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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:
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| fibrous dysplasia | Experimental |
| |
| healthy volunteer | Active Comparator | Healthy volunteer matched for age and sex |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Visit 1 at the center | Other | Pain assessment and quality of life evaluation |
|
| Measure | Description | Time Frame |
|---|---|---|
| Central sensitization tests, measurement of the Conditioned Pain Modulation (CPM) effect | The patients are seated, the ATS thermode associated with the Pathway is applied to the dominant forearm. From the baseline value of 32°C, the Pathway delivers a "Pain 60 / Test stimulus" for 10 seconds, and the patient scores the pain on a visual numerical scale from 0 to 100. Then, the Pathway delivers a "Pain 60 / Test stimulus" for 30 seconds, and the patient scores the pain on the same scale. Fifteen minutes after the end of the two stimulations, the patient immersed the non-dominant arm for 60 seconds in a water bath at 46.5°C. Then a second identical sequence of 10 and 30 second stimulations was performed, with the scores recorded after each stimulation on the visual numerical scale from 0 to 100. The CPM effect is measured by taking the difference between the pain scores on the visual numerical scale before and after immersion. | Visit 1 / Day 1 |
| Measure | Description | Time Frame |
|---|---|---|
| Visual Analog Scale | This scale allows the patient to rate the pain on a 100-mm horizontal line with a movable cursor. It ranges from 0 mm (0 cm), corresponding to "no pain," to 100 mm (10 cm), corresponding to "worst pain imaginable." Participants indicate, using the cursor, the point on the line that best represents their level of pain. The distance (in mm or cm) between 0 and the participant's mark determines the intensity of pain. |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Lise Laclautre | Contact | +33473754963 | promo_interne_drci@chu-clermontferrand.fr | |
| Lise Laclautre | Contact |
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| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| CHU clermont-Ferrand | Clermont-Ferrand | France |
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| ID | Term |
|---|---|
| D005357 | Fibrous Dysplasia of Bone |
| D005359 | Fibrous Dysplasia, Polyostotic |
| D010146 | Pain |
| ID | Term |
|---|---|
| D010009 | Osteochondrodysplasias |
| D001848 | Bone Diseases, Developmental |
| D001847 | Bone Diseases |
| D009140 | Musculoskeletal Diseases |
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Case control study
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| Visit 1 - Day 1 |
| The Brief Pain Inventory Questionnaire (BPI) | This self-assessment scale allows the patient to characterize the pain in terms of its intensity and its psychosocial repercussions by means of 11 scales rated from 0 (no pain or does not bother) to 10 (the most horrible pain you can imagine or completely bothers you). The BPI also asks the patient to black out the painful areas on a diagram (front and back) and to put an "S" if the pain is on the surface or a "P" if it is deep. The questionnaire also asks the patient to indicate what treatment or medication he or she is taking for the pain and what percentage improvement has been obtained. | Visit 1 - Day 1 |
| Measurement of the threshold of sensitivity and pain perception induced by a thermal stimulus (hot and cold) at the Pathway - Médoc® | The measurements will be performed using an ATS thermode applied to the dominant arm of the patients. The Pathway-Medoc system associated with the thermode allows, from a base value of 32°C, to deliver adjustable temperature peaks (in the hot or in the cold and according to a regular slope of 1°C) and controlled by fast feedback, which allows to adapt to the different sensitivity thresholds of the C and A fibers. This device will be used to evaluate: the sensitivity threshold to heat, the sensitivity threshold to cold, the pain threshold to heat and the pain threshold to cold. The determination of each threshold will be established by an average of three measurements. | Visit 1 - Day 1 |
| Measurement of mechanical pain thresholds and mechanical temporal summation | Mechanical pain thresholds and mechanical temporal summation will be assessed using standardized mechanical stimulation. Mechanical pain thresholds will be measured with calibrated PinPrick stimulators using a modified method of limits, with stimuli applied to the palm of the dominant hand (or non-dominant if necessary). Thresholds will be calculated as the geometric mean of ascending and descending series. Mechanical temporal summation will be assessed using a 180 g Von Frey filament applied to the forearm. Pain intensity after a single stimulus and after a train of 10 stimuli at 1 Hz will be rated on a 0-10 visual analog scale. The temporal summation ratio will be calculated as the ratio between repeated and single stimulus pain ratings. Matched healthy volunteers will be tested at the same sites as patients. | Visit 1 - Day 1 |
| Pain assessment using the Neuropathic Pain Questionnaire (DN4) | Neuropathic Pain (DN4): This questionnaire estimates the probability of neuropathic pain in a patient, by means of four questions divided into ten items to be ticked. The practitioner or clinical research associate in charge of the study interviews or examines the patient and fills in the questionnaire himself. Each item is marked with a "yes" or "no" answer. Each "yes" is worth a score of 1, and each "no" is worth a score of 0. The sum of the scores gives the patient's score (out of 10); if the patient's score is equal to or greater than 4/10, the test is positive. | Visit 1 - Day 1 |
