Efficacy and Safety of Anti-Osteoporotic Agents across CKD Stages: A Meta-Analysis of Randomized Clinical Trials

Osteoporosis, characterized by diminished bone density and heightened fracture susceptibility, poses a significant health burden, especially for individuals with chronic kidney disease (CKD) [1‒3]. CKD disrupts mineral and bone metabolism, exacerbating fracture risks and complicating osteoporosis management [4, 5]. In addressing these challenges, various anti-osteoporotic agents, including teriparatide, denosumab, romosozumab, raloxifene, risedronate, and alendronate have been utilized to maintain bone health in individuals with CKD [6, 7]. With distinct mechanisms of action, these medications play specific roles in the osteoporosis management [8‒11]. Despite ongoing investigations into their comparative efficacy in reducing vertebral fractures across different stages of the CKD [12‒14], there remains a critical need for understanding the significance of stages 4 and 5. Although some studies exist, data on the strengths and limitations of each intervention for managing osteoporosis in different stages of CKD are limited, especially for those with severe CKD [15, 16]. This systematic review and meta-analysis are designed to comprehensively evaluate and compare the effectiveness of osteoporosis treatments in individuals with different stages of CKD.

We conducted a comprehensive search in the PubMed/MEDLINE, EMBASE, and Cochrane CENTRAL databases to find studies available up to June 15, 2024. These studies focused on the efficacy and safety of osteoporosis treatments in patients with CKD. The search strategy included terms such as “osteoporosis,” “chronic kidney disease,” “randomized controlled trial,” and relevant synonyms and MeSH terms (details in online suppl. Table; for all online suppl. material, see https://doi.org/10.1159/000540235). Only studies published in English were considered. This review adhered to the PRISMA guidelines (registration: PROSPERO ID: CRD42023484553) [17].

The criteria for selecting studies were based on the PICO framework:

• Participants: studies involving patients diagnosed with CKD.

• Interventions: investigations into osteoporosis treatments.

• Comparisons: comparisons between patients receiving treatment and those given a placebo.

• Outcomes: primary outcomes were the risk of vertebral fractures, BMD, and adverse effects.

Two reviewers, T.S. and M.J.N., conducted a thorough assessment of the records and any disagreements were resolved by a third reviewer (P.D.).

A structured data extraction form was collaboratively developed by two reviewers (T.S. and M.J.N.), who independently extracted data from the included studies. Discrepancies were resolved by consensus. Extracted information included the study design, number and characteristics of CKD patients, intervention details, outcomes, and adverse effects.

The quality of the included studies was evaluated by two reviewers (T.S. and M.J.N.) using the Cochrane risk of bias tool [18]. If there were disagreements, a third reviewer (P.D.) was involved to reach a consensus. The assessment criteria covered allocation concealment, blinding of participants and personnel, selective reporting, random sequence generation, blinding of outcome, completeness of outcome, and other potential biases. Studies were classified as having a low, high, or unclear risk of bias.

Pooled odds ratios (ORs) with 95% confidence intervals (CIs) were calculated. Heterogeneity among the studies was assessed using the I² statistic and p value [18]. For low heterogeneity (I² ≤50% or p ≥ 0.1), a fixed-effect model was used. For high heterogeneity (I² >50% or p < 0.1), a random-effects model was applied. Cochran’s Q test and the I² statistic were used to evaluate inter-study heterogeneity. Publication bias was assessed using Begg’s test, with a p value of less than 0.05 indicating significant bias. Statistical analyses were performed using CMA software, version 3.0 (Biostat Inc., Englewood, NJ, USA).

Figure 1 depicts the flow diagram of the systematic review process. This comprehensive review identified a total of 12 records, encompassing 31,027 patients that satisfied the specified eligibility criteria.

Table 1 outlines the characteristics of studies conducted over various years, examining the effects of anti-osteoporotic interventions in populations with varied stages of CKD, with three specifically focusing on patients with stage 5 CKD. CKD classification was derived from the data provided in the included studies.

The studies span multiple countries, including the USA, Japan, Iran, Australia, and Venezuela. Notably, interventions such as Romosozumab, Risedronate, Denosumab, Raloxifene, Alendronate, and Teriparatide were assessed against respective placebos, with sample sizes ranging from 31 to 7,808 participants. The mean age of the study population was 68 years, and the follow-up durations ranged from 8 to 18 months.

The assessment of risk of bias across the included studies revealed an acceptable level of methodological rigor (Table 2). Most studies, including those conducted by Miller (2022), Sugimoto, Iseri, Shigematsu, Jamal (2011), Toussaint, Jamal (2007), Miller (2007), Wetmore, and Hernández, exhibit generally low risk across these criteria. However, the study by Haghverdi stands out due to a high risk of bias in allocation concealment and blinding of participants, which may influence the overall reliability of its findings.

Pooling of trials demonstrated a significantly lower risk for vertebral fractures with anti-osteoporotic agents (teriparatide, denosumab, romosozumab, raloxifene) compared to placebo (pooled OR, 0.28 [95% CI, 0.22–0.36], I²: 0.00) (Fig. 2). Subsequently, we stratified our analysis by comparing anti-osteoporotic agents with placebo in terms of CKD stages. For stages 1–3, trials indicated a significantly lower risk for vertebral fractures with anti-osteoporotic agents compared to placebo (pooled OR, 0.28 [95% CI, 0.22–0.36]).

