Cortical Matrix Mineral Density Measured Noninvasively in Pre- and Postmenopausal Women and a Woman With Vitamin D-Dependent Rickets.

Reduced bone mineral density (BMD) may be due to reduced mineralized bone matrix volume, incomplete secondary mineralization, or reduced primary mineralization. Because bone biopsy is invasive, we hypothesized that noninvasive image acquisition at high resolution can accurately quantify matrix mineral density (MMD). Quantification of MMD was confined to voxels attenuation photons above 80% of that produced by fully mineralized bone matrix because attenuation at this level is due to variation in mineralization, not porosity. To assess accuracy, 9 cadaveric distal radii were imaged at a voxel size of 82 microns using high-resolution peripheral quantitative computed tomography (HR-pQCT; XtremeCT, Scanco Medical AG, Bruttisellen, Switzerland) and compared with VivaCT 40 (µCT) at 19-micron voxel size. Associations between MMD and porosity were studied in 94 healthy vitamin D-replete premenopausal women, 77 postmenopausal women, and in a 27-year-old woman with vitamin D-dependent rickets (VDDR). Microstructure and MMD were quantified using StrAx (StraxCorp, Melbourne, Australia). MMD measured by HR-pQCT and µCT correlated (R = 0.87; p < 0.0001). The precision error for MMD was 2.43%. Cortical porosity and MMD were associated with age (r2 = 0.5 and -0.4, respectively) and correlated inversely in pre- and postmenopausal women (both r2 = 0.9, all p < 0.001). Porosity was higher, and MMD was lower, in post- than in premenopausal women (porosity 40.3% ± 7.0 versus 34.7% ± 3.5, respectively; MMD 65.4% ± 1.8 versus 66.6% ± 1.4, respectively, both p < 0.001). In the woman with VDDR, MMD was 5.6 SD lower and porosity was 5.6 SD higher than the respective trait means in premenopausal women. BMD was reduced (Z-scores femoral neck -4.3 SD, lumbar spine -3.8 SD). Low-radiation HR-pQCT may facilitate noninvasive quantification of bone's MMD and microstructure in health, disease, and during treatment. © 2018 American Society for Bone and Mineral Research.

Bone turnover marker determinants in young women: results from the Safe-D study.

Background Bone turnover markers (BTMs) may provide insight into bone health in young women, but have been little studied in this demographic. We aimed to explore the association between body composition, hormonal contraception, bone mineral density and biochemical parameters and BTMs in young women. Methods Participants were community-dwelling females aged 16-25 years, living in Victoria, Australia. Carboxy-terminal cross-linking telopeptide of type 1 collagen (CTX) and total procollagen type 1 N-propeptide (P1NP) were analysed on the Roche Elecsys automated analyzer. A total of 305 were evaluated, after excluding participants with medical conditions or medications (except hormonal contraceptives), which may affect bone metabolism. Results Median (Q1, Q3) BTM values were 540 (410, 690) ng/L for CTX and 61.7 (46.2, 83.7) µg/L for P1NP. Serum CTX and P1NP were inversely associated with chronological age ( P < 0.001), transferrin ( P < 0.020) and serum dehydroepiandrosterone sulphate concentration ( P < 0.001). BTM values were up to 22% lower in combined oral contraceptive (COC) pill users ( P < 0.001). Serum CTX was inversely associated with per cent body fat ( P = 0.009) and tibial cortical volumetric bone mineral density (vBMD; P = 0.003). Serum P1NP concentrations were 23 µg/L higher in participants who reported using an osteopath in the previous year ( P = 0.007). Conclusions These data suggest that BTMs are influenced by age, COC use, body composition, iron status and hormonal profiles. Higher CTX values were associated with lower tibial cortical vBMD. Examining BTMs in relation to interventions aimed at improving bone health in young women is warranted.

Bone turnover marker reference intervals in young females.

Background The use of bone turnover markers in clinical practice and research in younger people is limited by the lack of normative data and understanding of common causes of variation in bone turnover marker values in this demographic. To appropriately interpret bone turnover markers, robust reference intervals specific to age, development and sex are necessary. This study aimed to determine reference intervals of bone turnover markers in females aged 16-25 years participating in the Safe-D study. Methods Participants were recruited through social networking site Facebook and were asked to complete an extensive, online questionnaire and attend a site visit. Participants were tested for serum carboxy-terminal cross-linking telopeptide of type 1 collagen and total procollagen type 1 N-propeptide using the Roche Elecsys automated analyser. Reference intervals were determined using the 2.5th to 97.5th percentiles of normalized bone turnover marker values. Results Of 406 participants, 149 were excluded due to medical conditions or medication use (except hormonal contraception) which may affect bone metabolism. In the remaining 257 participants, the reference interval was 230-1000 ng/L for serum carboxy-terminal cross-linking telopeptide of type 1 collagen and 27-131 µg/L for procollagen type 1 N-propeptide. Both marker concentrations were inversely correlated with age and oral contraceptive pill use. Therefore, intervals specific to these variables were calculated. Conclusions We defined robust reference intervals for cross-linking telopeptide of type 1 collagen and procollagen type 1 N-propeptide in young females grouped by age and contraceptive pill use. We examined bone turnover markers' relationship with several lifestyle, clinical and demographic factors. Our normative intervals should aid interpretation of bone turnover markers in young females particularly in those aged 16 to 19 years where reference intervals are currently provisional.

Hypocalcemia post denosumab in patients with chronic kidney disease stage 4-5.

