Glucocorticoid Excess in Bone and Muscle

Glucocorticoids (GC), produced and released by the adrenal glands, regulate numerous physiological processes in a wide range of tissues. Because of their profound immunosuppressive and anti-inflammatory actions, GC are extensively used for the treatment of immune and inflammatory conditions, the management of organ transplantation, and as a component of chemotherapy regimens for cancers. However, both pathologic endogenous elevation and long-term use of exogenous GC are associated with severe adverse effects. In particular, excess GC has devastating effects on the musculoskeletal system. GC increase bone resorption and decrease formation leading to bone loss, microarchitectural deterioration and fracture. GC also induce loss of muscle mass and strength leading to an increased incidence of falls. The combined effects on bone and muscle account for the increased fracture risk with GC. This review summarizes the advance in knowledge in the last two decades about the mechanisms of action of GC in bone and muscle and the attempts to interfere with the damaging actions of GC in these tissues with the goal of developing more effective therapeutic strategies

OR13-3 Effects of Iron Isomaltoside versus Ferric Carboxymaltose on Hormonal Control of Phosphate Homeostasis: The PHOSPHARE-IDA04/05 Randomized Controlled Trials

Iron isomaltoside (IIM) and ferric carboxymaltose (FCM) are newer intravenous iron preparations that can be administered in high-doses to rapidly correct iron deficiency anemia (IDA). FCM can cause hypophosphatemia due to fibroblast growth factor 23 (FGF23) mediated renal phosphate wasting, which has been associated with osteomalacia, but the comparative effects of IIM are unknown. In two separate, identically designed, open label randomized controlled trials, we 1:1 randomized 245 adults with IDA to receive IIM (single infusion of 1000 mg) or FCM (FDA-approved dosing schedule: 2 infusions of 750 mg administered 1 week apart). We compared the incidence, severity and duration of hypophosphatemia, and effects on renal phosphate excretion, FGF23, PTH, vitamin D, and biomarkers of bone turnover measured in blood and urine samples collected at study visits at baseline (day 0) and on days 1, 7, 8, 14, 21, and 35. In pooled analyses of both trials, the incidence of hypophosphatemia 35 days. FCM but not IIM also induced changes in vitamin D and calcium homeostasis that triggered secondary hyperparathyroidism, which likely contributed to persistence of hypophosphatemia. Consistent with case reports of pathological fractures following FCM use, FCM also induced significant elevations of biomarkers of bone turnover that are associated with osteomalacia

Phosphorus Balance in Adolescent Girls and the Effect of Supplemental Dietary Calcium

There are limited data on phosphorus balance and the effect of dietary calcium supplements on phosphorus balance in adolescents. The purpose of this study was to determine phosphorus balance and the effect of increasing dietary calcium intake with a supplement on net phosphorus absorption and balance in healthy adolescent girls. This study utilized stored urine, fecal, and diet samples from a previously conducted study that focused on calcium balance. Eleven healthy girls ages 11 to 14 years participated in a randomized crossover study, which consisted of two 3-week periods of a controlled diet with low (817 ± 19.5 mg/d) or high (1418 ± 11.1 mg/d) calcium, separated by a 1-week washout period. Phosphorus intake was controlled at the same level during both placebo and calcium supplementation (1435 ± 23.5 and 1453 ± 28.0 mg/d, respectively, p = 0.611). Mean phosphorus balance was positive by about 200 mg/d and was unaffected by the calcium supplement (p = 0.826). Urinary phosphorus excretion was lower with the calcium supplement (535 ± 42 versus 649 ± 41 mg/d, p = 0.013), but fecal phosphorus and net phosphorus absorption were not significantly different between placebo and calcium supplement (553 ± 60 versus 678 ± 63 versus mg/d, p = 0.143; 876 ± 62 versus 774 ± 64 mg/d, p = 0.231, respectively). Dietary phosphorus underestimates using a nutrient database compared with the content measured chemically from meal composites by ∼40%. These results show that phosphorus balance is positive in girls during adolescent growth and that a calcium dietary supplement to near the current recommended level does not affect phosphorus balance when phosphorus intake is at 1400 mg/d, a typical US intake level

Serum 25-Hydroxyvitamin D and Intact Parathyroid Hormone Influence Muscle Outcomes in Children and Adolescents

