The Vitamin D Metabolite Diagnostic Ratio Associates With Phenotypic Traits of Idiopathic Hypercalciuria.

Introduction: Underlying mechanisms for hypercalciuria remain unknown in most cases; thus, the designation "idiopathic." We hypothesized that the vitamin D-inactivating enzyme, CYP24A1 contributes to the pathogenesis of hypercalciuria in kidney stone formers. Methods: We conducted association analyses between CYP24A1 activity, estimated by the vitamin D metabolite diagnostic ratio (25(OH) vitamin D3/total 24,25 (OH)2 vitamin D ratio; VMDR), and the phenotype of participants in 2 observational cohorts of kidney stone formers, the Swiss Kidney Stone Cohort (SKSC) and the Bern Kidney Stone Registry (BKSR). Circulating 25(OH)- and 24,25 (OH)2 vitamin D were quantified using a validated liquid chromatography tandem mass spectrometry assay. Results: A total of 974 participants were included in the analysis. We found a positive association of VMDR (and hence negative association of CYP24A1 activity) with total (ß 0.009 mmol/l; 95% confidence interval [CI]: 0.002, 0.016; P = 0.02) and ionized plasma calcium (ß 0.005 mmol/l; 95% CI: 0.002, 0.008; P < 0.01), absolute and fractional excretion of urinary calcium (ß 0.054 mmol/24h; 95% CI: 0.010, 0.097; P = 0.02 and ß 0.046%; 95% CI: 0.018, 0.074; P < 0.01, respectively). Further, VMDR was associated with an increased likelihood of forming calcium oxalate dihydrate stones (Odds ratio [OR] 1.64; 95% CI: 1.22, 2.35; P < 0.01) and reduced bone mineral density (BMD) at the femoral neck (ß -0.005 g/cm2; 95% CI: -0.010, -0.001; P = 0.04). The described associations became stronger when the analysis was confined to idiopathic calcium stone formers. Conclusion: Our study reveals that CYP24A1 activity, estimated by VMDR, is associated with clinical traits previously linked to idiopathic hypercalciuria.

Predictors of Bone Mineral Density in Kidney Stone Formers.

Introduction: Nephrolithiasis is associated with an increased fracture risk, but predictors of bone mineral density (BMD) in stone formers (SFs) remain poorly defined. Methods: We conducted a retrospective analysis in the Bern Kidney Stone Registry (BKSR), an observational cohort of kidney SFs. Inclusion criteria were age ≥18 years and ≥1 past stone episode. Participants with non-calcium (Ca)-containing kidney stones, a history of primary hyperparathyroidism or antiresorptive or anabolic bone treatment were excluded. Multivariable linear regression analyses were used to assess the association of blood and 24-hours urine parameters and stone composition with BMD at the lumbar spine and femoral neck. Results: In the analysis, 504 participants were included, mean age was 46 years, and 76% were male. In multivariable analyses, fasting (ß: -0.031; P = 0.042), postload (ß: -0.059; P = 0.0028) and Δ postload - fasting (ß: -0.053; P = 0.0029) urine Ca-to-creatinine ratios after 1 week of a sodium- and Ca- restricted diet and Ca oxalate dihydrate stone content (ß: -0.042; P = 0.011) were negatively associated with z scores at the lumbar spine. At the femoral neck, alkaline phosphatase (ß: -0.035; P = 0.0034) and parathyroid hormone (PTH) (ß: -0.035; P = 0.0026) were negatively associated with z scores, whereas 24-hours urine Ca (ß: 0.033; P = 0.0085), magnesium (ß: 0.043; P = 3.5 × 10-4), and potassium (ß: 0.032; P = 0.012) correlated positively with z scores at the femoral neck. Conclusion: Our study reveals distinct predictors of BMD in SFs. Commonly available clinical parameters, such as kidney stone composition results, can be used to identify SFs at risk for low BMD.

