Pharmacological Interventions Targeting Pain in Fibrous Dysplasia/McCune-Albright Syndrome

Fibrous dysplasia (FD) is a rare, non-inherited bone disease occurring following a somatic gain-of-function R201 missense mutation of the guanine-nucleotide binding protein alpha subunit stimulating activity polypeptide 1 (GNAS) gene. The spectrum of the disease ranges from a single FD lesion to a combination with extraskeletal features; an amalgamation with cafe-au-lait skin hyperpigmentation, precocious puberty, and other endocrinopathies defines McCune-Albright Syndrome (MAS). Pain in FD/MAS represents one of the most prominent aspects of the disease and one of the most challenging to treat-an outcome driven by (i) the heterogeneous nature of FD/MAS, (ii) the variable presentation of pain phenotypes (i.e., craniofacial vs. musculoskeletal pain), (iii) a lack of studies probing pain mechanisms, and (iv) a lack of rigorously validated analgesic strategies in FD/MAS. At present, a range of pharmacotherapies are prescribed to patients with FD/MAS to mitigate skeletal disease activity, as well as pain. We analyze evidence guiding the current use of bisphosphonates, denosumab, and other therapies in FD/MAS, and also discuss the potential underlying pharmacological mechanisms by which pain relief may be achieved. Furthermore, we highlight the range of presentation of pain in individual cases of FD/MAS to further describe the difficulties associated with employing effective pain treatment in FD/MAS. Potential next steps toward identifying and validating effective pain treatments in FD/MAS are discussed, such as employing randomized control trials and probing new pain pathways in this rare bone disease.

Automated summary

Fibrous dysplasia (FD) is a rare non-inherited bone disease caused by a somatic gain-of-function mutation of the GNAS gene. The disease can manifest as a single FD lesion or with extraskeletal features, known as McCune-Albright Syndrome (MAS). Pain is a prominent and challenging aspect of FD/MAS, due to the heterogeneous nature of the disease, variable pain phenotypes, lack of pain mechanism studies, and limited validated analgesic strategies. Current pharmacotherapies, such as bisphosphonates and denosumab, are used to manage skeletal disease activity and pain in FD/MAS. However, there is a need for further research and randomized control trials to identify effective pain treatments and explore new pain pathways in this rare bone disease.