Forearm Bone Mineral Density in Familial Hypocalciuric Hypercalcemia and Primary Hyperparathyroidism: A Comparative Study

Studies have shown that cancellous bone is relatively preserved in primary hyperparathyroidism (PHPT), whereas bone loss is seen in cortical bone. Familial hypocalciuric hypercalcemia (FHH) patients seem to preserve bone mineral in spite of hypercalcemia and often elevated plasma parathyroid hormone (PTH). The objective of this study was to compare total and regional forearm bone mineral density (BMD) in patients with PHPT and FHH and to examine if differences can be used to separate the two disorders. We included 63 FHH, and 121 PHPT patients in a cross-sectional study. We performed dual-energy X-ray absorptiometry scans of the forearm, hip and lumbar spine and measured a number of biochemical variables. PTH patients had significantly lower Z-scores in all parts of the forearm compared to FHH. This was also the case after adjustment for body mass index. When stratifying for age, gender and PTH, T-scores were still significantly lower in PHPT patients than in FHH patients at the total, the mid and the ultradistal forearm, but not at the proximal 1/3 forearm. In a multiple regression analysis BMD Z-score was lower in PHPT compared to FHH at the total forearm, the mid forearm and the ultradistal forearm but not the proximal forearm when adjusting for biochemical variables including PTH, 1,25(OH)₂D and Ca²⁺. These observations support that inactivating mutations in the CASR gene in bone cells in FHH may protect against forearm bone loss. Differences between the two groups in total or regional forearm BMD were inferior to the calcium/creatinine clearance ratio as a diagnostic tool to separate FHH from PHPT.     

Familial Hypocalciuric Hypercalcemia in Israel: A Preliminary Report

Familial hypocalciuric hypercalcemia (FHH) is often considered in the differential diagnosis of hyperparathyroidism, but is rarely diagnosed. So far, FHH has not been documented in Israel. This report presents preliminary evidence for the occurrence of FHH in Israel. Received: 11 June 1996 / Accepted: 31 December 1996     

Cinacalcet Rectifies Hypercalcemia in a Patient With Familial Hypocalciuric Hypercalcemia Type 2 (FHH2) Caused by a Germline Loss‐of‐Function Gα11 Mutation

G‐protein subunit α‐11 (Gα₁₁) couples the calcium‐sensing receptor (CaSR) to phospholipase C (PLC)‐mediated intracellular calcium (Ca²⁺_i) and mitogen‐activated protein kinase (MAPK) signaling, which in the parathyroid glands and kidneys regulates parathyroid hormone release and urinary calcium excretion, respectively. Heterozygous germline loss‐of‐function Gα₁₁ mutations cause familial hypocalciuric hypercalcemia type 2 (FHH2), for which effective therapies are currently not available. Here, we report a novel heterozygous Gα₁₁ germline mutation, Phe220Ser, which was associated with hypercalcemia in a family with FHH2. Homology modeling showed the wild‐type (WT) Phe220 nonpolar residue to form part of a cluster of hydrophobic residues within a highly conserved cleft region of Gα₁₁, which binds to and activates PLC; and predicted that substitution of Phe220 with the mutant Ser220 polar hydrophilic residue would disrupt PLC‐mediated signaling. In vitro studies involving transient transfection of WT and mutant Gα₁₁ proteins into HEK293 cells, which express the CaSR, showed the mutant Ser220 Gα₁₁ protein to impair CaSR‐mediated Ca²⁺_i and extracellular signal‐regulated kinase 1/2 (ERK) MAPK signaling, consistent with diminished activation of PLC. Furthermore, engineered mutagenesis studies demonstrated that loss of hydrophobicity within the Gα₁₁ cleft region also impaired signaling by PLC. The loss‐of‐function associated with the Ser220 Gα₁₁ mutant was rectified by treatment of cells with cinacalcet, which is a CaSR‐positive allosteric modulator. Furthermore, in vivo administration of cinacalcet to the proband harboring the Phe220Ser Gα₁₁ mutation, normalized serum ionized calcium concentrations. Thus, our studies, which report a novel Gα₁₁ germline mutation (Phe220Ser) in a family with FHH2, reveal the importance of the Gα₁₁ hydrophobic cleft region for CaSR‐mediated activation of PLC, and show that allosteric CaSR modulation can rectify the loss‐of‐function Phe220Ser mutation and ameliorate the hypercalcemia associated with FHH2. © 2017 The Authors. Journal of Bone and Mineral Research Published by Wiley Periodicals Inc.     