Increases in 25-hydroxyvitamin D concentrations are shown to improve strength in adults; however, data in pediatric populations are scant and equivocal. In this ancillary study of a larger-scale, multi-sited, double-blind, randomized, placebo-controlled vitamin D intervention in US children and adolescents, we examined the associations between changes in vitamin D metabolites and changes in muscle mass, strength, and composition after 12 weeks of vitamin D3 supplementation. Healthy male and female, black and white children and adolescents between the ages of 9 and 13 years from two US states (Georgia 34°N and Indiana 40°N) were enrolled in the study and randomly assigned to receive an oral vitamin D3 dose of 0, 400, 1000, 2000, or 4000 IU/d for 12 weeks between the winter months of 2009 to 2011 (N = 324). Analyses of covariance, partial correlations, and regression analyses of baseline and 12-week changes (post-baseline) in vitamin D metabolites (serum 25(OH)D, 1,25(OH)2 D, intact parathyroid hormone [iPTH]), and outcomes of muscle mass, strength, and composition (total body fat-free soft tissue [FFST], handgrip strength, forearm and calf muscle cross-sectional area [MCSA], muscle density, and intermuscular adipose tissue [IMAT]) were assessed. Serum 25(OH)D and 1,25(OH)2 D, but not iPTH, increased over time, as did fat mass, FFST, forearm and calf MCSA, forearm IMAT, and handgrip strength (p < 0.05). Vitamin D metabolites were not associated with muscle strength at baseline nor after the 12-week intervention. Changes in serum 25(OH)D correlated with decreases in forearm IMAT, whereas changes in serum iPTH predicted increases in forearm and calf MCSA and IMAT (p < 0.05). Overall, increases in 25(OH)D did not influence muscle mass or strength in vitamin D-sufficient children and adolescents; however, the role of iPTH on muscle composition in this population is unknown and warrants further investigation

Oral calcium carbonate affects calcium but not phosphorus balance in stage 3–4 chronic kidney disease

Chronic kidney disease (CKD) patients are given calcium carbonate to bind dietary phosphorus and reduce phosphorus retention, and to prevent negative calcium balance. Data are limited on calcium and phosphorus balance in CKD to support this. The aim of this study was to determine calcium and phosphorus balance and calcium kinetics with and without calcium carbonate in CKD patients. Eight stage 3/4 CKD patients, eGFR 36 mL/min, participated in two 3-week balances in a randomized placebo-controlled cross-over study of calcium carbonate (1500 mg/d calcium). Calcium and phosphorus balance were determined on a controlled diet. Oral and intravenous 45calcium with blood sampling and urine and fecal collections were used for calcium kinetics. Fasting blood and urine were collected at baseline and end of each week of each balance period for biochemical analyses. Results showed that patients were in neutral calcium and phosphorus balance while on placebo. Calcium carbonate produced positive calcium balance, did not affect phosphorus balance, and produced only a modest reduction in urine phosphorus excretion compared with placebo. Calcium kinetics demonstrated positive net bone balance but less than overall calcium balance suggesting tissue deposition. Fasting biochemistries of calcium and phosphate homeostasis were unaffected by calcium carbonate. If they can be extrapolated to effects of chronic therapy, these data caution against the use of calcium carbonate as a phosphate binder

Serum fibroblast growth factor 23, serum iron and bone mineral density in premenopausal women

Fibroblast growth factor 23 (FGF23) circulates as active protein and inactive fragments. Low iron status increases FGF23 gene expression, and iron deficiency is common. We hypothesized that in healthy premenopausal women, serum iron influences C-terminal and intact FGF23 concentrations, and that iron and FGF23 associate with bone mineral density (BMD). Serum iron, iron binding capacity, percent iron saturation, phosphorus, and other biochemistries were measured in stored fasting samples from healthy premenopausal white (n=1898) and black women (n=994), age 20-55years. Serum C-terminal and intact FGF23 were measured in a subset (1631 white and 296 black women). BMD was measured at the lumbar spine and femur neck. Serum phosphorus, calcium, alkaline phosphatase and creatinine were lower in white women than black women (p<0.001). Serum iron (p<0.0001) and intact FGF23 (p<0.01) were higher in white women. C-terminal FGF23 did not differ between races. Phosphorus correlated with intact FGF23 (white women, r=0.120, p<0.0001; black women r=0.163, p<0.01). However, phosphorus correlated with C-terminal FGF23 only in black women (r=0.157, p<0.01). Intact FGF23 did not correlate with iron. C-terminal FGF23 correlated inversely with iron (white women r=-0.134, p<0.0001; black women r=-0.188, p<0.01), having a steeper slope at iron <50mcg/dl than ≥50mcg/dl. Longitudinal changes in iron predicted changes in C-terminal FGF23. Spine BMD correlated with iron negatively (r=-0.076, p<0.01) in white women; femur neck BMD correlated with iron negatively (r=-0.119, p<0.0001) in black women. Both relationships were eliminated in weight-adjusted models. BMD did not correlate with FGF23. Serum iron did not relate to intact FGF23, but was inversely related to C-terminal FGF23. Intact FGF23 correlated with serum phosphorus. In weight-adjusted models, BMD was not related to intact FGF23, C-terminal FGF23 or iron. The influence of iron on FGF23 gene expression is not important in determining bone density in healthy premenopausal women

Effect of Hesperidin with and without a Calcium (Calcilock®) Supplement on Bone Health in Postmenopausal Women

Context: Citrus fruits contain unique flavanones. One of the most abundant of the flavanones, hesperidin, has been shown to prevent bone loss in ovariectomized rats. Objective: The objective of the study was to measure the effect of hesperidin with or without calcium supplementation on bone calcium retention in postmenopausal women. Design: The study was a double-blind, placebo-controlled, randomized-order crossover design of 500 g hesperidin with or without 500 mg calcium supplement in 12 healthy postmenopausal women. Bone calcium retention was determined from urinary excretion of the rare isotope, 41Ca, from bone. Results: Calcium plus hesperidin, but not hesperidin alone, improved bone calcium retention by 5.5% (P < .04). Conclusion: Calcium supplementation (Calcilock), in combination with hesperidin, is effective at preserving bone in postmenopausal women. - See more at: http://press.endocrine.org/doi/10.1210/jc.2015-3767#sthash.ztalWWcv.dpu