The effect of a previous created distal arteriovenous-fistula on radial bone DXA measurements in prevalent renal transplant recipients.

BACKGROUND: Accelerated bone loss occurs rapidly following renal transplantation due to intensive immunosuppression and persistent hyperparathyroidism. In renal transplant recipients (RTRs) due to the hyperparathyroidism the non-dominant forearm is often utilized as a peripheral measurement site for dual-energy x-ray absorptiometry (DXA) measurements. The forearm is also the site of previous created distal arteriovenous fistulas (AVF). Although AVF remain patent long after successful transplantation, there are no data available concerning their impact on radial bone DXA measurements. METHODS: In this cross-sectional study we performed DXA in 40 RTRs with preexisting distal AVF (RTRs-AVF) to assess areal bone mineral density (aBMD) differences between both forearms (three areas) and compared our findings to patients with chronic kidney disease (CKD, n = 40), pre-emptive RTRs (RTRs-pre, n = 15) and healthy volunteers (n = 20). In addition, we assessed relevant demographic, biochemical and clinical aspects. RESULTS: We found a marked radial asymmetry between the forearms in RTRs with preexisting AVF. The radial aBMD at the distal AVF forearm was lower compared to the contralateral forearm, resulting in significant differences for all three areas analyzed: the Rad-1/3: median (interquartile range) in g/cm2, Rad-1/3: 0.760 (0.641-0.804) vs. 0.742 (0.642, 0.794), p = 0.016; ultradistal radius, Rad-UD: 0.433 (0.392-0.507) vs. 0.420 (0.356, 0.475), p = 0.004; and total radius, Rad-total: 0.603 (0.518, 0.655) vs. 0.599 (0.504, 0.642), p = 0.001). No such asymmetries were observed in any other groups. Lower aBMD in AVF forearm subregions resulted in misclassification of osteoporosis. CONCLUSIONS: In renal transplant recipients, a previously created distal fistula may exert a negative impact on the radial bone leading to significant site-to-site aBMD differences, which can result in diagnostic misclassifications.

Bone Mass Distribution of the Distal Tibia in Normal, Osteopenic, and Osteoporotic Conditions: An Ex Vivo Assessment Using HR-pQCT, DXA, and Computational Modelling.

Osteoporosis leads to bone loss and structural deterioration, which increase the risk of fractures. The aim of this study was to characterize the three-dimensional (3D) bone mass distributions of the distal tibia in normal, osteopenic, and osteoporotic conditions. High-resolution peripheral quantitative computed tomography (HR-pQCT) of the 33 % of the distal tibia and local dual-energy X-ray absorptiometry were applied to 53 intact, fresh-frozen tibiae. The HR-pQCTs were graded to assign local T-scores and merged into three equally sized average normal, osteopenic, and osteoporotic surface models. Volumetric bone mineral density (vBMD) was determined using categorized T-scores, volumetric visualization, and virtual bore probes at the dia-, meta-, and epiphyseal sites (T-DIA, T-META, and T-EPI). We observed a distinct 3D bone mass distribution that was gradually uninfluenced by T-score categories. T-DIA was characterized by the lowest bone mass located in the medullary cavity and a wide homogenous cortex containing the maximum vBMD. The T-META showed decreased cortical thickness and maximal vBMD. At the T-EPI, the relatively low vBMD of the mostly trabecular bone was similar to the maximal cortical vBMD in this sub-region. Four trabecular regions of low bone mass were identified in the recesses. The bone content gradually decreased at all sites, whereas the pattern of bone mass distribution remained essentially unchanged, with the exception of disproportionate losses at T-DIA, T-META, and T-EPI that consistently showed increased endocortical, intracortical, and trabecular bone loss. Extra information can be obtained from the specific pattern of bone mass distribution, potential disproportionate bone losses, and method used.

Bone mineral density (BMD) and vertebral trabecular bone score (TBS) for the identification of elderly women at high risk for fracture: the SEMOF cohort study.

