Uncovering a Hidden Risk: The Link Between CDK4/6 Inhibitors and Jaw Bone Health

Cyclin-dependent kinase (CDK) 4/6 inhibitors have significantly improved outcomes in hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer treatment. These drugs, especially palbociclib and abemaciclib, have been a major boost to both progression-free and overall survival when paired with endocrine therapy. However, they come with their own set of side effects with palbociclib which targets both CDK4 and CDK6 can lead to myelosuppression (a drop in white blood cells), whereas abemaciclib, which is more CDK4-specific, tends to cause digestive issues like diarrhea. Recently there has been a serious concern on reports that suggest a potential link between CDK4/6 inhibitors and medication-related osteonecrosis of the jaw (MRONJ). This is when parts of the jawbone essentially die due to a lack of proper blood supply. The data, especially regarding palbociclib, has been all over the place—some reports suggest a connection, while others do not. As for abemaciclib, there is not much information at all. We already know that MRONJ can happen with drugs like bisphosphonates and denosumab, which affect bone turnover, but the role CDK4/6 inhibitors play in this process has remained unclear. To this account, new research paper published in International Journal of Cancer and conducted by Associate Professor Yoshihiro Noguchi, Rikuto Masuda, and Professor Tomoaki Yoshimura from the Gifu Pharmaceutical University together with Ms Makiko Go, Hiroki Asano, Michio Kimura, and Eiseki Usami from the Ogaki Municipal Hospital, the team analyzed data from the FDA Adverse Events Reporting System (FAERS) and wanted to determine whether palbociclib or abemaciclib could independently contribute to MRONJ risk and to map out the kinds of oral health issues these drugs might trigger.

One of the biggest challenges in research like this is separating the effects of the drugs from other factors. Many patients taking CDK4/6 inhibitors are also on bisphosphonates or denosumab—both of which are already known to be linked to MRONJ. This makes it difficult to pinpoint if CDK4/6 inhibitors are actually playing a role or if the jaw issues are just a side effect of the other medications. On top of that, FAERS relies on spontaneous reporting, not every adverse reaction gets documented, and there is always a risk of bias in what gets reported. To tackle this question, the researchers pulled FAERS data from 2004 to 2021 and looked specifically at reports related to oral health issues from patients taking CDK4/6 inhibitors. They made sure to filter out duplicate reports and focused on key terms in the Medical Dictionary for Regulatory Activities (MedDRA), such as “osteonecrosis of the jaw,” “stomatitis and ulceration,” and “oral soft tissue infections.” Then, they ran a statistical analysis using crude and adjusted reporting odds ratios (cROR and aROR) to assess whether these drugs were disproportionately linked to these conditions. The authors found a significant association between palbociclib and MRONJ, especially in women. The reporting odds ratio for osteonecrosis of the jaw with palbociclib use was 2.42 (which indicated a signal of disproportionate reporting), and after adjusting for other factors like age and concurrent medication use, the association became even stronger (aROR: 5.74). The authors concluded that even after accounting for patients who were also taking bisphosphonates or denosumab, the link between palbociclib and MRONJ still held up. On the other hand, abemaciclib did not show the same pattern. It was not significantly linked to MRONJ, but it was associated with other oral issues—mainly stomatitis (inflammation in the mouth) and ulcers. Palbociclib, meanwhile, seemed to be connected to a broader range of oral soft tissue problems, including infections and mucosal damage, reinforcing the idea that it may negatively impact oral health in multiple ways. Interestingly, the MRONJ risk from palbociclib seemed to be most pronounced in women over 40. This makes sense since this is the demographic most commonly prescribed CDK4/6 inhibitors for breast cancer treatment.

In conclusion, the researchers’ findings raise an important red flag for oncologists and dentists alike. If palbociclib truly increases the risk of MRONJ, patients taking this drug—especially those with other risk factors like prior bisphosphonate therapy—should be closely monitored for early signs of jaw problems. Routine dental check-ups, early treatment of oral infections, and avoiding invasive dental procedures where possible could go a long way in reducing the likelihood of MRONJ developing in these patients. From a bigger-picture standpoint, this study also underscores how crucial post-marketing surveillance is. Clinical trials do a great job of catching common side effects, but rare ones like MRONJ might not show up until years after a drug hits the market. FAERS and other pharmacovigilance systems help bridge this gap by continuously monitoring for unexpected safety concerns. That being said, while this study strongly suggests a connection, more research is needed to confirm the findings. Future studies, preferably with large prospective patient cohorts will be necessary to understand the underlying mechanisms at play. There is also a broader scientific takeaway here. The fact that abemaciclib did not show the same risk as palbociclib hints that CDK4 selectivity might be a key factor in determining adverse effects. These valuable results could help guide the development of future CDK4/6 inhibitors that are both effective and have fewer side effects. Additionally, the new study sheds new light on a potentially serious side effect of a widely used cancer drug. Therefore, although CDK4/6 inhibitors are excellent drugs for  breast cancer treatment, it is important to recognize and mitigate their risks with further research like this research work, also better screening, and increased awareness among healthcare providers.