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Review
. 2023 Jan 29;24(3):2550.
doi: 10.3390/ijms24032550.

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

Anthony Tucker-Bartley  1   2 , Daryl J Selen  3 , Emma Golden  1 , Raquel van Gool  1 , David Ebb  4 , Michael Mannstadt  5 , Jaymin Upadhyay  1   6
Affiliations
Review

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

Anthony Tucker-Bartley et al. Int J Mol Sci. .

Abstract

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 café-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.

Keywords: McCune–Albright syndrome; analgesia; bisphosphonates; denosumab; fibrous dysplasia; pain.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 4
Figure 4
(A) RANK-L binds to RANK on osteoclasts resulting in differentiation and maturation of osteoclasts and subsequent bone resorption [97]. Denosumab binds to RANK-L and inhibits its action, and prevents osteoclast recruitment and maturation, resulting in slowed bone resorption [35]. Bisphosphonates prevent bone resorption by binding to hydroxyapatite and inhibiting osteoclast function [98]. (B) Nociceptive signaling molecules on primary sensory neurons innervating skeletal tissue can include the transient receptor potential (TRP) family channels, acid-sensing ion channels (ASICs), mechanosensitive ion channels (Piezo1), purinergic receptors (P2X3), and Glial cell line-derived neurotrophic factor (GDNF)/ GDNF Family Receptor Alpha (GFRα) receptors [72]. Bone pain may involve the activation and sensitization of neurons via Glial cell line-derived neurotrophic factor (GDNF)/GFRα1, neurturin/GFRα2, and artemin/GFRα3 signaling pathways [75,95]. The percephin/GFRα4 complex is not included. When peripheral afferent neurons in bone tissue, with their cell bodies located in the dorsal root ganglion (DRG), are activated, nociceptive signals are carried via the spinothalamic and ascending pain pathways to convey pain signals to various regions in the brain [99,100]. Note that the activation of GFRα receptors may yield a potential increase in synaptic channel or receptor expression and/or sensitization (Created with BioRender.com, accessed on 5 August 2022).
Figure 1
Figure 1
Whole-body 18F-NaF PET/CT and non-contrast craniofacial MRI for Patient 1 at age 23 (A,B) and Patient 2 at age 53 (C,D). (A) There is diffuse radioactive uptake in the axial and appendicular skeleton with pronounced focus in the craniofacial regions indicating polyostotic FD. (B) Craniofacial regions with diffuse FD lesions. Skull-based lesions are highlighted. (C) There is pronounced 18F-NaF uptake in the craniofacial region with limited uptake in the rest of the body. (D) Extensive FD affecting the nasal bones and distorting the structure of the sinus cavity. 18F-NaF PET = 18F-sodium fluoride positron emission tomography, CT = computed tomography, MRI = magnetic resonance imaging, FLAIR = fluid-attenuated inversion recovery, STIR = short tau inversion recovery.
Figure 2
Figure 2
(A) The 12-week daily pain diary completed by Patient 1 while undergoing treatment with denosumab at age 23. Average pain was assessed using a 0–10 numerical rating scale and was initiated before the onset of denosumab treatment. (B) At baseline and using the BPI, anatomical regions where pain was experienced was identified on a body map. Pain was widespread and present in craniofacial and axial–appendicular locations.
Figure 3
Figure 3
(A) The 10-week daily pain diary completed by Patient 2 at age 53. Average pain was assessed using a 0–10 numerical rating scale and was initiated before surgical treatment to lessen craniofacial FD lesions. (B) At baseline and using the BPI, anatomical regions where pain was experienced were confined to craniofacial areas.
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