Chronic Pain and Bone-Related Pathologies: A Narrative Review.

Purpose: Pain related to bone may occur as a result of trauma, bone fracture, genetic disease, arthritis, benign or malignant primary bone tumors and bone cancer metastases. We discuss the pathophysiology of chronic bone-related pain, treatment options and therapeutic perspectives. Methods: Using predefined terms, we searched PubMed, MEDLINE, and Google Scholar for meta-analyses, evidence-based reviews, and clinical practice guidelines. This narrative article reviews pathologies linked to chronic bone pain and discusses the preventive and therapeutic strategies for better bone pain management. Results: Pathophysiology of bone-related pain is complex, especially in cancer conditions and missing gaps are underlined. Treatment of pain, after adequate evaluation, includes classical analgesics, adjuvants for neuropathic and refractory pain, specific bone drugs, surgery and non-pharmacological approaches. Prevention of chronic bone pain encompasses prevention of central sensitization and of causal diseases. Conclusion: Translational research, drug repurposing, an interdisciplinary approach and a person-centered assessment to evaluate, beyond pain, physical, social and functional abilities, are proposed future directions to improve chronic bone pain management and optimize independence and quality of life. Summary: Chronic bone-related pain is frequent and is associated with an impairment of quality of life. In this review, we summarize the pathophysiology of chronic bone pain, describe treatment approaches and envisage new avenues for pain alleviation. Our article will help doctors manage chronic bone pain and address unmet needs for future research to alleviate bone-related pain.

ACSM1 and ACSM3 Regulate Fatty Acid Metabolism to Support Prostate Cancer Growth and Constrain Ferroptosis.

Solid tumors are highly reliant on lipids for energy, growth, and survival. In prostate cancer, the activity of the androgen receptor (AR) is associated with reprogramming of lipid metabolic processes. Here, we identified acyl-CoA synthetase medium chain family members 1 and 3 (ACSM1 and ACSM3) as AR-regulated mediators of prostate cancer metabolism and growth. ACSM1 and ACSM3 were upregulated in prostate tumors compared with nonmalignant tissues and other cancer types. Both enzymes enhanced proliferation and protected prostate cancer cells from death in vitro, whereas silencing ACSM3 led to reduced tumor growth in an orthotopic xenograft model. ACSM1 and ACSM3 were major regulators of the prostate cancer lipidome and enhanced energy production via fatty acid oxidation. Metabolic dysregulation caused by loss of ACSM1/3 led to mitochondrial oxidative stress, lipid peroxidation, and cell death by ferroptosis. Conversely, elevated ACSM1/3 activity enabled prostate cancer cells to survive toxic levels of medium chain fatty acids and promoted resistance to ferroptosis-inducing drugs and AR antagonists. Collectively, this study reveals a tumor-promoting function of medium chain acyl-CoA synthetases and positions ACSM1 and ACSM3 as key players in prostate cancer progression and therapy resistance. Significance: Androgen receptor-induced ACSM1 and ACSM3 mediate a metabolic pathway in prostate cancer that enables the utilization of medium chain fatty acids for energy production, blocks ferroptosis, and drives resistance to clinically approved antiandrogens.

Library size confounds biology in spatial transcriptomics data.

Spatial molecular data has transformed the study of disease microenvironments, though, larger datasets pose an analytics challenge prompting the direct adoption of single-cell RNA-sequencing tools including normalization methods. Here, we demonstrate that library size is associated with tissue structure and that normalizing these effects out using commonly applied scRNA-seq normalization methods will negatively affect spatial domain identification. Spatial data should not be specifically corrected for library size prior to analysis, and algorithms designed for scRNA-seq data should be adopted with caution.

Prevalence of FGF23 elevation in patients with hypophosphatemia.

