Mandibular bone loss: a hidden side effect of botulinum toxin type A injection in masticatory muscles.

bone bone by of the receptor activator for nuclear factor Kappa Beta ligand the proximal tibia T-cells bone cells

and atrophy, 1 but much less studied are the side effects that could affect bone homeostasis. The musculoskeletal system maintains a fine regulation between muscles and bones, in which both tissues sustain a cross-talk through biomechanical (generation of force, tension) and biochemical signals (molecules released by the muscle that contribute to bone homeostasis and vice versa). 3 So, what happens to the structure and function of the adjacent bone when muscle paralysis is induced by BoNTA injection?
The intramuscular (IM) intervention with BoNTA promotes bone loss in underlying structures. As demonstrated by Warner et al in adult female C57BL/6 mice, IM intervention in the quadriceps and calf muscles with Botox® (0.5U/19.2µl) significantly reduced the trabecular bone volume fraction by 43%, in the distal femoral epiphysis and by 54% in proximal tibial metaphysis after 21 days. 4 In the same model, Aliprantis et al described that acute bone loss induced by this intervention occurs as a response to a significant increase of the receptor activator for nuclear factor Kappa Beta ligand (R ANKL) in the proximal tibia metaphysis.
R ANKL is necessary to differentiate and increase the number of osteoclasts (bone resorption cells). Moreover, the treatment with human recombinant osteoprotegerin (the R ANKL physiological antagonist), or conditional deletion of the osteoclastogenesis master regulator "nuclear factor of activated T-cells c1" (NFATc1), prevented the bone loss in this animal model. 5 In addition, direct effects of BoNTA on bone cells were not detected, suggesting that bone loss may be produced by muscle load or signaling after this intervention. 5

Mandibular bone loss: a hidden side effect of botulinum toxin type A injection in masticatory muscles.
Considering that the temporomandibular joint requires the activity of masticatory muscles for its development and homeostasis, it is highly relevant to understand the effect of the BoNTA intervention in the masticatory apparatus.

Kün-Darbois et al. reported trabecular bone loss in alveolar
(-20%) and condylar (-35%) areas in adult rats 4 weeks after a unilateral injection of 1U of Botox® in both the masseter and temporalis muscles. 6 The same intervention in masseter muscles of growing mice ( BoNTA IM injections for facial pain, were compared with those from 9 demographically matched control patients. 9 Two independent oral and maxillofacial radiologists, blinded to BoNTA exposure conditions, rated bone density patterns in the trabecular region of mandibular heads.
Both radiologists noted a reduction in bone density in all the patients exposed to BoNTA, and in none of the 9 control subjects. 9 In a recent Letter to the Editor, Aziz et al. Authors are cautious to point out that is difficult to tell if Botox® was the cause of bone resorption, because this is an isolated cause and iatrogenic injury cannot be excluded.
However, they highlight the idea that the condylar degeneration may be associated with BoNTA injections.
These reports, reinforced by results from experimental studies in animal models, makes it highly recommended for both clinicians and patients to consider the putative bone loss evoked by BoNTA-induced masseter muscle atrophy as a relevant factor prior to a treatment. 10 Therefore, the presented evidence suggests the importance of considering the need to develop follow-up protocols to permanently monitor the associated bone structure by proper imaging techniques after BoNTA intervention in the masseter muscle. This is especially relevant in patients who require multiple successive applications of toxin to maintain the desired effect. Finally, there is not enough evidence to know if BoNTA intervention in the masseter muscle (or other masticatory muscles) predisposes, initiates or perpetuates the TMJD.