Update on osteoporosis from the 2014 Santa Fe Bone symposium.

The 2014 Santa Fe Bone Symposium provided a setting for the presentation and discussion of the clinical relevance of recent advances in the fields of osteoporosis and metabolic bone disease. The format included oral presentations of abstracts by endocrinology fellows, plenary lectures, panel discussions and breakout sessions, with ample opportunities for informal discussions before and after scheduled events. Topics addressed in these proceedings included a review of the important scientific publications in the past year, fracture prevention in patients with dysmobility and immobility, fracture liaison services for secondary fracture prevention, management of pre-menopausal osteoporosis, the role of bone microarchitecture in determining bone strength, measurement of microarchitecture in clinical practice and methods to improve the quality of bone density testing. This is a report of the proceedings of the 2014 Santa Fe Bone Symposium.

Adjusting fracture probability by trabecular bone score.

The aim of the present study was to determine the impact of trabecular bone score on the probability of fracture above that provided by the clinical risk factors utilized in FRAX. We performed a retrospective cohort study of 33,352 women aged 40-99 years from the province of Manitoba, Canada, with baseline measurements of lumbar spine trabecular bone score (TBS) and FRAX risk variables. The analysis was cohort-specific rather than based on the Canadian version of FRAX. The associations between trabecular bone score, the FRAX risk factors and the risk of fracture or death were examined using an extension of the Poisson regression model and used to calculate 10-year probabilities of fracture with and without TBS and to derive an algorithm to adjust fracture probability to take account of the independent contribution of TBS to fracture and mortality risk. During a mean follow-up of 4.7 years, 1754 women died and 1639 sustained one or more major osteoporotic fractures excluding hip fracture and 306 women sustained one or more hip fracture. When fully adjusted for FRAX risk variables, TBS remained a statistically significant predictor of major osteoporotic fractures excluding hip fracture (HR/SD 1.18, 95 % CI 1.12-1.24), death (HR/SD 1.20, 95 % CI 1.14-1.26) and hip fracture (HR/SD 1.23, 95 % CI 1.09-1.38). Models adjusting major osteoporotic fracture and hip fracture probability were derived, accounting for age and trabecular bone score with death considered as a competing event. Lumbar spine texture analysis using TBS is a risk factor for osteoporotic fracture and a risk factor for death. The predictive ability of TBS is independent of FRAX clinical risk factors and femoral neck BMD. Adjustment of fracture probability to take account of the independent contribution of TBS to fracture and mortality risk requires validation in independent cohorts.

Trabecular bone score (TBS) as a new complementary approach for osteoporosis evaluation in clinical practice.

Trabecular bone score (TBS) is a recently-developed analytical tool that performs novel grey-level texture measurements on lumbar spine dual X-ray absorptiometry (DXA) images, and thereby captures information relating to trabecular microarchitecture. In order for TBS to usefully add to bone mineral density (BMD) and clinical risk factors in osteoporosis risk stratification, it must be independently associated with fracture risk, readily obtainable, and ideally, present a risk which is amenable to osteoporosis treatment. This paper summarizes a review of the scientific literature performed by a Working Group of the European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis. Low TBS is consistently associated with an increase in both prevalent and incident fractures that is partly independent of both clinical risk factors and areal BMD (aBMD) at the lumbar spine and proximal femur. More recently, TBS has been shown to have predictive value for fracture independent of fracture probabilities using the FRAX® algorithm. Although TBS changes with osteoporosis treatment, the magnitude is less than that of aBMD of the spine, and it is not clear how change in TBS relates to fracture risk reduction. TBS may also have a role in the assessment of fracture risk in some causes of secondary osteoporosis (e.g., diabetes, hyperparathyroidism and glucocorticoid-induced osteoporosis). In conclusion, there is a role for TBS in fracture risk assessment in combination with both aBMD and FRAX.

Dendritic Cells Cause Bone Lesions in a New Mouse Model of Histiocytosis.

