PAINDYS_Characterizing Pain in Fibrous Dysplasia of Bone/McCune-Albright Syndrome: an Exploratory Pilot Study

Characterizing Pain in Fibrous Dysplasia of Bone/McCune-Albright Syndrome: an Exploratory Pilot Study

Fibrous dysplasia of bone (FD) / McCune-Albright syndrome (MAS) is a rare congenital bone disorder affecting one or multiple bones, caused by a mosaic somatic mutation of the GNAS gene. In some cases, it may be associated with endocrine or cutaneous abnormalities. The spectrum of bone disease is broad, ranging from isolated monostotic fibrous dysplasia to complete skeletal involvement. Functional prognosis can be complex due to pain, bone deformities, and fracture risk. The disease may initially be identified through non-specific clinical signs such as pain. Indeed, bone pain has been reported in up to 81% of adults and 49% of children, mainly affecting the lower limbs and the spine, with highly variable pain intensity that does not always correlate with the extent of bone lesions. This pain may persist throughout life and impact patients' daily activities.

In the general population, it is well known that chronic musculoskeletal pain following events such as surgery or fractures can be associated with central sensitization, a neurophysiological phenomenon characterized by hyperreactivity of the central nervous system, along with impaired modulation of pain through descending inhibitory pathways, a normally protective mechanism that becomes reduced. The pathophysiology of bone pain in FD/MAS remains poorly studied and poorly understood. The presence of central sensitization, reduced pain modulation, and hypersensitivity to everyday stimuli are rarely described but suggested by the existence of chronic pain often lasting many years. The mixed characteristics of pain experienced (nociceptive, neuropathic, inflammatory, or nociplastic) are also poorly defined. To date, no study has explored pain in FD/MAS using a psychophysical approach in comparison with a control population.

Our hypothesis is that patients with FD/MAS exhibit central sensitization with reduced pain modulation. This exploratory pilot study aims to investigate, through psychophysical approaches, the pathophysiological mechanisms underlying pain in FD/MAS.

This exploratory pilot study aims to compare central pain sensitization in adults with FD/MAS to that observed in age- and sex-matched healthy volunteers. The primary objective is to assess differences in conditioned pain modulation (CPM), a measure of descending inhibitory pain control and central pain modulation capacity. Secondary objectives include characterization of pain intensity and phenotype, clinical description of FD/MAS manifestations, comparison of thermal and mechanical pain sensitivity thresholds, identification of pain mechanisms (nociceptive, neuropathic, inflammatory, or nociplastic), and comparison of quality of life, sleep quality, anxiety/depression levels, and pain catastrophizing between patients and healthy controls. Blood biomarkers related to bone metabolism will also be compared between groups.

Patients regularly followed in the Rheumatology Department will be informed about the study during routine clinical visits. Patients not requiring regular hospital follow-up may be contacted by their rheumatologist, who will present the study and provide written information. A reflection period of at least seven days will be respected before scheduling the study visit. Participation remains voluntary, and informed consent will be obtained prior to any study procedures.

Healthy volunteers will be preselected from the Clinical Investigation Center volunteer registry and contacted to assess interest in participation. Eligible volunteers will receive study information and will benefit from the same reflection period before inclusion procedures.

Both groups of participants will attend a single visit at the center. During this visit, the objectives and procedures of the study will be explained by the physician. After verification of eligibility criteria and once written informed consent has been obtained, the following assessments will be performed:

• A medical examination and inclusion-related questionnaires (including medical history and clinical characteristics, comorbidities, medication treatments, the WPI and the Kosek nociplastic pain algorithm).
• A blood sample to assess bone biological markers (Fibroblast Growth Factor 23 (FGF23) and C-terminal telopeptides of type I collagen (CTX)).
• A pain assessment including the visual analog scale, the Brief Pain Inventory (BPI), DN4, the PainDetect questionnaire, psychophysical pain assessment (thermal pain thresholds for heat and cold, mechanical pain thresholds, Sudoscan), and evaluation of central sensitization using the conditioned pain modulation (CPM) test, as well as the Pain Catastrophizing Scale (PCS).
• Quality-of-life-related questionnaires including the Pittsburgh Sleep Quality Index (PSQI), the SF-36 quality of life questionnaire, and the Hospital Anxiety and Depression Scale (HADS).

Inclusion Criteria:

• For patients :
• Male or female over 18 years of age with fibrous dysplasia/McCune-Albright syndrome diagnosed by a rheumatologist.
• Mentally and legally able to provide informed consent to participate in the study.
• Affiliated with a health insurance system.
• For healthy volunteers :
• Male or female over 18 years of age.
• Matched to patients by age and sex.
• Mentally and legally able to provide informed consent to participate in the study.
• Affiliated with a health insurance system.

Exclusion Criteria:

• For patients :
• Medical and/or surgical history considered by the investigator or delegated physician to be incompatible with study procedures (e.g., amputation or physical limitation preventing completion of pain assessment tests).
• Recurrent pain at sites planned for stimulation during thermal and mechanical testing (forearms or palms).
• Presence of anxiety and/or depression defined as Hospital Anxiety and Depression Scale (HADS) score >11.
• Use of analgesic medication within the week preceding inclusion.
• Use of complementary treatments for analgesic purposes (e.g., vitamins, herbal products, cannabinoids).
• Individuals under legal protection (guardianship or trusteeship) or deprived of liberty.
• Pregnant or breastfeeding women.
• Refusal to participate.
• For heathly volunteers :
• Medical and/or surgical history considered by the investigator or delegated physician to be incompatible with study procedures (e.g., amputation or physical limitation preventing completion of pain assessment tests).
• Presence of sleep disorders defined as Pittsburgh Sleep Quality Index (PSQI) score >5.
• Presence of anxiety and/or depression defined as HADS score >11.
• Use of analgesic medication within the week preceding inclusion.
• Use of complementary treatments for analgesic purposes (e.g., vitamins, herbal products, cannabinoids).
• Individuals under legal protection (guardianship or trusteeship) or deprived of liberty.
• Pregnant or breastfeeding women.
• Refusal to participate.