PURPOSE: To determine the predictive value of the vertebral trabecular bone score (TBS) alone or in addition to bone mineral density (BMD) with regard to fracture risk. METHODS: Retrospective analysis of the relative contribution of BMD [measured at the femoral neck (FN), total hip (TH), and lumbar spine (LS)] and TBS with regard to the risk of incident clinical fractures in a representative cohort of elderly post-menopausal women previously participating in the Swiss Evaluation of the Methods of Measurement of Osteoporotic Fracture Risk study. RESULTS: Complete datasets were available for 556 of 701 women (79 %). Mean age 76.1 years, LS BMD 0.863 g/cm2, and TBS 1.195. LS BMD and LS TBS were moderately correlated (r 2 = 0.25). After a mean of 2.7 ± 0.8 years of follow-up, the incidence of fragility fractures was 9.4 %. Age- and BMI-adjusted hazard ratios per standard deviation decrease (95 % confidence intervals) were 1.58 (1.16-2.16), 1.77 (1.31-2.39), and 1.59 (1.21-2.09) for LS, FN, and TH BMD, respectively, and 2.01 (1.54-2.63) for TBS. Whereas 58 and 60 % of fragility fractures occurred in women with BMD T score ≤-2.5 and a TBS <1.150, respectively, combining these two thresholds identified 77 % of all women with an osteoporotic fracture. CONCLUSIONS: Lumbar spine TBS alone or in combination with BMD predicted incident clinical fracture risk in a representative population-based sample of elderly post-menopausal women.

Microstructural parameters of bone evaluated using HR-pQCT correlate with the DXA-derived cortical index and the trabecular bone score in a cohort of randomly selected premenopausal women.

BACKGROUND: Areal bone mineral density is predictive for fracture risk. Microstructural bone parameters evaluated at the appendicular skeleton by high-resolution peripheral quantitative computed tomography (HR-pQCT) display differences between healthy patients and fracture patients. With the simple geometry of the cortex at the distal tibial diaphysis, a cortical index of the tibia combining material and mechanical properties correlated highly with bone strength ex vivo. The trabecular bone score derived from the scan of the lumbar spine by dual-energy X-ray absorptiometry (DXA) correlated ex vivo with the micro architectural parameters. It is unknown if these microstructural correlations could be made in healthy premenopausal women. METHODS: Randomly selected women between 20-40 years of age were examined by DXA and HR-pQCT at the standard regions of interest and at customized sub regions to focus on cortical and trabecular parameters of strength separately. For cortical strength, at the distal tibia the volumetric cortical index was calculated directly from HR-pQCT and the areal cortical index was derived from the DXA scan using a Canny threshold-based tool. For trabecular strength, the trabecular bone score was calculated based on the DXA scan of the lumbar spine and was compared with the corresponding parameters derived from the HR-pQCT measurements at radius and tibia. RESULTS: Seventy-two healthy women were included (average age 33.8 years, average BMI 23.2 kg/m(2)). The areal cortical index correlated highly with the volumetric cortical index at the distal tibia (R  =  0.798). The trabecular bone score correlated moderately with the microstructural parameters of the trabecular bone. CONCLUSION: This study in randomly selected premenopausal women demonstrated that microstructural parameters of the bone evaluated by HR-pQCT correlated with the DXA derived parameters of skeletal regions containing predominantly cortical or cancellous bone. Whether these indexes are suitable for better predictions of the fracture risk deserves further investigation.

Real-life results of balloon kyphoplasty for vertebral compression fractures from the SWISSspine registry.