However, for stages 4 and 5, there was no significant reduction in the risk of vertebral fractures with anti-osteoporotic agents compared to placebo (pooled OR, 0.33 [95% CI, 0.05–2.17]). The effectiveness and associated statistics for four different anti-osteoporotic interventions are presented in Figure 3. Teriparatide, denosumab, and romosozumab show statistically significant effectiveness in reducing the risk of a vertebral fracture, as reflected by their low p values, while raloxifene, with a p value of 0.49, does not exhibit a statistically significant effect.

In studies comparing raloxifene to placebo in postmenopausal women with varying CKD severity, no significant differences in lumbar spine and femoral neck BMD were observed. The impact of risedronate and alendronate on lumbar spine, femoral neck, and total hip BMD could not be conclusively determined due to a high risk of bias and inconsistent results. Similarly, conclusive findings regarding the effects of teriparatide and denosumab on BMD compared to placebo could not be established due to a high risk of bias.

In contrast, the least-square mean percent change from baseline BMD in the romosozumab groups was significantly greater compared to controls across all kidney function categories. It is important to note that this analysis was based on data extracted from the included studies, and we only systematically reported them without conducting meta-analysis due to limited data availability.

The investigations into cardiovascular adverse events found no statistically significant differences in the rates of stroke, heart failure, and hypertension between the interventions and the placebo. The analysis of renal adverse events showed no significant differences in the estimated glomerular filtration rate for anti-osteoporosis drugs. Similarly, there were no statistically significant differences observed in the occurrence of gastrointestinal adverse events. None of the trials provided information on hyperphosphatemia, hypophosphatemia, and hypersensitivity reactions. Notably, none of the trials reported any side effects in patients with CKD stages 4 and 5. The safety analysis was solely based on data from the included studies, which we systematically presented without conducting meta-analysis due to limitations in data availability.

The primary finding of the analysis underscores a substantially lower risk of vertebral fractures with anti-osteoporotic agents compared to placebo in stages 1–3. However, in stages 4 and 5, there was no significant reduction in the risk of vertebral fractures with anti-osteoporotic agents compared to placebo, suggesting a necessity for further studies to investigate this specific population.

When comparing our results with the study by Wilson et al. [18], our findings align, demonstrating a statistically significant reduction in vertebral Fracture risk for medications in CKD patients. Notably, Wilson et al. did not stratify the analysis based on different stages of CKD, emphasizing the importance of considering severe stages. Furthermore, while Wilson et al. provided insights into the impact of raloxifene, teriparatide, and denosumab on vertebral fractures, they lacked specific information about romosozumab. In our data, romosozumab exhibited a significant result in reducing vertebral fracture risk in CKD patients. Indeed, this comparison underscores the complexities involved in interpreting findings and highlights the imperative need for additional research to deepen our understanding of the efficacy of these medications in CKD populations, particularly those in severe stages.

The clinical implications of this analysis are noteworthy, indicating a significant reduction in the risk of vertebral fractures with anti-osteoporotic agents compared to placebo in Stages 1–3 of CKD. This finding emphasizes the potential benefit of anti-osteoporotic medications in preserving bone health in early to moderate CKD stages. However, the absence of a significant reduction in vertebral fracture risk in stages 4 and 5 suggests a critical need for further studies to comprehensively assess the efficacy of these agents in individuals with advanced CKD. Clinicians should consider these findings when formulating osteoporosis management strategies, and tailoring interventions based on the CKD stage to ensure optimal outcomes for their patients [31‒33].

This study holds several notable strengths. By pooling data from various trials, the study provides a robust assessment of the overall risk reduction associated with these medications. The stratification of results based on CKD stages enhances the specificity of findings, offering valuable insights into the varying effectiveness of anti-osteoporotic agents at different disease severity levels. Additionally, the study’s identification of a significant reduction in vertebral fracture risk in stages 1–3 underscores the potential clinical benefit in early to moderate CKD, contributing valuable information for clinicians in tailoring osteoporosis management strategies. The acknowledgment of the need for further research in stages 4 and 5 reflects the study’s commitment to thorough investigation and the advancement of knowledge in this specific population.

While our study provides valuable insights, it is important to acknowledge some inherent limitations. Pooling data from trials involving drugs with different mechanisms of action, without considering bone turnover, further complicates the interpretation of our findings and may impact the accuracy of our conclusions regarding the efficacy of osteoporosis treatment in CKD. The nature of the research design introduces potential confounding factors, which may limit our ability to establish definitive causal relationships between medication use and outcomes. Moreover, the varying durations of follow-up across different studies could contribute to heterogeneity, potentially impacting the overall consistency of our results. Additionally, the lack of detailed patient-level data and information on concurrent medications presents a challenge for conducting a more nuanced and granular analysis.

In summary, this analysis highlights the effectiveness of anti-osteoporotic agents in lowering vertebral fracture risk in CKD patients, particularly in stages 1–3. However, this benefit is not apparent in stages 4 and 5, necessitating further research. Despite the absence of reported side effects in CKD patients, clinicians should carefully assess the suitability of these medications, considering individual risks and benefits.

Ethical approval and consent were not required as this study was based on publicly available data.

The authors have no conflicts of interest to declare.

The research did not receive any funding.

All authors (Tahereh Sabaghian, Parisa Delkash, Maryam Rahmannia, Amir Hashem Shahidi Bonjar, Rosella Centis, Lia D’Ambrosio, Giovanni Sotgiu, Mohammad Javad Nasiri, and Giovanni Battista Migliori) contributed equally to this work.

The data used to support the findings of this study are included in the article. Further inquiries can be directed to the corresponding author.