BACKGROUND AND AIMS: To investigate the contribution of FGF23 in explaining the cases of hypophosphatemia observed in clinical practice, we aimed to determine for the first time the prevalence of FGF23 elevation in patients with hypophosphatemia and to describe the different mechanisms of FGF23-related hypophosphatemic disorders. MATERIALS AND METHODS: We performed a prospective, observational, multicenter, cohort study of 260 patients with hypophosphatemia. Blood measurements (PTH, 1,25-dihydroxyvitamin D, bone alkaline phosphatase, 25-hydroxyvitamin D, and FGF23) were performed on a Liaison XL® (DiaSorin) analyzer. RESULTS: Primary elevation of FGF23 (>95.4 pg/mL) was reported in 10.4% (95CI: 7.0-14.7) of patients (n = 27) with hypophosphatemia, suggesting that at least 1 in 10 cases of hypophosphatemia was erroneously attributed to an etiology other than FGF23 elevation. Patients with elevated blood FGF23 were grouped according to the etiology of the FGF23 elevation. Thus, 10 patients had a renal pathology, chronic kidney disease or post-renal transplantation condition. The remaining patients (n = 17) had the following etiologies: malignancies (n = 9), benign pancreatic tumor (n = 1), post-cardiac surgery (n = 4), cirrhosis (n = 2), and chronic obstructive pulmonary disease (n = 1). CONCLUSION: In order to improve patient management, it seems essential to better integrate plasma FGF23 measurement into the routine evaluation of hypophosphatemia.

Osteoporosis treatment and pain relief: A scoping review.

BACKGROUND AND OBJECTIVE: Anti-osteoporosis (OP) drugs have been suggested to contribute to pain reduction during OP management. This scoping review aimed at mapping the literature on pain relief with anti-OP drugs in OP treatment. DATABASES AND DATA TREATMENT: Medline, Pubmed and Cochrane databases were searched by two reviewers with keywords combinations. Randomized controlled and real-life English studies, pain as an endpoint, antiosteoporosis drugs were inclusion criteria. Case reports, surveys, comment letters, conference abstracts, animal studies and grey literature were excluded. Predetermined data were extracted by two reviewers and disagreement solved through discussion. RESULTS: A total of 130 articles were identified, 31 publications were included, 12 randomized clinical trials and 19 observational studies. Pain reduction was assessed by different tools: Visual Analogue Scale, Verbal Rating Scale, Facial Scale or as a domain of quality of life questionnaires including Short form 8, 36, mini-OP, Japanese OP, Qualeffo, Roland Morris Disability questionnaires. Collective data show that anti-OP drugs may display an analgesic effect that may be linked to the local mode of action of drugs on bone and consecutive modulation of pain sensitization. The methodology of the studies showed a heterogeneity of endpoints, comparators, statistical approaches and follow-up duration. CONCLUSION: Considering the limitations of the literature, there is a need for more rigorous trials and larger real-life studies taking into account the recommendations published for research in rheumatology and in pain medicine. The identification of responders, patient subtypes, and of analgesic-effect doses would allow optimization and individualization for pain relief in patients with OP. SIGNIFICANCE STATEMENT: This scoping review shows that anti-OP drugs may improve pain and quality of life of patients with OP. The heterogeneity in design, choice of endpoints, methodology, comparators and follow-up duration of included randomized clinical trials and real-life studies does not allow so far to identify a predominant antiosteoporosis drug or an optimal dosage for pain relief. These gaps need to be addressed and warrant further research in the future for optimizing pain improvement in the course of OP drug treatment.

Glucocorticoid trajectories over 2 years in patients with rheumatoid arthritis in a real-life setting.

