Osteoporosis is a common metabolic bone disease in the elderly, and its incidence continues to rise with the global aging population. Calcitonin analogs (including synthetic salmon, human, and porcine calcitonin preparations) are a classic treatment option for osteoporosis; however, the safety and efficacy of their long-term use remain controversial despite widespread application.
This study aims to systematically assess the safety and efficacy of long-term use of calcitonin analogs in the treatment of osteoporosis in the elderly through pharmacovigilance analysis and meta-analysis.
The study evaluated the long-term effectiveness and adverse effects of calcitonin analogs using pharmacovigilance data from the FAERS database and a meta-analysis of randomized controlled trials (RCTs). The pharmacovigilance analysis included adverse event data from osteoporosis patients aged 65 and older from 2004 to 2023, and signal detection was performed using the reporting odds ratio (ROR), proportional reporting ratio (PRR), and Bayesian confidence propagation neural network (BCPNN) methods. The meta-analysis included RCT studies related to calcitonin published after 2010, and a random-effects model was used to calculate the hazard ratio (HR) with a 95% confidence interval.
Pharmacovigilance analysis revealed that nasal discomfort (ROR = 283.4, PRR = 264.5, IC = 7.3, IC 025 = 6.8) and abnormal product odor (ROR = 206.2, PRR = 201.9, IC = 7.1, IC 025 = 6.1) were the most significant adverse reactions associated with calcitonin. Meta-analysis results showed no significant effect of calcitonin analogs in preventing new non-vertebral fractures and vertebral fractures (HR = 0.97, 95% CI: 0.76–1.24; HR = 0.93, 95% CI: 0.77–1.14). Changes in lumbar spine and femoral neck bone mineral density showed a slight upward trend but were not statistically significant. The analysis of NTx-1 levels (N-terminal telopeptide of type I collagen, a marker of bone resorption) revealed substantial heterogeneity, with significant variation in results across studies.
Long-term use of calcitonin analogs for the treatment of osteoporosis in the elderly does not confer additional benefits and instead increases the risk of adverse reactions.
Osteoporosis is one of the most common metabolic bone diseases in the elderly, characterized by reduced bone mass and deterioration of bone microarchitecture, leading to increased bone fragility and a significantly higher risk of fractures. With the intensifying trend of global population aging, the prevalence of osteoporosis continues to rise. Meta-analysis results indicate that the global prevalence of osteoporosis is 18.3% (95% CI 16.2–20.7), with a prevalence of 23.1% (95% CI 19.8–26.9) in women and 11.7% (95% CI 9.6–14.1) in men. Osteoporosis-related hip fractures result in an approximate mortality rate of 8% in men and 3% in women over the age of 50 4. Additionally, osteoporosis-related fractures impose a significant economic burden on society, costing approximately 17.9 billion USD annually in the United States and 4 billion GBP annually in the United Kingdom. Treatment strategies for osteoporosis are categorized into anabolic and catabolic approaches, each targeting different aspects of bone metabolism. Although a variety of treatment options exist, including bisphosphonates, selective estrogen receptor modulators (SERMs), calcitonin analogs, and bone formation promoters, the long-term safety and efficacy of these treatments remain a critical issue in clinical practice.
Calcitonin analogs have been widely recognized as a classic therapeutic option for osteoporosis since the 1980s. In a real-world study, calcitonin accounted for 90.5% of all anti-osteoporotic medications prescribed. Calcitonin reduces bone resorption by inhibiting osteoclast activity, thereby decreasing bone loss and playing a crucial role in preventing osteoporotic fractures. Systematic reviews have also shown that elcatonin, a form of calcitonin, can significantly reduce pain scores in patients with osteoporosis. However, in recent years, concerns have emerged regarding the potential risks associated with the long-term use of calcitonin, particularly its possible link to certain cancers, raising doubts about the safety of this treatment option. The 2023 edition of the China guideline for diagnosis and treatment of senile osteoporosis (2023) recommends using calcitonin analogs in elderly patients with osteoporosis to alleviate pain, prevent rapid bone loss, and promote fracture healing, with a suggested treatment duration of no more than 3 months. However, the level of evidence supporting this recommendation is relatively low (Grade 2C). Thus, significant uncertainty remains regarding the long-term efficacy and safety of calcitonin in fracture prevention, highlighting the need for a more systematic and rigorous evaluation of its long-term use. This study aims to comprehensively assess the safety and efficacy of long-term calcitonin use in the treatment of osteoporosis in the elderly by combining pharmacovigilance data from the FDA Adverse Event Reporting System (FAERS) and results from a meta-analysis. The integration of pharmacovigilance data from FAERS with meta-analysis provides complementary insights: real-world safety signals from spontaneous reports, and efficacy data from controlled trials. This approach allows for a more comprehensive understanding of the benefit-risk profile of calcitonin analogs.
