In a groundbreaking study emerging from the University of São Paulo (USP) in Brazil, researchers have unveiled promising new uses for two well-established osteoporosis medications, etidronate and tiludronate, suggesting these drugs may offer a novel therapeutic avenue for managing iron overload disorders. Iron accumulation in the body, particularly at toxic levels, contributes to a spectrum of severe diseases characterized by oxidative cellular damage. The USP team’s latest work, recently published in the esteemed journal BioMetals, reveals that these bisphosphonate compounds, traditionally employed to combat bone density loss, can bind excess iron in human cell cultures, thereby significantly reducing oxidative stress and protecting cellular integrity.
The challenge of managing iron overload conditions is a compelling clinical problem. Excessive iron catalyzes the formation of reactive oxygen species (ROS), which overwhelm the body’s natural antioxidant defenses and lead to extensive molecular and cellular damage. Currently, treatment options rely on iron chelators—agents that bind iron and facilitate its removal. However, the established chelators often bring about severe adverse effects including gastrointestinal distress, overwhelming patients with nausea and vomiting, thereby complicating consistent therapeutic adherence. Professor Breno Pannia Espósito, who leads the investigative team at USP’s Institute of Chemistry, highlights this gap as motivation for their research into alternative compounds with better tolerability profiles.
The team’s approach diverges markedly from traditional drug repositioning studies. Rather than screening a broad panel of compounds for unforeseen activity, they began with a targeted hypothesis: the chemical architecture of bisphosphonates, characterized by phosphate-rich moieties, might foster strong affinity for iron ions, resembling and competing with calcium binding in physiological milieus. This chemical trait led researchers to envision bisphosphonates as potent iron chelators. Importantly, the interplay between calcium and iron is biologically intricate, as both metals compete for similar binding sites in tissues and blood. Conducting experiments in the presence of physiological calcium concentrations was pivotal in validating the chelation potential under realistic biological conditions.
At the core of their biological investigation was the balance between iron’s indispensable and toxic roles. Iron’s fundamental contribution to oxygen transport and enzymatic energy production is well documented, with its deficiency giving rise to the prevalent iron deficiency anemia. Conversely, iron overload, which can arise from genetic disorders like hemochromatosis or iatrogenic causes such as repeated blood transfusions in thalassemia patients, leads to the generation of damaging free radicals at rates surpassing antioxidant neutralization capacity. These radicals induce oxidative stress, impinging upon lipids, proteins, and DNA, and ultimately triggering cell death and tissue dysfunction.
Bisphosphonates have historically been employed as bone antiresorptives, attenuating the excessive bone resorption characteristic of osteoporosis by inhibiting osteoclast-mediated bone degradation. The current study extends their potential utility beyond skeletal health by demonstrating that molecules like etidronate and tiludronate possess the necessary chemical features for iron ion binding—an interaction hitherto unexplored in the context of iron overload management, particularly in cases without concomitant bone disease. This discovery opens the door to repurposing existing drugs with known safety profiles for a highly unmet therapeutic need.
The research team methodically tested a cohort of bisphosphonates, observing that while many could effectively suppress iron-induced oxidation in physiological media, some exhibited higher cytotoxicity in vitro, underscoring the necessity for careful toxicity evaluation before clinical translation. Remarkably, the presence of physiological calcium did not abolish chelation capacity but did attenuate the efficacy of these agents, reflecting the dynamic competition between metal ions in biological systems. Overall, etidronate and tiludronate exhibited chelation properties on par with standard iron chelators, reinforcing their promise as alternative therapeutic candidates.
In addition to bisphosphonates, the researchers assessed strontium ranelate, another bone antiresorptive agent, but found no iron chelation activity, emphasizing the specificity of bisphosphonate’s phosphate groups for iron binding. This contrasts underline the importance of molecular structure-function relationships in pharmacological repurposing efforts and suggests that not all bone-modifying agents will be suitable for iron overload therapy.
Despite the encouraging biochemical and cellular results, Professor Espósito is cautious about immediate clinical application. “These findings represent a proof of concept rather than a finalized therapy,” he notes. The experiments, thus far limited to cell culture models, require extensive follow-up in vivo studies and clinical trials to assess efficacy, pharmacodynamics, optimal dosing, and safety profiles in humans. Thorough investigations remain essential to establish whether bisphosphonates can be integrated into standard iron chelation protocols without compromising patient health or inducing unforeseen complications.
This research also carries broader implications for managing diseases involving iron-driven pathology. Iron overload is a known exacerbator of oxidative stress in conditions that extend beyond hereditary hemoglobinopathies, potentially influencing the progression of liver diseases, neurodegenerative disorders, and cardiovascular complications. By expanding the arsenal of chelators with drugs that may exhibit fewer side effects, new therapeutic strategies could better address these diverse pathological contexts.
Moreover, the study exemplifies the power of intelligent drug repositioning founded on a clear mechanistic hypothesis rather than blind screening. Understanding bisphosphonate chemistry and its physiological interactions allowed the USP researchers to target a specific molecular challenge—iron excess—with precision. This approach could inspire future research into other drugs with phosphate-rich or analogous functional groups for metal chelation, broadening the scope of pharmacological innovation through repurposing.
In sum, the USP research team’s discovery illuminates a new horizon in iron overload therapy, melded with the practical advantages of existing osteoporosis medications. Should subsequent studies confirm their findings in clinical settings, etidronate and tiludronate could dramatically improve patient outcomes in iron toxicity conditions. Although early, this avenue holds the promise of making the management of iron overload diseases safer, more tolerable, and more effective, representing an exciting leap forward in translational medicine.
Subject of Research:
Article Title: Bone antiresorptives as potential chelators for iron overload diseases
News Publication Date: 26-Nov-2025
Web References:
– https://link.springer.com/article/10.1007/s10534-025-00777-4
– http://dx.doi.org/10.1007/s10534-025-00777-4
Keywords:
Pharmaceuticals, Osteoporosis, Iron deficiency, Free radicals