OBJECTIVES: To analyse glucocorticoid (GC) use and trajectories in a real-life cohort of rheumatoid arthritis (RA). METHODS: Patients with RA included in the longitudinal RCVRIC cohort for initiating or changing biological disease-modifying antirheumatic drugs, were compared for the use of GCs at baseline. Among the GC users, the GC dose was analysed over 2 years of follow-up by group-based trajectory models. Characteristics and outcomes were compared between the trajectories. RESULTS: Among the 184 patients (RA duration 4.2 years (1.3; 12.6), Disease Activity Scores (DAS)28-C reactive protein (CRP) 4.24±2.14), 81 (44%) were on GCs. The GC users were significantly older, had higher CRP and Health Assessment Questionnaire (HAQ), more hypertension and lower lumbar T-score, but similar activity and erosive scores. Among the GC users, two trajectories were identified: trajectory 1 (n=20, 25%) with GC discontinuation in the first year and trajectory 2 (n=61, 75%) with maintenance of low-dose GCs at 2 years. Trajectory 2 was significantly associated with higher HAQ, a longer GC duration and a less frequent methotrexate association. After adjustment for HAQ, GC duration and MTX use, good EULAR responses were less frequent at 6 months and 1 year in the GC maintenance trajectory (38.3% vs 81.3%, p=0.03; 42.0% vs 82.4%, p=0.02). Diabetes, fractures and increased body mass index were noted in trajectory 2. CONCLUSION: GCs were used in almost half of patients with established RA in real-world practice. For the majority of GC users, a long-term low dose of GCs is maintained over 2 years. These results highlight the difficulties with stopping GCs, the lack of consensus for the efficacy-safety balance of GCs, and the need to individualise the best GC tapering.

Common miRNAs of Osteoporosis and Fibromyalgia: A Review.

A significant clinical association between osteoporosis (OP) and fibromyalgia (FM) has been shown in the literature. Given the need for specific biomarkers to improve OP and FM management, common miRNAs might provide promising tracks for future prevention and treatment. The aim of this review is to identify miRNAs described in OP and FM, and dysregulated in the same direction in both pathologies. The PubMed database was searched until June 2023, with a clear mention of OP, FM, and miRNA expression. Clinical trials, case-control, and cross-sectional studies were included. Gray literature was not searched. Out of the 184 miRNAs found in our research, 23 are shared by OP and FM: 7 common miRNAs are dysregulated in the same direction for both pathologies (3 up-, 4 downregulated). The majority of these common miRNAs are involved in the Wnt pathway and the cholinergic system and a possible link has been highlighted. Further studies are needed to explore this relationship. Moreover, the harmonization of technical methods is necessary to confirm miRNAs shared between OP and FM.

Comparison of the cardiovascular risk profile of rheumatoid arthritis versus hand osteoarthritis patients.

It is clear that there is an increased cardiovascular (CV) risk in rheumatoid arthritis (RA) as a result of systemic inflammation. Hand osteoarthritis (HOA) patients, also have an increased CV risk, but the causes are still debated. Our objective was to compare CV risk factors and risk scores between HOA and RA patients. Thirty-five HOA patients were matched by age (< 3 years) and sex to 35 RA patients in a case-control study. We compared their CV risk profiles and their risk of occurrence of CV events at 10 years using the risk equations SCORE1, SCORE2, and QRISK3. There was a significant increase in SCORE1, SCORE2, but not in QRISK3 in the RA group compared to the HOA group, provided that the multiplication coefficient for RA was applied. This increase was found to no longer be significant for SCORE1 when RA patients have low disease activity (DAS28 ≤ 3.2; n = 8). There was no difference between groups in the frequency of metabolic syndrome, blood pressure, abdominal circumference, body mass index, uricemia, triglyceridemia, HDL cholesterolemia, or pain intensity. Conversely, HOA patients had higher LDL cholesterol and fasting blood glucose levels, in the main analysis and in the subgroup of moderate/high RA activity patients (DAS28 > 3.2; n = 26). We found a higher CV risk in RA compared to HOA patients with moderate/high disease activity. The increased CV risk reported in OA remains to be confirmed in HOA, but these patients appear to have a pro-atherogenic lipid and glycemic profile.

Periostin in Osteoporosis and Cardiovascular Disease.