Langerhans cell histiocytosis (LCH) is a rare disease caused by the clonal accumulation of dendritic Langerhans cells, which is often accompanied by osteolytic lesions. It has been reported that osteoclast-like cells play a major role in the pathogenic bone destruction seen in patients with LCH and these cells are postulated to originate from the fusion of DCs. However, due to the lack of reliable animal models the pathogenesis of LCH is still poorly understood. In this study, we have established a mouse model of histiocytosis- recapitulating human disease for osteolytic lesions seen in LCH patients. At 12 weeks after birth, severe bone lesions were observed in our multisystem histiocytosis (Mushi) model, when CD8α conventional dendritic cells (DCs) are transformed (MuTuDC) and accumulate. Most importantly, our study demonstrates that bone loss in LCH can be accounted for the transdifferentiation of MuTuDCs into functional osteoclasts both in vivo and in vitro. Moreover, we have shown that injected MuTuDCs reverse the osteopetrotic phenotype of oc/oc mice in vivo. In conclusion, our results support a crucial role of DCs in bone lesions in histiocytosis patients. Furthermore, our new model of LCH based on adoptive transfer of MuTuDC lines, leading to bone lesions within 1-2 weeks, will be an important tool for investigating the pathophysiology of this disease and ultimately for evaluating the potential of anti-resorptive drugs for the treatment of bone lesions.

Brain metastases in gastro-oesophageal adenocarcinoma: insights into the role of the human epidermal growth factor receptor 2 (HER2).

BACKGROUND: Gastro-oesophageal adenocarcinomas rarely metastasize to the central nervous system (CNS). The role of the human epidermal growth factor receptor 2 (HER2) in patients with these cancers and CNS involvement is presently unknown. PATIENTS AND METHODS: A multicentre registry was established to collect data from patients with gastro-oesophageal adenocarcinomas and CNS involvement both retrospectively and prospectively. Inclusion in the study required a predefined clinical data set, a central neuro-radiological or histopathological confirmation of metastatic CNS involvement and central assessment of HER2 by immunohistochemistry (IHC) and in situ hybridisation (ISH). In addition, expression of E-cadherin and DNA mismatch repair (MMR) proteins were assessed by IHC. RESULTS: One hundred patients fulfilled the inclusion criteria. The population's median age was 59 years (interquartile range: 54-68), of which 85 (85%) were male. Twenty-five patients were of Asian and 75 of Caucasian origin. HER2 status was positive in 36% (95% CI: 26.6-46.2) of cases. Median time from initial diagnosis to the development of brain metastases (BMets) or leptomeningeal carcinomatosis (LC) was 9.9 months (95% CI: 8.5-15.0). Median overall survival from diagnosis was 16.9 months (95% CI: 14.0-20.7) and was not related to the HER2 status. E-cadherin loss was observed in 9% of cases and loss of expression in at least one DNA MMR proteins in 6%. CONCLUSIONS: The proportion of a positive HER2 status in patients with gastro-oesophageal adenocarcinoma and CNS involvement was higher than expected. The impact of anti-HER2 therapies should be studied prospectively.

Bone structure assessed by HR-pQCT, TBS and DXL in adult patients with different types of osteogenesis imperfecta.

UNLABELLED: Bone microarchitecture by high-resolution peripheral quantitative computed tomography (HR-pQCT) was assessed in adult patients with mild, moderate, and severe osteogenesis imperfecta (OI). The trabecular bone score (TBS), bone mineral density (BMD) by dual-energy X-ray absorptiometry (DXA), and dual X-ray and laser (DXL) at the calcaneus were likewise assessed in patients with OI. Trabecular microstructure and BMD in particular were severely altered in patients with OI. INTRODUCTION: OI is characterized by high fracture risk but not necessarily by low BMD. The main purpose of this study was to assess bone microarchitecture and BMD at different skeletal sites in different types of OI. METHODS: HR-pQCT was performed in 30 patients with OI (mild OI-I, n = 18 (41.8 [34.7, 55.7] years) and moderate to severe OI-III-IV, n = 12 (47.6 [35.3, 58.4] years)) and 30 healthy age-matched controls. TBS, BMD by DXA at the lumbar spine and hip, as well as BMD by DXL at the calcaneus were likewise assessed in patients with OI only. RESULTS: At the radius, significantly lower trabecular parameters including BV/TV (p = 0.01 and p < 0.0001, respectively) and trabecular number (p < 0.0001 and p < 0.0001, respectively) as well as an increased inhomogeneity of the trabecular network (p < 0.0001 and p < 0.0001, respectively) were observed in OI-I and OI-III-IV in comparison to the control group. Similar results for trabecular parameters were found at the tibia. Microstructural parameters were worse in OI-III-IV than in OI-I. No significant differences were found in cortical thickness and cortical porosity between the three subgroups at the radius. The cortical thickness of the tibia was thinner in OI-I (p < 0.001), but not OI-III-IV, when compared to controls. CONCLUSIONS: Trabecular BMD and trabecular bone microstructure in particular are severely altered in patients with clinical OI-I and OI-III-IV. Low TBS and DXL and their significant associations to HR-pQCT parameters of trabecular bone support this conclusion.