BACKGROUND CONTEXT: The Swiss Federal Office of Public Health mandated a nationwide health technology assessment-registry for balloon kyphoplasty (BKP) for decision making on reimbursement of these interventions. The early results of the registry led to a permanent coverage of BKP by basic health insurance. The documentation was continued for further evidence generation. PURPOSE: This analysis reports on the 1 year results of patients after BKP treatment. STUDY DESIGN: Prospective multicenter observational case series. PATIENT SAMPLE: The data on 625 cases with 819 treated vertebrae were documented from March 2005 to May 2012. OUTCOME MEASURES: Surgeon-administered outcome instruments were primary intervention form for BKP and the follow-up form; patient self-reported measures were EuroQol-5D questionnaire, North American Spine Society outcome instrument /Core Outcome Measures Index (including visual analog scale), and a comorbidity questionnaire. Outcome measures were back pain, medication, quality of life (QoL), cement extrusions, and new fractures within the first postoperative year. METHODS: Data were recorded preoperatively and at 3 to 6-month and 1-year follow-ups. Wilcoxon signed-rank test was used for comparison of pre- with postoperative measurements. Multivariate logistic regression was used to identify factors with a significant influence on the outcome. RESULTS: Seventy percent of patients were women with mean age of 71 years (range, 18-91 years); mean age of men was 65 years (range, 15-93 years). Significant and clinically relevant reduction of back pain, improvement of QoL, and reduction of pain killer consumption was seen within the first postoperative year. Preoperative back pain decreased from 69.3 to 29.0 at 3 to 6-month and remained unchanged at 1-year follow-ups. Consequently, QoL improved from 0.23 to 0.71 and 0.75 at the same follow-up intervals. The overall vertebra-based cement extrusion rates with and without extrusions into intervertebral discs were 22.1% and 15.3%, respectively. Symptomatic cement extrusions with radiculopathy were five (0.8%). A new vertebral fracture within a year from the BKP surgery was observed in 18.4% of the patients. CONCLUSIONS: The results of the largest observational study for BKP so far are consistent with published randomized trials and systematic reviews. In this routine health care setting, BKP is safe and effective in reducing pain, improving QoL, and lowering pain_killer consumption and has an acceptable rate of cement extrusions. Postoperative outcome results show clear and significant clinical improvement at early follow-up that remain stable during the first postoperative year.

DensiProbe Spine: an intraoperative measurement of bone quality in spinal instrumentation. A clinical feasibility study.

BACKGROUND CONTEXT: A new device, DensiProbe, has been developed to provide surgeons with intraoperative information about bone strength by measuring the peak breakaway torque. In cases of low bone quality, the treatment can be adapted to the patient's condition, for example, by improving screw-anchorage with augmentation techniques. PURPOSE: The objective of this study was to investigate the feasibility of DensiProbe Spine in patients undergoing transpedicular fixation. STUDY DESIGN: Prospective feasibility study on consecutive patients. PATIENT SAMPLE: Fourteen women and 16 men were included in this study. OUTCOME MEASURES: Local and general bone quality. METHODS: These consecutive patients scheduled for transpedicular fixation were evaluated for bone mineral density (BMD), which was measured globally by dual-energy X-ray absorptiometry and locally via biopsies using quantitative microcomputed tomography. The breakaway torque force within the vertebral body was assessed intraoperatively via the transpedicular approach with the DensiProbe Spine. The results were correlated with the areal BMD at the lumbar spine and the local volumetric BMD (vBMD) and a subjective impression of bone strength. The feasibility of the method was evaluated, and the clinical and radiological performance was evaluated over a 1-year follow-up. This study was funded by an AO Spine research grant; DensiProbe was developed at the AO Research Institute Davos, Switzerland; the AO Foundation is owner of the intellectual property rights. RESULTS: In 30 patients, 69 vertebral levels were examined. The breakaway torque consistently correlated with an experienced surgeon's quantified impression of resistance as well as with vBMD of the same vertebra. Beyond a marginal prolongation of surgery time, no adverse events related to the usage of the device were observed. CONCLUSIONS: The intraoperative transpedicular measurement of the peak breakaway torque was technically feasible, safe, and reliably predictive of local vBMD during dorsal spinal instrumentations in a clinical setting. Larger studies are needed to define specific thresholds that indicate a need for the augmentation or instrumentation of additional levels.