Context: Osteoporosis (OP) and cardiovascular disease (CVD), prevalent disorders worldwide, often coexist and share common risk factors. The identification of common biomarkers could significantly improve patients' preventive care. Objectives: The objectives are 1, to review periostin (Postn) involvement in osteoporosis and in CVD, and 2, identify if Postn could be a common biomarker. Design: This is a scoping review on Postn in OP and CVD. Methods: Databases were searched, in vitro and in vivo, for publications in English on Postn, bone, and the cardiovascular system, with no limit regarding publication date. Results: Postn appears as a key factor in OP and CVD. Its role as a potential biomarker in both pathologies is described in recent studies, but a number of limitations have been identified. Conclusions: Current evidence provides fragmented views on Postn in OP and CVD and does not encapsulate Postn as a common pivotal thread linking these comorbidities. A number of gaps impede highlighting Postn as a common biomarker. There is room for future basic and clinical research with Postn as a marker and a target to provide new therapeutic options for aging patients with concomitant OP and CVD.

Tumor-Induced Osteomalacia in Patients With Malignancy: A Meta-analysis and Systematic Review of Case Reports.

CONTEXT: Tumor-induced osteomalacia (TIO) due to fibroblast growth factor 23 (FGF23) overexpression is becoming recognized in patients with malignancy. The condition may be underdiagnosed, with a scarce medical literature. OBJECTIVE: To perform a meta-analysis of case reports to allow a better understanding of malignant TIO and its clinical implications. METHODS: Full texts were selected according to strict inclusion criteria. All case reports were included where patients had hypophosphatemia, malignant TIO, and FGF23 blood levels. Thirty-two of 275 eligible studies (n = 34 patients) met inclusion criteria. A list of desired data was extracted and graded for methodological quality. RESULTS: Prostate adenocarcinoma (n = 9) were the most tumors reported. Twenty-five of 34 patients had a metastatic disease and a poor clinical outcome was reported for 15 of 28 patients. The median levels of blood phosphate and C-terminal FGF23 (cFGF23) were 0.40 mmol/L and 788.5 RU/mL, respectively. For most of patients, blood PTH was elevated or within range, and calcitriol levels were inappropriately low or normal. Alkaline phosphatase concentrations were increased for 20 of 22 patients. The cFGF23 values were significantly higher for patients with a poor clinical outcome when compared to other patients (1685 vs 357.5 RU/mL). In case of prostate cancer, cFGF23 levels were significantly lower (429.4 RU/mL) than for other malignancies (1007.5 RU/mL). CONCLUSION: We report for the first time a detailed description of the clinical and biological characteristics of malignant TIO. In this context, FGF23 blood measurement would be of value for the diagnostic workup, prognostication, and follow-up of patients.

A case of restitution ad integrum in Gorham-Stout disease.

Gorham-Stout disease (or "vanishing bone" disease) is a rare mono or polyostotic disease of unknown etiology, characterized by intraosseous angiomatous proliferation leading to bone resorption. We report the case of a 17-year-old woman presenting with symptomatic osteolytic lesions of the frontal vault. Imaging was suggestive of Gorham-Stout disease without argument for other diagnoses. An unusual evolution of the "vanishing bone" lesions was observed on the scan after one year, with a full recovery of the lytic lesions. This report shows for the first time a spontaneous restitutio ad integrum of bone matrix in Gorham-Stout disease.

Hypophosphatemia related to a neuro-endocrine tumor of the pancreas: A case report.

