ENOrphanet Journal of Rare Diseases | Cross-disease analysis of pain characteristics in rare bone diseases reveals the dominant role of non-skeletal factors
Date: February 02, 2026
Classification: Frontiers
Recommend:
This study systematically compared pain characteristics across three rare bone diseases using large-scale patient self-reported data, revealing that despite different etiologies, pain manifestations are highly similar, suggesting a key role for non-skeletal factors in pain mechanisms and offering new perspectives for clinical management.
Literature Overview
The article titled 'Addressing the unmet challenge of pain in rare bone diseases: new insights from the RUDY UK registry', published in Orphanet Journal of Rare Diseases, reviews and summarizes the frequency and characteristics of self-reported pain among adult patients with fibrous dysplasia/McCune-Albright syndrome (FD/MAS), osteogenesis imperfecta (OI), and X-linked hypophosphatemia (XLH). Utilizing data from the UK RUDY rare disease registry, the study employed the painDETECT questionnaire (PD-Q) and a modified widespread pain index (WPI) to multidimensionally assess pain, systematically analyzing pain distribution, intensity, phenotypes, and their relationships with psychological status and sleep quality. Results indicate that although the skeletal pathophysiological mechanisms of these three diseases are distinct, patients report highly similar pain prevalence, intensity, and temporal patterns, while pain locations show disease-specific distributions. Additionally, neuropathic-like pain and female sex are significantly associated with worse pain outcomes, and widespread pain is closely linked to anxiety, depression, and sleep disturbances, suggesting that nociplastic pain mechanisms may play an important role in chronic pain associated with rare bone diseases. This study emphasizes the clinical importance of looking beyond skeletal lesions in pain management, focusing instead on non-skeletal factors such as central sensitization.Background Knowledge
Rare bone diseases such as FD/MAS, OI, and XLH are primarily characterized by skeletal fragility and deformities, often accompanied by chronic pain that severely impacts patients' quality of life. FD/MAS is caused by somatic mutations in the GNAS gene, leading to fibrous dysplasia and endocrine abnormalities; OI is mostly due to mutations in type I collagen genes causing increased bone fragility; XLH results from PHEX gene mutations causing renal phosphate wasting and impaired bone mineralization. Although their pathogenic mechanisms differ significantly, all three present bone pain as a primary symptom, yet it remains unclear whether their pain characteristics share commonalities. The traditional view holds that bone pain arises from structural abnormalities such as fractures, deformities, or lesion irritation. However, in some patients, pain severity does not match imaging findings, suggesting other mechanisms may be involved. In recent years, nociplastic pain (i.e., central sensitization) has gained increasing attention in chronic pain, characterized by widespread pain, fatigue, sleep disturbances, and mood disorders, commonly seen in conditions like fibromyalgia. However, systematic research on the involvement of nociplastic mechanisms in rare bone diseases remains lacking. Moreover, current pain management largely relies on empirical treatments, without mechanism-targeted individualized strategies. Therefore, systematically comparing pain phenotypes across different rare bone diseases may help identify shared non-skeletal drivers, providing a theoretical basis for developing more effective multimodal interventions. This study fills this gap by using large-scale online registry data to perform the first cross-disease analysis of pain characteristics in three rare bone diseases, offering new evidence for understanding the complex mechanisms of chronic bone pain.
Methods and Experiment
This study used a cross-sectional design based on adult participant data from the UK RUDY rare disease registry, including 94 FD/MAS, 94 OI, and 93 XLH patients, totaling 281 adults. All participants completed the baseline painDETECT questionnaire (PD-Q), which assessed pain phenotypes (categorized as nociceptive, neuropathic-like, or 'unclear'), pain intensity (current, average, and peak pain over the past four weeks), pain location, and evolution patterns. Body map data from the PD-Q were used to construct a modified widespread pain index (modified-WPI) to evaluate the presence of widespread pain. Demographic information, disease-specific features, and quality-of-life measures including the Hospital Anxiety and Depression Scale (HADS) and Pittsburgh Sleep Quality Index (PSQI) were also collected. Descriptive statistics were performed using R® and GraphPad software. Group comparisons used Kruskal-Wallis or chi-square tests, with post-hoc analyses using Dunn’s or Fisher’s exact tests, including correction for multiple testing. Multivariable analyses used linear and binomial regression models, adjusting for age and sex, to assess independent associations between pain phenotypes and pain, mental health, and sleep outcomes.Key Findings and Perspectives
Research Implications and Outlook
This study is the first to systematically reveal the striking consistency of pain characteristics across three distinct rare bone diseases, challenging the traditional view of explaining pain solely through skeletal pathology. It emphasizes that pain should be viewed as a multifactorial syndrome, in which non-skeletal factors such as central sensitization may play a central role. These findings have important clinical implications: pain assessment should extend beyond local skeletal abnormalities to include systematic screening for widespread pain, mood disorders, and sleep problems, to identify patients who may benefit from centrally targeted therapies (e.g., antidepressants, anticonvulsants). Future studies should adopt longitudinal designs to explore dynamic changes in pain phenotypes and their relationships with disease activity and treatment interventions, and use neuroimaging techniques to validate the presence of central sensitization. Furthermore, disease-specific pain management pathways should be developed, integrating pharmacological, psychological, and rehabilitative interventions to improve overall quality of life.
Conclusion
By analyzing 281 patients with FD/MAS, OI, and XLH, this study found that despite differing etiologies of these three rare bone diseases, their pain prevalence, intensity, and phenotype distribution are strikingly similar, suggesting non-skeletal factors may play a dominant role in pain mechanisms. While pain locations are disease-specific, widespread pain was present in 18% of patients and was significantly associated with anxiety, depression, and sleep disturbances, supporting the involvement of nociplastic pain mechanisms. Both neuropathic-like and 'unclear' pain phenotypes were independently associated with more severe pain and poorer quality of life, further underscoring the importance of central sensitization. Female sex was a significant predictor of pain, whereas age had no significant effect, reflecting the complex role of sex in chronic pain perception. These findings call on clinicians managing pain in rare bone disease patients to move beyond assessing local skeletal lesions, systematically screen for psychological and sleep comorbidities, and consider the potential of centrally targeted treatments. Future research should validate these findings and explore individualized multimodal intervention strategies to improve long-term outcomes. In summary, this study provides a new perspective on the complexity of chronic pain in rare bone diseases, advancing the paradigm shift from a 'bone-centric' to a 'patient-centric' approach in pain management.
