title: Deciphering the mechanisms of pain in Paget's disease
Creators: name: Berg, Kathryn
Publisher: name: The University of Edinburgh
Year: 2023
Subjects: subject: Paget's Disease of Bone
subject: Pain
subject: Quantitative Sensory Testing

description: BACKGROUND: Pain is the most common symptom of Paget’s Disease of Bone (PDB), affecting between 60% and 70% of patients who present to clinic, but its mechanisms are incompletely understood. In some cases, the bone pain is related to bone remodelling which is reflected by elevated alkaline phosphatase (ALP) in the blood. However, many patients with elevated biochemical markers of bone remodelling do not experience any pain. Conversely, some patients with elevated biochemical markers see no improvement in pain following treatment with bisphosphonates. The Pain in Paget’s (PiP) Study was established in 2019 to explore the different mechanisms of pain in this patient group. AIMS: The aim of this research project was to establish the likely cause of pain in patients with PDB, evaluate the effectiveness of bisphosphonate treatment, and to explore the sensory profiles of patients with PDB. METHODS: The PiP Study was a cross-sectional study which was managed and undertaken by the author in 12 centres around the UK. This thesis refers to the data related to the first 120 participants recruited to the PiP Study. Clinical data was recorded which related to demographics, comorbidities, treatment and treatment response, presence of pain and the likely cause of that pain. Questionnaires were answered in-clinic by each participant. A novel approach in this work was Quantitative Sensory Testing (QST) which was performed on each participant to assess differences in somatosensory processing on the skin above affected bone and contralateral unaffected bone. Blood samples were taken to assess ALP values. Data was collected using REDCap software on a secure database held on the Institute of Genetics and Cancer servers. Data was analysed and graphed using MiniTab and GraphPad software. RESULTS: Data relating to 120 study participants was analysed for the purpose of this thesis. Participants who reported any musculoskeletal pain were allocated to the ‘Pain’ group, while those who didn’t were allocated to the ‘No Pain’ group. Participants who did not experience musculoskeletal pain were typically diagnosed at an earlier age (p=0.040) than those who did experience pain but there were no significant differences between groups in gender, smoking history, BMI or family history. There was no significant difference in disease severity between the two groups as measured by ALP levels (p=0.418) and mean number of affected bones (p = 0.494). PDB of the pelvis was significantly more common (p=0.032) in the group who experienced pain, as was the presence of osteoarthritis (p=&lt;0.001). The cause of pain attributed to each participant was determined by a combination of a medical record search, a physical clinical examination and a clinical history. Of the 82 participants who reported bone pain, 22 (26.8%) were thought to have pain which was attributable to PDB. Of the 60 participants who did not have pain attributable to PDB, 38 (63.3%) had pain associated with OA unrelated to a PDB lesion. The ‘No Pain’ group was significantly more likely to report that their pain has ‘Disappeared’ following anti-Pagetic treatment (p = 0.022). Quantitative Sensory Testing (QST) indicated that there was a significantly higher pain response above the site of PDB when compared to the non-Pagetic site in the following: hot roller testing (p = 0.047), pain threshold testing (p = 0.007), pin prick testing (p=0.003), and wind-up pinprick testing (p = &lt;0.001). Pain thresholds were significantly reduced above Pagetic bone (p = 0.023). CONCLUSIONS: The PiP Study is the largest study specifically looking at pain in PDB and is the first study to utilise QST in its assessment. The pain reported by participants with PDB in this study was most often caused by unrelated OA. Although current pain was not attributed to PDB in the majority of the participants studied, there are differences noted in the way that pain is processed above Pagetic bone when compared to contralateral non-Pagetic bone. Disease severity as measured by ALP and mean number of affected bones does not appear to influence the presence of pain in a clinically recruited patient group. This emphasises the importance of defining the cause of pain in patients with PDB so that appropriate treatment can be given.