Genetic determinants of Paget’s Disease of Bone

PURPOSE OF REVIEW: To provide an overview of the role of genes and loci that predispose to Paget’s disease of bone and related disorders. RECENT FINDINGS: Studies over the past ten years have seen major advances in knowledge on the role of genetic factors in Paget’s disease of bone (PDB). Genome wide association studies have identified six loci that predispose to the disease whereas family based studies have identified a further eight genes that cause PDB. This brings the total number of genes and loci implicated in PDB to fourteen. Emerging evidence has shown that a number of these genes also predispose to multisystem proteinopathy syndromes where PDB is accompanied by neurodegeneration and myopathy due to the accumulation of abnormal protein aggregates, emphasising the importance of defects in autophagy in the pathogenesis of PDB. SUMMARY: Genetic factors play a key role in the pathogenesis of PDB and the studies in this area have identified several genes previously not suspected to play a role in bone metabolism. Genetic testing coupled to targeted therapeutic intervention is being explored as a way of halting disease progression and improving outcome before irreversible skeletal damage has occurred

Role of cannabinoids in the regulation of bone remodeling

The endocannabinoid system plays a key role in regulating a variety of physiological processes such as appetite control and energy balance, pain perception, and immune responses. Recent studies have implicated the endocannabinoid system in the regulation of bone cell activity and bone remodelling. These studies showed that endogenous cannabinoid ligands, cannabinoid receptors and the enzymes responsible for ligand synthesis and breakdown all play important roles in bone mass and in the regulation of bone disease. These findings suggest that the endocannabinoid pathway could be of value as a therapeutic target for the prevention and treatment of bone diseases. Here, we review the role of the skeletal endocannabinoid system in the regulation of bone remodelling in health and disease

Communicating absolute fracture risk reduction and the acceptance of treatment for osteoporosis

Healthcare professionals frequently communicate the benefits of treatments as a relative risk reduction (RRR) in the likelihood of an event occurring. Here we evaluated whether presenting the benefits of osteoporosis treatment as a RRR in fractures compared with an absolute risk reduction (ARR) changed the patient’s attitudes towards accepting treatment. We surveyed 160 individuals attending a specialised osteoporosis clinic for face-to-face consultations between May 2018 and Jan 2021. They were presented with information on RRR for the treatment being considered followed by ARR and after each question were asked about how likely they would be to start treatment on a 5-point scale (1 = very likely, 5 = very unlikely). Participants were less likely to accept treatment when it was presented as ARR (mean score 2.02 vs. 2.67, p < 0.001, 95% CI for difference − 0.82 vs − 0.47) and thirty-eight participants (23.7%) declined treatment with knowledge of their ARR when they would have accepted the same treatment based on the RRR. Individuals who declined treatment had a lower 5-year risk of fracture than those who accepted treatment (9.0 vs. 12.5%, p < 0.001, 95% CI − 5.0 to − 1.6) and as fracture risk decreased, the participant was less likely to accept treatment (Spearman r − 0.32, 95% CI − 0.46 to − 0.17, p ≤ 0.001). Whilst presentation of data as ARR more accurately reflects individual benefit and helps facilitate shared decision-making, clinicians should be aware that this will lead to a proportion of patients with lower fracture risk declining treatment for osteoporosis

Probiotics inhibit cartilage damage and progression of osteoarthritis in mice

Increasing interest has focussed on the possible role of alterations in the microbiome in the pathogenesis of metabolic disease, inflammatory disease, and osteoporosis. Here we examined the role of the microbiome in a preclinical model of osteoarthritis in mice subjected to destabilisation of medical meniscus (DMM). The intestinal microbiome was depleted by broad-spectrum antibiotics from 1 week before birth until the age of 6 weeks when mice were subjected reconstitution of the microbiome with faecal microbial transplant (FMT) followed by the administration of a mixture of probiotic strains Lacticaseibacillus paracasei 8700:2, Lactiplantibacillus plantarum HEAL9 and L. plantarum HEAL19 or vehicle. All mice were subjected to DMM at the age of 8 weeks. The severity of osteoarthritis was evaluated by histological analysis and effects on subchondral bone were investigated by microCT analyses. The combination of FMT and probiotics significantly inhibited cartilage damage at the medial femoral condyle such that the OARSI score was 4.64 ± 0.32 (mean ± sem) in the FMT and probiotic group compared with 6.48 ± 0.53 in the FMT and vehicle group (p = 0.007). MicroCT analysis of epiphyseal bone from the femoral condyle showed that the probiotic group had higher BV/TV, increased Tb.Th, and moderately thicker subchondral bone plates than the control group. There was no difference between groups in joint inflammation or in serum concentrations of inflammatory cytokines and chemokines. We conclude that treatment with probiotics following FMT in mice where the microbiome has been depleted inhibits DMM-induced cartilage damage and impacts on the structure of subchondral bone particularly at the femoral condyle. While further studies are required to elucidate the mechanism of action, our research suggests that these probiotics may represent a novel intervention for the treatment of osteoarthritis

Diagnosis and management of primary hyperparathyroidism in Europe

Background: There is continued debate as to the optimal strategy for diagnosis and management of primary hyperparathyroidism (PHPT). Aim: To compare the strategies used for the diagnosis and management of PHPT by physicians in five European countries. Design: Questionnaire-based survey. Methods: Physicians in France, Germany, the UK, Italy and Spain were invited to participate in the survey which was conducted using a web-based interface and were included in the evaluation if they had treated a minimum of four patients suffering from PHPT in the past year. Results: A total of 421 physicians completed the survey. The majority of respondents were endocrinologists (68%) but other specialities included rheumatologists (10.9%), internists (11.8%) and urologists (9.2%). Diagnostic methods were similar across different countries and specialities but there were significant differences in the proportion of physicians who recommended parathyroidectomy in asymptomatic patients with indications for surgery according to the 2002 National Institutes of Health (NIH) consensus conference statement (χ(2 )= 26.1, P < 0.001). The proportion of patients referred for surgery ranged from 32% in Italy to 66% in Spain with intermediate values in Germany (64%), France (55%) and the UK (53%). Conversely, pharmacological therapy was used most frequently for these patients in Italy (32%) and least frequently in Spain (14%). Conclusion: Significant differences exist in the management of patients with asymptomatic PHPT in countries across Europe who have accepted indications for surgery according to the NIH consensus statement. Further research will be required to explore the reasons for this and to determine if these differences affect the clinical outcome of PHPT