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BACKGROUND: In fibrous dysplasia/McCune-Albright syndrome (FD/MAS), mosaic mutations in the GNAS gene lead to locally abnormal bone turnover. Additionally, patients with FD/MAS, particularly with thoracic lesions, have an increased risk for breast cancer. Development and progression of breast cancer has been associated with expression of Receptor Activator of NF-κB ligand (RANKL) in mammary tissue, and due to the GNAS mutation, RANKL is systemically increased in patients with FD/MAS. Yet it is unknown whether breast cancer in FD/MAS is also dependent on RANKL. We hypothesized that the GNAS mutation might induce RANKL overproduction and an oncogenic niche in mammary tissue, and examined RANKL expression in breast cancer tissue of patients with FD/MAS compared to controls.METHODS: Nine patients with FD/MAS and breast cancer were included and clinical data were retrieved. Patients were matched to controls with breast cancer without FD/MAS based on age and tumor type. Three pregnant breast cancer patients were included as positive controls. Immunohistochemical detection of RANKL was performed on formalin-fixed paraffin-embedded breast cancer specimens. Staining intensity was classified as weak, moderate or intense. The area of positive RANKL staining divided by the total ductal-lobular area was assessed (positive area percentage, PAP). Number of patients with RANKL expression was compared between FD/MAS and control group by chi-square (χ 2) test, the PAP by Mann-Whitney U test (MWU). RESULTS: RANKL expression was observed in 3 patients with FD/MAS (38 %), mainly in healthy tissue, and none of the control patients (χ 2p = 0.055). The FD/MAS group demonstrated considerably more intense staining than the control group, comparable to positive controls. The median PAP was 0.64 % (range 0.14-2.04 %) in the 3 FD/MAS patients with RANKL expression, 0.01 % (Q1-Q3: 0.0003-0.514 %) in the entire FD/MAS group, 0.006 % (Q1-Q3: 0.001-0.012 %) in the control group (MWU = 0.574), and 0.19 % (0.08-0.32 %) in the pregnant patients. All patients with FD/MAS and RANKL expression had thoracic bone lesions, but no correlation was observed between RANKL expression and presence of the GNAS mutation or FD disease burden. CONCLUSIONS: The triad of a higher number of patients, higher positive area percentage and stronger intensity in the FD/MAS compared to the control group indicates that RANKL may be upregulated in mammary tissue in a subset of patients with FD/MAS, which may explain the increased risk for breast cancer, although the clinical significance remains unclear. Further research is needed to establish risk profiles for the development of RANKL-positive breast cancer and to improve early screening and treatment.

Fibrodysplasia ossificans progressiva (FOP) is a rare genetic disorder leading to progressive heterotopic ossifications (HO) of muscles, tendons, and ligaments, which can be induced by trauma or by surgery. Despite strong medical advice to the contrary, an FOP patient insisted on surgery to alleviate her complete trismus, which caused an unbearable impact on her quality of life (QOL). The entire trismus history of this FOP patient is presented. [18F]-NaF position emission tomography/computed tomography (PET/CT) scans were introduced as an imaging method for heterotopic bone formation activity. To place our findings into context, a systematic review on jaw surgery in FOP was performed. After falling down the stairs, a 9-year-old patient developed mobility impairment of her left-sided jaw. During the following 13 years bone scintigraphy showed persistent activity of the disease leading to progressive left-sided zygomatico-mandibular fusion by HO, resulting in complete trismus. Within 1 month after HO removal on the left side and a matching right coronoidectomy, [18F]-NaF PET/CT demonstrated a substantial flare-up activity followed by new HO in both masseter and temporalis muscles. Despite recurrent HO and trismus her QOL increased due to a stable increased interincisal opening of 5.5 mm. Although systematic review reveals a 100% risk of HO recurrence after jaw surgery, information on improved QOL is scarce. In conclusion, surgery in FOP may be beneficial for QOL despite new HO formation. Assessment of disease activity using [18F]-NaF PET/CT is possible before HO is evident on CT and may serve as a new and quantitative marker of the disease. © 2017 The Authors. JBMR Plus Published by Wiley Periodicals, Inc. on behalf of the American Society for Bone and Mineral Research.

Background & Aims: Crohn's disease (CD) is associated with an increased prevalence of osteoporosis, but the pathogenesis of this bone loss is only partly understood. We assessed bone structure and remodeling at the tissue level in patients with quiescent CD. We also investigated the roles of osteocyte density and apoptosis in CD-associated bone loss. Methods: The study included 23 patients with quiescent CD; this was a subgroup of patients from a large randomized, double-blind, placebo-controlled, multicenter trial. We obtained transiliac bone biopsy samples and performed histomorphometric analysis. Results: were compared with data from age- and sex-matched healthy individuals (controls). Results: Trabecular bone volume was decreased among patients with CD compared with controls (18.90% vs 25.49%; P < .001). The low bone volume was characterized by decreased trabecular thickness (120.61 vs 151.42 μm; P < .01). Bone formation and resorption were reduced, as indicated by a decreased mineral apposition rate (0.671 vs 0.746 μm/day; P < .01) and a low osteoclast number and surface area compared with controls and published values, respectively. In trabecular bone of patients with CD, osteocyte density and apoptosis were normal. The percentage of empty lacunae among patients was higher than that of published values in controls. Conclusions:: In adult patients with quiescent CD, bone histomorphometric analysis revealed a reduction in bone mass that was characterized by trabecular thinning. The CD-associated bone loss was caused by reduced bone formation, possibly as a consequence of decreased osteocyte viability in the patients' past. © 2011 AGA Institute.

Background: Polymorphisms of the vitamin D receptor (VDR) gene have been implicated in the genetic regulation of bone mineral density (BMD). However, the clinical impact of these variants remains unclear. Objective: To evaluate the relation between VDR polymorphisms, BMD, and fractures. Design: Prospective multicenter large-scale association study. Setting: The Genetic Markers for Osteoporosis consortium, involving 9 European research teams. Participants: 26 242 participants (18 405 women). Measurements: Cdx2 promoter, FokI, BsmI, ApaI, and TaqI polymorphisms; BMD at the femoral neck and the lumbar spine by dual x-ray absorptiometry; and fractures. Results: Comparisons of BMD at the lumbar spine and femoral neck showed nonsignificant differences less than 0.011 g/cm2 for any genotype with or without adjustments. A total of 6067 participants reported a history of fracture, and 2088 had vertebral fractures. For all VDR alleles, odds ratios for fractures were very close to 1.00 (range, 0.98 to 1.02) and collectively the 95% CIs ranged from 0.94 (lowest) to 1.07 (highest). For vertebral fractures, we observed a 9% (95% CI, 0% to 18%; P = 0.039) risk reduction for the Cdx2 A-allele (13% risk reduction in a dominant model). Limitations: The authors analyzed only selected VDR polymorphisms. Heterogeneity was detected in some analyses and may reflect some differences in collection of fracture data across cohorts. Not all fractures were related to osteoporosis. Conclusions: The FokI, BsmI, ApaI, and TaqI VDR polymorphisms are not associated with BMD or with fractures, but the Cdx2 polymorphism may be associated with risk for vertebral fractures.