BACKGROUND: Denosumab, a RANK-ligand inhibitor, is an effective treatment for osteoporosis in postmenopausal women and men. Unlike the bisphosphonates, it is not excreted by the kidney. Little is known, however, about its efficacy and safety in patients with severe chronic kidney disease (CKD). METHODS: A retrospective study was performed in CKD 4-5D patients from a tertiary referral hospital who were treated with denosumab between 1st January 2011 and 31st March 2014. Data collected included information about the following: CKD stage, fracture history, bone mineral density, serum calcium levels pre and post denosumab treatment, episodes of hypocalcemia, relevant medications and adverse events. RESULTS: Eight patients with CKD-5 and 6 patients with CKD-4 were identified (all female, mean age 77.1 ± 9.9). The mean pre-denosumab calcium value was 2.42 ± 0.12 mmol/l, PTH 20.2 ± 14.7 pmol/l and 25-OH vitamin D 69.1 ± 30.1 nmol/l. After denosumab treatment, 6/8 patients with CKD-5/5D, and 2/5 patients with CKD-4 developed severe hypocalcemia. Two patients developed direct adverse complications of hypocalcemia (seizure, laryngospasm, prolonged QTc). Among the patients who developed hypocalcemia, the median time to serum calcium nadir was 21 days and the median time to correction of hypocalcemia was 71 days. Treatment of hypocalcemia required large doses of oral calcium and calcitriol, and increases in dialysate calcium concentration. CONCLUSIONS: A high rate of severe hypocalcemia was observed in patients with advanced CKD treated with denosumab. If denosumab is used in patients with severe CKD, close monitoring and aggressive replacement of calcium and calcitriol is required to avoid the development of hypocalcemia.

Lrp5 controls bone formation by inhibiting serotonin synthesis in the duodenum.

Loss- and gain-of-function mutations in the broadly expressed gene Lrp5 affect bone formation, causing osteoporosis and high bone mass, respectively. Although Lrp5 is viewed as a Wnt coreceptor, osteoblast-specific disruption of beta-Catenin does not affect bone formation. Instead, we show here that Lrp5 inhibits expression of Tph1, the rate-limiting biosynthetic enzyme for serotonin in enterochromaffin cells of the duodenum. Accordingly, decreasing serotonin blood levels normalizes bone formation and bone mass in Lrp5-deficient mice, and gut- but not osteoblast-specific Lrp5 inactivation decreases bone formation in a beta-Catenin-independent manner. Moreover, gut-specific activation of Lrp5, or inactivation of Tph1, increases bone mass and prevents ovariectomy-induced bone loss. Serotonin acts on osteoblasts through the Htr1b receptor and CREB to inhibit their proliferation. By identifying duodenum-derived serotonin as a hormone inhibiting bone formation in an Lrp5-dependent manner, this study broadens our understanding of bone remodeling and suggests potential therapies to increase bone mass.

Outcomes for general medical inpatients with diabetes mellitus and new hyperglycaemia.

OBJECTIVES: To investigate the relationship between admission glycaemic status and inpatient mortality in patients with and without pre-existing diabetes. DESIGN: Prospective observational cohort study. SETTING: A general medical ward in an Australian tertiary referral hospital. PARTICIPANTS: 903 patients admitted to the general medical ward between February 2003 and July 2004. MAIN OUTCOME MEASURE: Inpatient death. RESULTS: The overall inpatient mortality was 5.4% (n = 49). In the total cohort, age > 75 years and admission fasting plasma glucose (FPG) levels > or = 5.6 mmol/L were independent predictors of mortality. For patients without a known history of diabetes, each 1 mmol/L rise in admission FPG was associated with a 33% increase in mortality. In these patients, elevated (> 6.0%) and normal glycated haemoglobin (HbA(1c)) levels were associated with mortalities of 11.3% and 4.4%, respectively (odds ratio, 2.47; 95% CI, 1.16-5.26). In contrast, in patients with known diabetes, there was no association between admission FPG levels, HbA(1c) and mortality. Length of stay was not independently associated with FPG, HbA(1c), or diabetes status. CONCLUSIONS: In patients without known diabetes, the risk of death was increased for admission FPG levels > or = 5.6 mmol/L. However, pre-existing abnormal glucose metabolism, reflected by elevated HbA(1c) levels, appeared a more important predictor of inpatient mortality than glucose levels in patients without known diabetes.

A controlled, prospective study of neuropsychological outcomes post parathyroidectomy in primary hyperparathyroid patients.

BACKGROUND: There is an increasing number of primary hyperparathyroidism (PHPT) patients with neuropsychological or psychiatric symptoms. Many of these patients do not have osseous or renal complications to satisfy the criteria for parathyroidectomy according to the NIH guidelines. OBJECTIVE: To assess whether there is any improvement in neuropsychological and mood symptoms following parathyroidectomy. PATIENTS AND DESIGN: Twenty PHPT patients undergoing parathyroidectomy and 20 orthopaedic controls matched for age, gender and estimated intelligence were subjects to pre and postoperative assessment of cognition and mood with a mean surgery-retest interval of 3 months. RESULTS: Using two tests of attentional flexibility [the Stroop test, the Digit symbol test of the Wechsler Adult Intelligence Scale-Revised (WAIS-R)], and two memory tests for prose and nonverbal material, no significant change was found between the groups when comparing scores before and after surgery. There was no improvement between pre and postoperative measures of verbal (dominant hemisphere) as opposed to visuo-spatial (nondominant hemisphere) function when compared to controls. There was no relationship between the reduction in serum calcium and the change in the neuropsychological measures postoperatively. CONCLUSION: This controlled, prospective study demonstrates no significant improvement in neuropsychological indices using objective, validated psychometric tools in an unselected cohort of PHPT patients. No relationship was found between serum calcium level and the degree of neuropsychological deficit. More studies are needed to assess whether the effect of parathyroidectomy is beneficial and sustainable in PHPT patients with neuropsychological symptoms alone.