Osteoporosis persists as a notable public health issue, characterized by diminished bone density and integrity, thereby heightening susceptibility to fractures (Khosla and Hofbauer, 2017; Reid and Billington, 2022). With the global population aging, the prevalence of osteoporosis is on the rise. Fragility fractures, a primary sequel of osteoporosis, substantially contribute to morbidity, mortality, and healthcare expenditures (Sànchez-Riera and Wilson, 2017).

A spectrum of pharmacotherapeutic modalities exists for managing osteoporosis, including bisphosphonates, denosumab, raloxifene, calcitonin, and teriparatide (Arceo-Mendoza and Camacho, 2021). Pharmacological interventions predominantly encompass antiresorptive agents, impeding bone resorption, and anabolic medications, stimulating bone formation (Reid, 2020). Teriparatide, an anabolic agent, received approval from the U.S. Food and Drug Administration (FDA) in 2002 for treating osteoporosis in high-risk patients (Hodsman et al., 2005; Blick et al., 2008). Operating as a recombinant human parathyroid hormone fragment (rhPTH1-34), teriparatide fosters osteoblastic activity, thereby facilitating bone formation (Blick et al., 2009). Pivotal clinical trials have underscored teriparatide’s efficacy in augmenting bone mineral density and mitigating fracture occurrence (Lindsay et al., 2016; Oswald et al., 2019; Chiba et al., 2022).

While clinical trials have elucidated common adverse events such as nausea, dizziness, limb pain, and headaches, ongoing post-market surveillance assumes paramount significance owing to teriparatide’s widespread usage (Brixen et al., 2004). The drug label incorporates cautions concerning severe adverse effects like osteosarcoma, hypotension, hypercalcemia, and urolithiasis. Given the intricacies of adverse event reporting and the potential for underreporting in clinical trials, real-world data repositories like the FDA Adverse Event Reporting System (FAERS) assume a pivotal role (Dhodapkar et al., 2022). Harnessing FAERS facilitates researchers in comprehensively analyzing post-approval safety data, offering insights into teriparatide’s indications and associated adverse events in actual clinical scenarios. By delineating teriparatide’s safety profile through FAERS scrutiny, this investigation aims to enlighten and optimize clinical decision-making regarding its utilization, ultimately enhancing patient care and safety in osteoporosis management.

Studies have shown that subcutaneous teriparatide 20 mg/day is effective in women with postmenopausal osteoporosis, men with idiopathic or hypogonadal osteoporosis and patients with glucocorticoid-induced osteoporosis (Gallagher et al., 2006; Blick et al., 2008; Sethi et al., 2008). And it has been approved by the Food and Drug Administration and the European Medicine Agency for the clinical treatment of osteoporosis and bone destruction caused by glucocorticoids (Minisola et al., 2019; Johnston and Dagar, 2020; Hauser et al., 2021).

The distribution of teriparatide data and the frequency of signals extracted from the FAERS database in this study are consistent with the information provided in the FDA label and instructions. Our comprehensive analysis revealed that the overwhelming majority (89.58%) of AERs associated with teriparatide involved female patients, which should be associated with the higher incidence of postmenopausal osteoporosis in women (Shane et al., 2022). Excluding cases with unknown age data (43.57%), our findings underscored a notable predominance of AEs among patients aged 45 years and older (44.79%), in accordance with the typical epidemiology of osteoporosis. Furthermore, a significant observation emerged regarding the origin of these reports, with the majority emanating from consumers rather than healthcare professionals, indicative of potential underreporting from medical sources, thus emphasizing the imperative for heightened vigilance among healthcare providers in monitoring patients for serious adverse reactions.

The extensive real - world dataset pertaining to teriparatide from FAERS revealed compelling insights. For example, the subset analysis of reports by health - professionals showed that the top signals at the SOC level included musculoskeletal and connective tissue disorders, injury/poisoning/procedural complications, and ear and labyrinth disorders. At the PTs level, notable signals were detected for osteocalcin increased, X-ray of pelvis and hip abnormal, and chondroma. Additionally, the subset analysis of individuals aged 45 and older revealed that the most frequent systems at the SOC level were musculoskeletal and connective tissue disorders, general disorders and administration site conditions, and injury/poisoning/procedural complications. At the PTs level, significant signals were observed for osteocalcin increased, growing pains, and urine calcium increased. These findings not only corroborate teriparatide’s known mechanisms of action but also align with its approved indications for osteoporosis treatment.