Genome-wide association study of serum iron phenotypes in premenopausal women of European descent

A genome-wide association study was performed in 1,130 premenopausal women to detect common variants associated with three serum iron-related phenotypes. Total iron binding capacity was strongly associated (p=10−14) with variants in and near the TF gene (transferrin), the serum iron transporting protein, and with variants in HFE (p= 4×10−7), which encodes the human hemochromatosis gene. Association was also detected between percent iron saturation (p=10−8) and variants in the chromosome 6 region containing both HFE and SLC17A2, which encodes a phosphate transport protein. No significant associations were detected with serum iron, but variants in HFE were suggestive (p=10−6). Our results corroborate prior studies in older subjects and demonstrate that the association of these genetic variants with iron phenotypes can be detected in premenopausal women

Racial Differences in Cortical Bone Mass, Size and Estimated Strength at the Tibial Diaphysis in Early Pubertal Children

poster abstractOsteoporotic fracture rates differ according to race, with blacks having up to half the rate of whites. The reduced fracture rate in blacks has been suggested to be due to their superior bone mass; however, mass is not the sole determinant of bone strength. Bone strength, and consequent fracture risk, is also influenced by how bone material is distributed or structured. It is likely bone structure also contributes to the lower incidence of fractures in blacks and that racial differences in bone structure have roots in childhood. The aim of this study was to assess the influence of race on pQCT-derived cortical bone mass, size and estimated strength at the tibial diaphysis in early pubertal children. 160 children were recruited, with equal subjects according to race (black, n=80; white, n=80) and sex (female, n=80; male, n=80). Subjects were at sexual maturation stages 2 or 3. Tomographic slices of the tibial diaphysis at 66% proximal from the medial malleolus were acquired using pQCT. Slices were assessed for cortical volumetric BMD (Ct.vBMD), cortical BMC (Ct.BMC), total (Tt.Ar) and cortical (Ct.Ar) area, density weighted maximum (IMAX) and minimum (IMIN) second moments of area, density-weighted polar strength-strain index (SSIP), and muscle cross-sectional area (mCSA). Group differences were assessed by two-way analysis of covariance, with race (black vs. white) and sex (female vs. male) as independent variables. Covariates included predicted years from peak height velocity (maturity offset), tibial length and mCSA. There were no interactions between race and sex (all P=0.50-0.98) or main effect for sex (all P=0.08-0.45). Blacks had 15.7% more Ct.BMC, and 10.8-11.8% larger Tt.Ar and Ct.Ar than whites (all P<0.001). The greater enhancement of Ct.BMC relative to Ct.Ar resulted in blacks having 3.6% greater Ct.vBMD than whites (P<0.001). The combination of increased cortical bone mass, size and density in blacks contributed to enhanced estimated bone strength, with IMAX, IMIN and SSIP being 20.0%, 34.5% and 25.2% greater in blacks than whites, respectively (all P<0.001). These data indicate that early pubertal black children have enhanced bone mass, size and estimated bone strength at the tibial diaphysis versus whites, independent of tibial length and mCSA. They suggest bone structural differences may contribute to observed racial differences in fracture rates and that structural divergence between races develops during childhood

Bone Turnover is not Influenced by Serum 25-Hydroxyvitamin D in Pubertal Healthy Black and White Children

Low serum 25-hydroxyvitamin D [25(OH)D] is common in healthy children particularly in blacks. However, serum 25(OH)D concentrations for optimal bone turnover in children is unknown and few data exist that describe effects of increasing serum 25(OH)D on bone turnover markers during puberty. The purpose of this study was to determine the relationships between serum 25(OH)D and changes in serum 25(OH)D and bone turnover in white and black pubertal adolescents. Bone turnover markers were measured in 318 healthy boys and girls from Georgia (34°N) and Indiana (40°N) who participated in a study of oral vitamin D3 supplementation (0 to 4000 IU/d). Serum 25(OH)D, osteocalcin, bone alkaline phosphatase, and urine N-telopeptide cross-links were measured at baseline and 12 weeks. Relationships among baseline 25(OH)D and bone biomarkers, and between changes over 12 weeks were determined and tested for effects of race, sex, latitude, and baseline 25(OH)D. Median 25(OH)D was 27.6 ng/mL (n=318, range 10.1–46.0 ng/mL) at baseline and 34.5 ng/mL (n=302, range 9.7–95.1 ng/mL) at 12 weeks. Neither baseline nor change in 25(OH)D over 12 weeks were associated with bone turnover. The lack of association was not affected by race, sex, latitude, or baseline serum 25(OH)D. Serum 25(OH)D in the range of 10-46 ng/mL appears to be sufficient for normal bone turnover in healthy black and white pubertal adolescents