Low-dose onabotulinumtoxinA used for TMJ disorders does not affect jaw morphology

Low-dose onabotulinumtoxinA (BtxA) does not alter jaw morphology in women receiving BtxA to relieve jaw and facial pain due to temporomandibular joint (TMJ) disorders, a study has shown.

BtxA has been progressively used off-label for TMJ disorders that are refractory to conventional therapies*. However, there is growing concern regarding its use in this setting owing to increasing preclinical data reflecting mandibular bone underloading, leading to persistent bone loss following BtxA administration. [Bone 2012;50:651-662; Bone 2015;77:75-82; Am J Orthod Dentofacial Orthop 2015;148:999-1009; Toxins 2019;11:84]

“Given these concerning findings … and the limited findings from clinical studies, more research on the safety of BtxA for jaw muscles and bones is critically important,” said study lead author Professor Karen Raphael from the New York University College of Dentistry, US.

“[Our findings show that BtxA use did not] produce clinically significant changes in density or volume of the TMJ complex in women who received at least two … BtxA treatment cycles for myofascial TMJ disorders in the past year,” said Raphael and colleagues.

Bone densities of the condyles of BtxA-exposed and unexposed participants were similar across all primary regions of interest, ie, the superior poles (mean GSV**, 782 vs 855; p=0.22 [left] and 803 vs 845; p=0.43 [right]) and the trabecular regions (mean GSV, 478 vs 561; p=0.06 [left] and 474 vs 470; p=0.90 [right]). [J Oral Rehabil 2020;doi:10.1111/joor.13087]

There were also no significant differences between the BtxA-exposed and unexposed groups in terms of condylar volume, be it on the left (mean, 1291 vs 1325 mm³) or right side (1290 vs 1340 mm³).

“[These findings could] be attributed to a small sample, but measures of explained variance, which do not vary with sample size, also indicated small effects,” explained the researchers.

High doses = bone resorption?

Of the 79 women evaluated, 35 received BtxA, while 44 were unexposed to BtxA. A primary diagnosis of TMJ disorder required about 40 U of BtxA; those diagnosed with headache received only about half this dose, while the rest received an intermediate dose. Higher doses were given for comorbid cases (eg, migraine + myofascial TMJ disorder).

There was an inverse association between BtxA dose injected into the temporalis muscle and the density of the left (r=–0.44; p=0.01), and to a lesser extent, the right (r=–0.31; p=0.08), trabecular compartment of the mandible. As per the researchers, the reduced bone density associated with the temporalis dosing was “the most prominent effect” they have observed.

This correlates with evidence identifying osteopenia in the trabecular condylar regions of individuals with TMJ disorder following BtxA injections. [J Oral Rehabil 2014;41:555-563]

Of note was the severe unilateral condylar degeneration following massive doses of BtxA (140 U) for >1 year in one study. [Br J Oral Maxillofac Surg 2017;55:987-988] “While the dosing was far beyond any dosing seen at a single point in time in our … study, it shows the possibility for BtxA to cause clinically significant bone degradation,” explained the researchers. As such, it is imperative to explore the direct effect of BtxA on bone resorption in future trials, they said.

In-depth probing with imaging studies

A phase III trial exploring new indications for BtxA, including myofascial TMJ disorders, is underway. “[S]hould … myofascial TMJ disorders become an approved indication [for BtxA], it is strongly recommended that a phase IV study be conducted using CT/cone-beam CT and MRI to rule out plausible long-term and potential clinically significant adverse changes to the bone and muscle,” underscored the researchers.

“Unless specialized imaging of muscle and bone are conducted among patients who receive BtxA treatment over long periods, true cumulative adverse effects will remain unknown,” they stressed.

Understanding the cellular and molecular nature of the muscle-bone remodelling relationship as it relates to BtxA use may help in the development of interventional measures that could protect against potential bone resorption, they added.