Effects of zoledronate versus placebo on spine bone mineral density and microarchitecture assessed by the trabecular bone score in postmenopausal women with osteoporosis: a three-year study.

The trabecular bone score (TBS) is an index of bone microarchitectural texture calculated from anteroposterior dual-energy X-ray absorptiometry (DXA) scans of the lumbar spine (LS) that predicts fracture risk, independent of bone mineral density (BMD). The aim of this study was to compare the effects of yearly intravenous zoledronate (ZOL) versus placebo (PLB) on LS BMD and TBS in postmenopausal women with osteoporosis. Changes in TBS were assessed in the subset of 107 patients recruited at the Department of Osteoporosis of the University Hospital of Berne, Switzerland, who were included in the HORIZON trial. All subjects received adequate calcium and vitamin D3. In these patients randomly assigned to either ZOL (n = 54) or PLB (n = 53) for 3 years, BMD was measured by DXA and TBS assessed by TBS iNsight (v1.9) at baseline and 6, 12, 24, and 36 months after treatment initiation. Baseline characteristics (mean ± SD) were similar between groups in terms of age, 76.8 ± 5.0 years; body mass index (BMI), 24.5 ± 3.6 kg/m(2) ; TBS, 1.178 ± 0.1 but for LS T-score (ZOL-2.9 ± 1.5 versus PLB-2.1 ± 1.5). Changes in LS BMD were significantly greater with ZOL than with PLB at all time points (p < 0.0001 for all), reaching +9.58% versus +1.38% at month 36. Change in TBS was significantly greater with ZOL than with PLB as of month 24, reaching +1.41 versus-0.49% at month 36; p = 0.031, respectively. LS BMD and TBS were weakly correlated (r = 0.20) and there were no correlations between changes in BMD and TBS from baseline at any visit. In postmenopausal women with osteoporosis, once-yearly intravenous ZOL therapy significantly increased LS BMD relative to PLB over 3 years and TBS as of 2 years.

Prediction of bone strength at the distal tibia by HR-pQCT and DXA.

BACKGROUND: Areal bone mineral density (aBMD) at the distal tibia, measured at the epiphysis (T-EPI) and diaphysis (T-DIA), is predictive for fracture risk. Structural bone parameters evaluated at the distal tibia by high resolution peripheral quantitative computed tomography (HR-pQCT) displayed differences between healthy and fracture patients. With its simple geometry, T-DIA may allow investigating the correlation between bone structural parameter and bone strength. METHODS: Anatomical tibiae were examined ex vivo by DXA (aBMD) and HR-pQCT (volumetric BMD (vBMD) and bone microstructural parameters). Cortical thickness (CTh) and polar moment of inertia (pMOI) were derived from DXA measurements. Finally, an index combining material (BMD) and mechanical property (polar moment of inertia, pMOI) was defined and analyzed for correlation with torque at failure and stiffness values obtained by biomechanical testing. RESULTS: Areal BMD predicted the vBMD at T-EPI and T-DIA. A high correlation was found between aBMD and microstructural parameters at T-EPIas well as between aBMD and CTh at T-DIA. Finally, at T-DIA both indexes combining BMD and pMOI were strongly and comparably correlated with torque at failure and bone stiffness. CONCLUSION: Ex vivo, at the distal tibial diaphysis, a novel index combining BMD and pMOI, which can be calculated directly from a single DXA measurement, predicted bone strength and stiffness better than either parameter alone and with an order of magnitude comparable to that of HR-pQCT. Whether this index is suitable for better prediction of fracture risk in vivo deserves further investigation.

Glucocorticosteroid-induced spinal osteoporosis: scientific update on pathophysiology and treatment.

