Anti-inflammatories common in childhood can cause changes in teeth, shows study in rodents

A study carried out at the University of São Paulo (USP) and published in the Scientific Reports magazine reveals that anti-inflammatory drugs commonly used in childhood may be linked to defects in the development of tooth enamel, which today occur in approximately one in five children in the world .

The authors, linked to the Faculty of Dentistry of Ribeirão Preto (FORP-USP) and Pharmaceutical Sciences of Ribeirão Preto (FCFRP-USP), investigated the effects of drugs such as celecoxib and indomethacin, which belong to the class of non-steroidal anti-inflammatory drugs (NSAIDs) and represent —alongside paracetamol— the first rung of the WHO (World Health Organization) analgesic pain ladder.

In recent years, dentists at the Clínica do Esmalte Dentário at FORP-USP, who research and deal with the problem on a daily basis, have observed a considerable increase in the number of children treated with pain, white or yellow spots and tooth sensitivity and fragility, which they even end up fractured by the force of chewing — all classic symptoms of hypomineralization-type defects in the development of tooth enamel, whose central cause is still unknown.

As a consequence, carious lesions appear more quickly and more frequently in these patients and their restorations have less adhesion and more failures. And studies indicate that these people change restorations ten times more throughout their lives.

A coincidence aroused the researchers’ curiosity to delve deeper into the subject: the age of the patients. The first few years of life, when enamel defects form, coincide with the time when illnesses are most frequent, often with high fevers.

“These diseases are generally treated with non-steroidal anti-inflammatory drugs, which act by inhibiting the activity of the cyclooxygenase enzymes (COXs) and the production of the prostaglandin enzyme, whose levels are increased”, says Francisco de Paula-Silva, professor at the Department of Clinical Children at FORP-USP and study advisor. “However, we know that cyclooxygenases and prostaglandin are physiological for tooth enamel, which led us to question whether these drugs would not be interfering with the course of normal formation of this structure.”

The study, which had the support of FAPESP (projects 10/17611-4, 14/07125-6 and 21/09272-0), used rats to study the problem, since the animals have incisors with continuous growth, which facilitates the analysis. For 28 days, they were treated with celecoxib and indomethacin.

After this period, practically no differences visible to the naked eye were observed in the teeth of the animals. However, when the researchers started the extractions, what drew attention was the fact that the teeth broke more easily. Analyzes by imaging method and chemical composition indicated an impact on the mineralization of teeth, which contained less calcium and phosphate, important for the formation of dental enamel, and their mineral density was lower.

The next step was to investigate the reasons for this. The scientists found that proteins important for mineralization and signaling for cell differentiation were altered, indicating that treatment with drugs had an impact, in some way, on the composition of tooth enamel.

Next steps

“Right now, the study offers us a guide to understand a new actor that may be involved in defects in the development of tooth enamel, since until then we walked blindly”, says Paula-Silva. “We were only able to arrive at these important findings thanks to the efforts of the Clínica do Esmalte Dentário at FORP-USP and a collaboration with the professor at the Faculdade de Ciências Farmacêuticas de Ribeirão Preto Lúcia Helena Faccioli, fundamental for understanding the role of lipid mediators related to inflammatory diseases that affect the teeth.”

Based on the results observed in the animal model, the researchers intend to initiate a new study to confirm the clinical findings.

“We are going to retrieve the history of children with defects and their use of medication and correlate, in a clinical study, these two data to verify whether this also occurs in humans. Thus, we will be able to establish what should or should not be consumed and create, in the future , an adequate treatment protocol”, explains Paula-Silva, who compares the situation with the case of the antibiotic tetracycline, not recommended for children because it causes stains and darkening of the teeth.

According to the professor, another important point to be addressed is the access and indiscriminate use of over-the-counter drugs, which seems to have become increasingly common as a result of increased pediatric care, although there is still no concrete data on the theme.

The article Enamel biomineralization under the effects of indomethacin and celecoxib non-steroidal anti-inflammatory drugs can be read on the website of the journal Nature.