This study consisted of pharmacovigilance analysis based on the FDA Adverse Event Reporting System (FAERS) database and a meta-analysis of randomized controlled trials (RCTs) aimed at comprehensively evaluating the safety and efficacy of long-term use of calcitonin analogs in the treatment of osteoporosis in the elderly.
The pharmacovigilance data were obtained from the FDA Adverse Event Reporting System (FAERS) and accessed via AERSMine, a validated online platform that provides curated FAERS data. AERSMine applies the FDA’s recommended de-duplication procedures, using Individual Safety Reports (ISRs), Case IDs, and version numbers to ensure unique case identification. We selected data from the first quarter of 2004 to the third quarter of 2023 and extracted pharmacovigilance information related to calcitonin analogs, including calcitonin (salmon synthetic), calcitonin (human synthetic), and calcitonin (pork natural). Only records in which these agents were designated as the primary suspect drug were included in the analysis.
For the meta-analysis, we systematically searched PubMed, Embase, and the Cochrane Library databases using the keywords “calcitonin” and “osteoporosis.” We included only RCT studies published after 2010. Studies published after 2010 were selected to ensure the inclusion of recent trials with improved methodological quality, standardized reporting of outcomes, and greater clinical relevance to current treatment practices.Studies were eligible if they: (1) included elderly or postmenopausal osteoporosis patients; (2) evaluated long-term calcitonin treatment (≥3 months); and (3) reported efficacy or safety outcomes of interest. Studies were excluded if they: (1) evaluated calcitonin use <3 months; (2) had a sample size <100 participants; (3) enrolled non-osteoporotic populations; (4) were non-RCTs; or (5) lacked sufficient outcome data or failed to meet methodological quality standards.
Data extraction and analysis from FAERS were performed using the AERSmine platform. The target population of this study consisted of osteoporosis patients aged 65 years and older. All relevant adverse event reports were extracted, and specific adverse events related to calcitonin with six or more cases were analyzed in detail. The drug keywords used included “calcitonin preparations,” “calcitonin (salmon synthetic),” “calcitonin (human synthetic),” and “calcitonin (pork natural),” with the drug role limited to “primary suspect.”
For the meta-analysis, two independent researchers extracted study characteristics (author, year, sample size, baseline demographics, intervention, comparator, and primary outcomes). Risk of bias was assessed using the Cochrane Risk of Bias Tool, version 1 (RoB 1.0), and disagreements were resolved by discussion or a third reviewer. Study heterogeneity was quantified using the I 2 statistic.
Data analysis was performed using R software (version 4.2.3). Three widely used disproportionality analysis methods—the Reporting Odds Ratio (ROR), the Proportional Reporting Ratio (PRR), and the Bayesian Confidence Propagation Neural Network (BCPNN)—were employed to quantify the strength of the association between calcitonin analogs and specific adverse events. For each adverse event signal, RORs and PRRs with 95% confidence intervals (CIs) were estimated, and the BCPNN model provided information component (IC) values along with their lower 95% credibility bounds (IC 025). A signal was considered positive when predefined criteria were met: for ROR, the lower limit of the 95% CI exceeded 1 with at least three cases (a ≥3); for PRR, values met the thresholds of PRR ≥2, a ≥3; and for BCPNN, IC 025 was greater than 0, a > 0. Here, “a” represents the number of reports of the target adverse event associated with the drug of interest. The detailed calculation formulas and thresholds used for signal detection are provided in Supplementary Tables S1, S2.
For the meta-analysis, pooled hazard ratio (HR) with 95% CIs were estimated using a random-effects model, and forest plots were generated to visualize the results.
This study is based on secondary data analysis of publicly available data and does not involve direct research on individual patients. All data were anonymized, so no ethics committee approval was required.
From the first quarter of 2004 to the third quarter of 2023, a total of 20,346,289 reports were submitted, of which 115,362 cases involved osteoporosis patients aged 65 and older. Among these, there were 1,333 reports of adverse reactions associated with calcitonin treatment, with 285 cases identified where calcitonin was the primary suspected drug. The majority of patients in these adverse reaction reports were female (93.7%). The primary reporters were physicians and consumers. Additionally, the highest number of cases was reported between 2004 and 2008, after which the number of reports gradually declined. Regarding patient outcomes, 10 cases (3.5%) resulted in death, and 70 cases (24.6%) involved hospitalization or prolonged hospital stays due to calcitonin-related adverse reactions.
Basic characteristics of adverse events primarily suspected to be associated with calcitonin therapy in the elderly with osteoporosis.