BACKGROUND: Tumor-induced osteomalacia (TIO) is a paraneoplastic syndrome characterized by hypophosphatemia associated with elevated fibroblast growth factor 23 (FGF23). TIO is primarily caused by benign mesenchymal tumors of the soft tissue and skeleton. Rarely, it is associated with a solid tumor or hematological malignancy. To date, no case of osteomalacia related to pancreatic cancer has been reported in the literature. CASE REPORT: A 77-year-old woman was admitted to the rheumatology department (RD) of the Clermont-Ferrand University Hospital (France) for further evaluation of her hypophosphatemia. The patient reported bone pain, myalgia, and asthenia. Further laboratory tests revealed hyperphosphaturia, normocalcemia, low serum calcitriol, elevated serum alkaline phosphatase (ALP), and elevated plasma parathyroid hormone (PTH). A renal phosphate depletion disorder was suspected as an etiology for this hypophosphatemia. Finally, FGF23 levels were found to be significantly elevated, leading to a definitive diagnosis of pancreatic neuroendocrine tumor. CONCLUSION: This is the first report of hypophosphatemic osteomalacia related to pancreatic cancer. Therefore, in the setting of hypophosphatemia associated with renal phosphate wasting and low calcitriol level, plasma FGF23 measurement should be considered.

Cross-Talks between the Cardiovascular Disease-Sarcopenia-Osteoporosis Triad and Magnesium in Humans.

Magnesium (Mg) is a pivotal and very complex component of healthy aging in the cardiovascular-muscle-bone triad. Low Mg levels and low Mg intake are common in the general aging population and are associated with poorer outcomes than higher levels, including vascular calcification, endothelial dysfunction, osteoporosis, or muscle dysfunction/sarcopenia. While Mg supplementation appears to reverse these processes and benefit the triad, more randomized clinical trials are needed. These will allow improvement of preventive and curative strategies and propose guidelines regarding the pharmaceutical forms and the dosages and durations of treatment in order to optimize and adapt Mg prescription for healthy aging and for older vulnerable persons with comorbidities.

Magnesium for Pain Treatment in 2021? State of the Art.

BACKGROUND: Magnesium (Mg) is commonly used in clinical practice for acute and chronic pain and has been reported to reduce pain intensity and analgesics consumption in a number of studies. Results are, however, contested. OBJECTIVES: This review aims to investigate randomised clinical trials (RCTs) on the effectiveness of Mg treatment on pain and analgesics consumption in situations including post-operative pain, migraine, renal pain, chronic pain, neuropathic pain and fibromyalgia. RESULTS: The literature search identified 81 RCTs (n = 5447 patients) on Mg treatment in pain (50 RCTs in post-operative pain, 18 RCTs in migraine, 5 RCTs in renal pain, 6 RCTs in chronic/neuropathic pain, 2 RCTs in fibromyalgia). CONCLUSION: The level of evidence for the efficacy of Mg in reducing pain and analgesics consumption is globally modest and studies are not very numerous in chronic pain. A number of gaps have been identified in the literature that need to be addressed especially in methodology, rheumatic disease, and cancer. Additional clinical trials are needed to achieve a sufficient level of evidence and to better optimize the use of Mg for pain and pain comorbidities in order to improve the quality of life of patients who are in pain.

The Effect of TNF and Non-TNF-Targeted Biologics on Body Composition in Rheumatoid Arthritis.

Rheumatoid arthritis (RA) is associated with a decrease in lean mass and stability or even an increase in fat and ectopic adipose tissue. A few data are available on body composition changes under treatment, and data are still controversial. Body composition was assessed before initiation of biologic disease-modifying antirheumatic drug (bDMARD) and after 6 and 12 months of stable treatment. Eighty-three RA patients were included (75% of women, mean age 58.5 ± 10.8 years) of whom 47 patients treated with TNF inhibitor (TNFi), 18 with non-TNF-targeted biologic (Non-TNFi), and 18 with conventional DMARD (cDMARD) alone. In the TNFi group, total lean mass, fat-free mass index, and skeletal muscle mass index significantly increased at 1 year. An increase in subcutaneous adipose tissue (SAT) without change for the visceral or body fat composition was associated. These changes were associated with an improvement in strength and walking test. In non-TNFi or cDMARD groups, no significant changes for body composition or muscle function were observed at 1 year. However, no significant differences for treatment x time interaction were noted between group treatments. In active RA patients starting first bDMARD, treatment with TNFi over 1 year was associated with favorable changes of the body composition and muscle function.

