0.011) may be related to its preference for targeting high bone turnover regions (such as the trabecular bone of the femoral neck) (Reid et al., 2018; Bolland et al., 2025), which reduces bone resorption by inhibiting osteoclast function.

It is worth noting that the incidence of influenza-like symptoms in the ZA group was as high as 25% (P < 0.001), which may be associated with the activation of γδ-T cells by bisphosphonates to release pro-inflammatory factors such as IL-6 (Campisi et al., 2022; Shiraki et al., 2021). In contrast, denosumab, which does not directly act on the immune system, has a significantly lower incidence of adverse reactions (4.1%) and is more suitable for elderly patients (Cummings et al., 2009). Besides, denosumab alone significantly reduced 25-(OH)D levels. It is speculated that these changes in 25-(OH)D may be related to feedback regulation triggered by alterations in calcium metabolism, and may also involve dilution effects or redistribution of vitamin D. Additionally, although no cases of severe hypocalcemia were reported in the denosumab group, serum calcium levels were significantly elevated compared to baseline (P = 0.048), suggesting the need for individualized adjustment of calcium supplementation, particularly in patients with impaired renal function.

The findings of this study partially align with the previous finding that denosumab demonstrates greater efficacy in improving spinal BMD (McConnell et al., 2022). However, it was also observed that ZA exhibited more pronounced therapeutic effects on lower limb bones. Nevertheless, Miller noted that the long-term safety profiles of both drugs (e.g., osteonecrosis of the jaw, atypical fractures) require further validation (Yassin et al., 2020). The limitations of this study include: ① the single-center retrospective design may lead to selection bias; ② the follow-up period was short (only 1 year), making it difficult to assess long-term efficacy and rare adverse reactions; ③ the sample size was small (n = 89), resulting in insufficient power for subgroup analysis; ④ ZA administration protocol differs from standard clinical practice, which may may limit the direct applicability of results; ⑤ no specific adverse reactions were recorded, nor were their severity or intervention measures documented. Future studies should include multicenter, large-sample, long-term research, particularly focusing on efficacy differences in patients with chronic kidney disease or diabetes (Chen and Sambrook, 2011), to clarify the drug’s applicability across different populations. Future adequately powered randomized controlled trials with longer follow-up period are needed to validate the comparative effectiveness and safety of denosumab versus zoledronic acid in elderly male patients. Additionally, our modified zoledronic acid administration protocol may limit generalizability to settings using standard protocols, warranting further studies with standardized dosing regimens.

From a clinical practice perspective, this study suggests that drugs should be selected individually based on the patient’s fracture risk location: patients at high risk of lumbar spine fractures should prioritize denosumab, while those at higher risk of hip or femoral neck fractures may consider ZA. Additionally, enhancing medication adherence management is crucial. A meta-analysis noted that denosumab must be strictly administered every 6 months to prevent bone density rebound (Chen et al., 2025; Burckhardt et al., 2021), while 10-year follow-up data for ZA showed its hip protection effect persists for 5 years post-discontinuation (Black et al., 2012). For elderly patients with poor tolerance, denosumab may be more advantageous due to fewer adverse reactions. Future research may explore combination therapy regimens (e.g., denosumab combined with teriparatide) to synergistically improve whole-body bone density (Sun et al., 2022), while also incorporating pharmacoeconomic assessments to optimize treatment costs.

In conclusion, our study found that denosumab led to superior bone mineral density (BMD) improvements in the lumbar spine, and ZA showed greater BMD improvements at the hip. These findings suggest a differential impact on fracture risk reduction based on anatomical site, with denosumab potentially offering more protection for lumbar spine fractures and ZA for hip fractures. Though both agents significantly improved bone metabolic parameters, denosumab exhibited a more favorable safety profile in the clinical application.