Glucocorticosteroid-induced spinal osteoporosis (GIOP) is the most frequent of all secondary types of osteoporosis. The understanding of the pathophysiology of glucocorticoid (GC) induced bone loss is of crucial importance for appropriate treatment and prevention of debilitating fractures that occur predominantly in the spine. GIOP results from depressed bone formation due to lower activity and higher death rate of osteoblasts on the one hand, and from increase bone resorption due to prolonged lifespan of osteoclasts on the other. In addition, calcium/phosphate metabolism may be disturbed through GC effects on gut, kidney, parathyroid glands and gonads. Therefore, therapeutic agents aim at restoring balanced bone cell activity by directly decreasing apoptosis rate of osteoblasts (e.g., cyclical parathyroid hormone) or by increasing apoptosis rate of osteoclasts (e.g., bisphosphonates). Other therapeutical efforts aim at maintaining/restoring calcium/phosphate homeostasis: improving intestinal calcium absorption (using calcium supplementation, vitamin D and derivates) and avoiding increased urinary calcium loss (using thiazides) prevent or counteract a secondary hyperparthyroidism. Bisphosphonates, particularly the aminobisphosphonates risedronate and alendronate, have been shown to protect patients on GCs from (further) bone loss to reduce vertebral fracture risk. Calcitonin may be of interest in situation where bisphosphonates are contraindicated or not applicable and in cases where acute pain due to vertebral fracture has to be manage. The intermittent administration of 1-34-parathormone may be an appealing treatment alternative, based on its documented anabolic effects on bone resulting from the reduction of osteoblastic apoptosis. Calcium and vitamin D should be a systematic adjunctive measure to any drug treatment for GIOP. Based on currently available evidence, fluoride, androgens, estrogens (opposed or unopposed) cannot be recommended for the prevention and treatment of GIOP. However, substitution of gonadal hormones may be indicated if GC-induced hypogonadism is present and leads to clinical symptoms. Data using the SERM raloxifene to treat or prevent GIOP are lacking, as are data using the promising bone anabolic agent strontium ranelate. Kyphoplasty performed in appropriately selected osteoporotic patients with painful vertebral fractures is a promising addition to current medical treatment.

Prevention of postmenopausal bone loss with long-cycle hormone replacement therapy.

OBJECTIVE: Postmenopausal bone loss and osteoporotic fractures can be prevented by hormone replacement therapy (HRT). However, opposed HRT may increase the risk of breast cancer above that associated with estrogen alone and in non-hysterectomized women estrogen substitution alone increases the risk of uterine cancer, which triggered renewed interest in long-cycle HRT regimens (estrogen replacement therapy with progesterone-free intervals up to 6 months). The effects on bone of such long-cycle HRT regimens are unknown. The objective of the present study was to compare the effects on bone and the endometrium of long-cycle HRT and conventional HRT. METHODS: Seventy-three healthy non-hysterectomized postmenopausal women were randomized to either conventional HRT (estradiol (E2) 2 mg/d during 12 days, E2 2 mg/d plus 1 mg/d of norethisterone acetate (NETA) during 10 days, E2 1 mg/d for 6 days) or long-cycle HRT treatment (two cycles with E2 2 mg/d during 28 days, followed by one cycle of conventional HRT and repeated every 3 months). Primary endpoint was the change in bone mineral density (BMD) at the lumbar spine (LS) over 24 months. RESULTS: BMD at LS increased significantly versus baseline in both treatment groups (conventional HRT +3.8 +/- 0.6%, long-cycle HRT +3.3 +/- 0.5%, p < 0.0001 for both) with no significant difference between treatment groups over 24 months. Similar significant BMD increases versus baseline were observed at the femoral neck, while biochemical markers of bone turnover (osteocalcin and deoxypyridinoline) were significantly decreased over 24 months. There were no endometrial or breast related adverse events reported. CONCLUSION: Long-cycle HRT may be a valid alternative to conventional HRT with regard to protection against postmenopausal bone loss.