A new LRP6 variant and Camurati-Engelmann-like disease.

INTRODUCTION: Camurati-Engelmann disease is a rare autosomal dominant bone dysplasia belonging to the group of craniotubular hyperostoses. Genetic analysis classically shows mutation on TGFß1 gene. CASE REPORT: A young woman was hospitalized with intense pain in lower limbs, associated to radiographic hyperostosis and sclerosis of the long bones. RESULTS: Mutation on LRP6 has recently been associated to high bone mass. In this case report, a rare missense variant on LRP6 gene was associated to radiographic features of Camurati-Engelmann. CONCLUSIONS: More studies should be conducted to assess the pathological role of this variant in Camurati-Engelmann-like disease.

Where Two Common Conditions of Aging Meet: Osteoarthritis and Sarcopenia.

Osteoarthritis and sarcopenia are the most frequently described musculoskeletal disorders in older persons but the intertwining of these conditions and of their functional and cellular causes is complex. This narrative review aims to identify the links between osteoarthritis and sarcopenia described 1-in clinical studies, 2-in in vitro studies, and 3-the available treatment strategies for both conditions. Electronic databases were used for the literature search of all studies investigating the relationship between sarcopenia and the presence of concomitant osteoarthritis. This review identified a limited number of clinical and morphometric studies on the complex relationship between osteoarthritis and sarcopenia. Studies present a number of methodological limitations due to definition and assessment of both entities. Low lean mass is one of the main actors of this cross-talk between muscle and bone, and adipose tissue plays a major role that had been underestimated. Bone Morphogenetic Proteins and myostatin pathways are key mediators and play an important role in both muscle and bone homeostasis. Common therapeutic recommendations are still missing. There is a need for good quality prospective studies on concomitant sarcopenia and osteoarthritis, more translational research, and pharmacological and non-pharmacological therapies in order to identify common denominators for the management of sarcopenia, osteoarthritis, and their comorbidities.

Selected serum microRNA, abdominal aortic calcification and risk of osteoporotic fracture.

CONTEXT: MicroRNA (miRNA) regulate post-transcriptionally the expression of osteogenesis and angiogenesis associated genes and emerge as potential non-invasive biomarkers in vascular and bone diseases. Severe abdominal aortic calcification (AAC) is associated with higher risk of cardiovascular event and of fragility fracture. OBJECTIVE: To identify miRNA linked to the aggravation of AAC and to incident osteoporotic fracture. DESIGN: Postmenopausal women (>50 years) with available serum at inclusion and data for each outcome (Kauppila score and incident fracture) were selected from the OFELY prospective cohort. We conducted a case-control study in 434 age-matched women, 50% with incident osteoporotic fracture over 20 years of follow-up and a second study in 183 women to explore AAC over 17 years. METHODS: Serum expression of three miRNA involved in vascular calcification and bone turnover regulation (miRs-26a-5p,-34a-5p, and -223-5p) was quantified at baseline by TaqMan Advanced miRNA technology and expressed by relative quantification. Outcomes were the association of miRNA levels with (1) incident osteoporotic fractures during 20 years, (2) AAC aggravation during 17 years. RESULTS: MiRNA level was not associated with incident fractures (miR-26a-5p: 1.06 vs 0.99, p = 0.07; miR-34a-5p: 1.15 vs 1.26, p = 0.35; miR-223a-5p: 1.01 vs 1.05, p = 0.32). 93 women had an increase in Kauppila score over 17 years while 90 did not. None of the miRNAs was associated with an aggravation in AAC (miR-26a-5p: 1.09 vs 1.10, p = 0.95; miR-34a-5p: 0.78 vs 0.73, p = 0.90; miR-223-5p: 0.97 vs 0.78, p = 0.11). CONCLUSIONS: Circulating miR-26a-5p, -34a-5p and -223-5p are not significantly associated with incident fracture and AAC aggravation.