| PainDETECT questionnaire | Neuropathic pain components will be assessed using the PainDETECT questionnaire. This self-administered questionnaire evaluates pain quality, temporal pattern, and radiation to estimate the likelihood of neuropathic pain. The total score allows classification of pain as unlikely, possible, or likely neuropathic | Visit 1 - Day 1 |
| Small fiber neuropathy assessment (Sudoscan®) | Small fiber neuropathy will be assessed using Sudoscan® (Impeto Medical, Paris, France), a rapid, non-invasive, and reproducible method for evaluating sudomotor function. The test measures electrochemical skin conductance of the hands and feet, reflecting sweat gland function and small fiber nerve integrity. Participants will be seated comfortably with palms and soles placed on stainless steel electrodes. A low-voltage current (4 V) will be applied for 2 minutes and 40 seconds. Electrochemical skin conductance values (µS) will be recorded for hands and feet, with lower conductance (<40 µS) indicating the presence of small fiber neuropathy and higher conductance (>60 µS) indicating normal function. Measurements will be performed twice, 30 minutes apart. | Visit 1 - Day 1 |
| Dynamic mechanical allodynia | Dynamic mechanical allodynia will be assessed using a soft brush gently moved back and forth over the non-dominant forearm while the participant is seated comfortably in a quiet room. Pain intensity perceived during brushing will be rated on a 0-100 numerical rating scale. | Visit 1 - Day 1 |
| Presence of inflammatory pain | Inflammatory pain will be assessed by the investigator during clinical examination according to current clinical criteria. The evaluation will be based on the presence of clinical signs suggestive of inflammation, including warmth, redness, swelling, edema, induration, and pain. The outcome will be reported as the presence or absence of inflammatory pain (Yes/No). | Visit 1 - Day 1 |
| Nociplastic pain | Signs of widespread pain will be assessed through clinical interview to calculate the Widespread Pain Index (WPI), commonly used in nociplastic pain conditions. In addition, the presence of nociplastic pain will be determined based on an integrative assessment combining results from pain testing and clinical evaluation. | Visit 1 - Day 1 |
| Clinical characteristics | Clinical characteristics will be collected from the clinical examination and routine care investigations and will include a description of skeletal involvement and extra-skeletal manifestations. | Visit 1 - Day 1 |
| The Pittsburgh Sleep Quality Index (PSQI) | he PSQI is a self-administered questionnaire with 19 items. It was developed to measure sleep quality in the month prior to the patient interview. This questionnaire includes 7 components: subjective sleep quality, sleep latency, sleep duration, habitual sleep efficiency, sleep disturbance, hypnotic medication use and daytime dysfunction. The global score (0 to 21) is obtained by adding the sub-scores of the 7 components, each ranging from 0 to 3 points. In the absence of an answer to one or more questions, the subtotal using this question cannot be calculated and will affect the overall score. The higher the overall score, the greater the impairment in sleep quality. An overall score >5 is an indicator of sleep disturbance. | Visit 1 - Day 1 |
| The Hospital Anxiety and Depression Scale (HAD) | It is a self-administered questionnaire completed by the patient and based on the Hamilton scale. The HAD scale is a tool for screening for anxiety and depressive disorders. It includes 14 items rated from 0 to 3. Seven questions relate to anxiety (total A) and seven others to the depressive dimension (total D), thus making it possible to obtain two scores (maximum score for each score = 21). To screen for anxiety and depressive symptomatology, the following interpretation can be proposed for each of the scores (A and D): ≤ 7: normal case; 8 to 10: borderline case; ≥ 11: abnormal case. | Visit 1 - Day 1 |
| The 36-Item Short Form Survey (SF-36) | The quality of life of patients is assessed by the general questionnaire 36-Item Short Form Survey (SF-36) which can be administered by self or hetero-questionnaire. The SF-36 questionnaire was developed from the Medical Outcome Study, a 149-item questionnaire that was developed to assess how the American healthcare system affects the outcome of care. The SF-36 questionnaire is composed of 36 items and makes it possible to assess the physical and mental health of an individual using eleven questions relating to eight aspects of health: Physical activity, limitations due to physical state, physical pain, perceived health, vitality, life and relationship with others, limitations due to the mental state and mental health. Scores between 0 and 100 are determined. Scores tending towards 100 indicate a better quality of life. | Visit 1 - Day 1 |
| Pain Catastrophizing Scale (PCS) | The PCS is a validated 13-item self-report questionnaire assessing catastrophic thoughts and feelings related to pain, including rumination, magnification, and helplessness. Items are rated from 0 to 4, with higher total scores indicating greater pain catastrophizing. | Visit 1 - Day 1 |
| C-terminal telopeptides of collagen type 1 dosage | Evaluation of the CTX evolution after one year, defined as the difference [after - before], relative to the basal value (µg/L). For this purpose, a blood sample will be taken using 5 mL dry tubes. | Visit 1 - Day 1 |
| Fibroblast Growth Factor 23 dosage | The dosage of FGF23 (pg/mL) will be performed in order to evaluate bone remodeling. For this purpose, a blood sample will be taken using 6 mL EDTA tube. | Visit 1 - Day 1 |
| D009461 | Neurologic Manifestations |
| D012816 | Signs and Symptoms |
| D013568 | Pathological Conditions, Signs and Symptoms |