Furthermore, employing disproportionality analysis, our study unveiled the potential involvement of various organs or tissues in teriparatide-related adverse events, with gastrointestinal manifestations such as nausea and vomiting emerging as frequent occurrences during teriparatide therapy. Notably, the most prevalent adverse events identified in our study included pain in extremity (n = 8,094), muscle spasms (n = 5,524), fractures, and musculoskeletal pain, consistent with the well-documented effects of teriparatide on bone and muscle physiology. Additionally, the detection of significant signals such as increased blood calcium (n = 1988), elevated heart rate (n = 1981), and heightened urine calcium (n = 83), mirrors the warnings outlined in the teriparatide label. Elevated blood calcium and hypercalcemia or hypercalciuria are relatively common occurrences following teriparatide therapy, resolving immediately upon treatment cessation (Karatoprak et al., 2012; Hajime et al., 2014). Persistent hypercalcemia in patients receiving calcium supplements warrants consideration of teriparatide’s influence (Rossini et al., 2016). Injection site reactions such as streaking and dermatitis were also discerned, aligning with the anticipated effects of subcutaneous drug administration. Of particular significance, our analysis identified disproportionate signals indicative of bone fissure (n = 40), medial tibial stress syndrome (n = 34), enchondromatosis (n = 7), and fear of falling (n = 68), thereby echoing the postmarketing experience of fragility fractures and the risk of falls associated with teriparatide use in real-world settings.

Significantly, although the teriparatide label includes warnings regarding the potential risk of osteosarcoma, our analysis revealed disproportionate signals suggestive of several benign or malignant neoplasms, including osteoma cutis (n = 4) and enchondromatosis (n = 7). Osteosarcoma is the most common non-haematological primary bone malignancy characterised by the production of bone matrix by tumour cells (Rojas et al., 2021). Despite the relatively small case numbers, these findings underscore the importance of sustained vigilance and further investigation into the long-term tumorigenic effects of teriparatide, given its anabolic mechanism of action. While the occurrence of osteosarcoma has not been observed in humans receiving teriparatide treatment at rates different from those in the general population, but in carcinogenicity studies with rats, near lifetime treatment with systemic exposure ranging from 3 to 60 times the exposure in humans was associated with osteosarcoma in rats (Vahle et al., 2002; Vahle et al., 2004; Khan et al., 2017). Therefore, teriparatide’s labeling still includes warnings to physicians and patients about potential tumor risks.

Furthermore, our study unveiled 35 unexpected and significant disproportionate signals that are not currently reported on the teriparatide label, encompassing sensory disturbances (n = 103), growing pains (n = 70), increased waist circumference (n = 21), tinnitus (n = 65), reduced visual acuity (n = 54), urethral carbuncle (n = 4) and acquired bladder malposition (n = 3), among others. The elucidation of the mechanisms and clinical significance underlying these potential associations necessitates meticulous investigation to comprehensively delineate the safety profile of teriparatide in real-world settings.

While our findings largely align with existing safety information, the identification of several unexpected and significant adverse events underscores the imperative for enhanced scrutiny and ongoing research. These revelations serve as a pivotal reference for future investigations and regulatory initiatives aimed at ensuring the safe and efficacious utilization of teriparatide in clinical practice.

This study, employing the FAERS database for teriparatide analysis, effectively addresses the limitations of small clinical study samples and short observation periods, thus providing real-world outcomes post-drug market approval. However, several limitations persist:① FAERS is a voluntary reporting system prone to data bias and underreporting, making it challenging to control confounding factors. Consequently, deeper descriptive and comparative analyses are hindered. Furthermore, the system does not provide total teriparatide user counts, precluding epidemiological analysis and accurate estimation of adverse event occurrence rates post-medication use.② Voluntary reporting extends beyond healthcare professionals, potentially leading to inaccurate drug-ADE associations from non-professional sources.③The PTs often correspond to those already noted in the drug label, diluting signals for off-label and rare ADEs, constraining the assessment of new signal-drug associations.④The statistical methods employed in this study, though sensitive, may exhibit increased false positive rates with rising report numbers.

Additionally, the signals unearthed only indicate a statistical association between the drug and ADEs, and do not necessarily imply a causal relationship between the two. Therefore, further clinical trials are needed to validate and guide clinical medication.

In conclusion, our comprehensive analysis of FAERS data provides valuable insights into the indications and AEs of teriparatide. Our study shows that reports submitted by healthcare professionals are still underreported compared to consumers, highlighting the importance of healthcare providers being vigilant in monitoring patients for serious adverse reactions. We found unexpected and significant adverse events, including urethral carbuncle and acquired bladder malposition. These findings highlight the need for healthcare providers to adjust their drug choices and closely monitor patients receiving teriparatide.

Furthermore, our study has unearthed numerous postmarketing safety signals congruent with clinical trials, alongside reports necessitating further regulatory scrutiny to ascertain their significance. To optimize teriparatide’s therapeutic utility, forthcoming inquiries are requisite to thoroughly elucidate its safety profile. These findings serve as a pivotal reference for forthcoming in-depth investigations and safety regulatory initiatives, underscoring the perpetual need for vigilant monitoring and research endeavors to uphold the safe and efficacious deployment of teriparatide in clinical settings.