A G‐protein Subunit‐α11 Loss‐of‐Function Mutation,Thr54Met,Causes Familial Hypocalciuric Hypercalcemia Type 2 (FHH2)

Familial hypocalciuric hypercalcemia (FHH) is a genetically heterogeneous disorder with three variants, FHH1 to FHH3. FHH1 is caused by loss‐of‐function mutations of the calcium‐sensing receptor (CaSR), a G‐protein coupled receptor that predominantly signals via G‐protein subunit alpha‐11 (Gα₁₁) to regulate calcium homeostasis. FHH2 is the result of loss‐of‐function mutations in Gα₁₁, encoded by GNA11, and to date only two FHH2‐associated Gα₁₁ missense mutations (Leu135Gln and Ile200del) have been reported. FHH3 is the result of loss‐of‐function mutations of the adaptor protein‐2 σ‐subunit (AP2σ), which plays a pivotal role in clathrin‐mediated endocytosis. We describe a 65‐year‐old woman who had hypercalcemia with normal circulating parathyroid hormone concentrations and hypocalciuria, features consistent with FHH, but she did not have CaSR and AP2σ mutations. Mutational analysis of the GNA11 gene was therefore undertaken, using leucocyte DNA, and this identified a novel heterozygous GNA11 mutation (c.161C>T; p.Thr54Met). The effect of the Gα₁₁ variant was assessed by homology modeling of the related Gα_q protein and by measuring the CaSR‐mediated intracellular calcium (Ca²⁺_i) responses of HEK293 cells, stably expressing CaSR, to alterations in extracellular calcium (Ca²⁺_o) using flow cytometry. Three‐dimensional modeling revealed the Thr54Met mutation to be located at the interface between the Gα₁₁ helical and GTPase domains, and to likely impair GDP binding and interdomain interactions. Expression of wild‐type and the mutant Gα₁₁ in HEK293 cells stably expressing CaSR demonstrate that the Ca²⁺_i responses after stimulation with Ca²⁺_o of the mutant Met54 Gα₁₁ led to a rightward shift of the concentration‐response curve with a significantly (p < 0.01) increased mean half‐maximal concentration (EC₅₀) value of 3.88 mM (95% confidence interval [CI] 3.76–4.01 mM), when compared with the wild‐type EC₅₀ of 2.94 mM (95% CI 2.81–3.07 mM) consistent with a loss‐of‐function. Thus, our studies have identified a third Gα₁₁ mutation (Thr54Met) causing FHH2 and reveal a critical role for the Gα₁₁ interdomain interface in CaSR signaling and Ca²⁺_o homeostasis. © 2016 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research (ASBMR).     

Heritability of Spinal Trabecular Volumetric Bone Mineral Density Measured by QCT in the Diabetes Heart Study

The heritability of trabecular volumetric bone mineral density (BMD) determined by quantitative computed tomography (QCT) has not yet been reported. The purpose of this study was to investigate the heritability of BMD as determined by QCT and DXA in 124 women and 120 men (age 39–83 years, BMI 17–75, 84% type 2 diabetics) from 101 families (232 sibling pairs) in the Diabetes Heart Study. Volumetric BMD had a heritability (h²) estimate of 0.73 (SE = 0.15, P < 0.0001) at the lumbar spine and 0.71 (SE = 0.15, P < 0.0001) at the thoracic spine. Areal BMD heritability estimates were 0.56 for PA spine, 0.43 for total hip, 0.43 for femoral neck, 0.45 for distal radius, 0.42 for mid-radius, and 0.52 for whole body (all P < 0.01). After accounting for familial correlation using generalized estimating equations, volumetric BMD was inversely associated with age (r = –0.52, P < 0.0001) and duration of diabetes (r = –0.24, P < 0.01) and positively associated with body weight (r = 0.25, P < 0.01). In multivariate analysis, adjustment for age, sex, and race lowered the h² estimates for volumetric BMD at the lumbar (h² = 0.41, P < 0.01) and thoracic (h² = 0.48, P < 0.001) spine, increased the h² estimate for areal BMD at the mid radius (h² = 0.58, P < 0.0001), and had little effect on the h² estimate for areal BMD at other sites (h² = 0.41–0.55, all P < 0.01). Additional adjustment for BMI, duration of diabetes, and physical activity had little effect on the h² estimates for volumetric BMD or areal BMD except at the hip where they were lowered (h² = 0.31–0.33, all P < 0.05). These data suggest that, like areal BMD, volumetric BMD is highly heritable and may be used in designing linkage studies to locate genes governing bone metabolism.     

Trabecular Bone Score has Poor Association With pQCT Derived Trabecular Bone Density in Indian Children With Type 1 Diabetes and Healthy Controls

Background: In children with type 1 diabetes mellitus (T1DM), low trabecular volumetric bone mineral density (Trab vBMD) has been reported. However, studies using the trabecular bone score (TBS) are scarce. The objective of our study was to assess areal bone mineral density at the lumbar spine (LS aBMD), the TBS and Trab vBMD in children with type 1 diabetes in comparison with healthy controls and to assess the relationship of Trab vBMD with TBS.Methods: A total of 205 children were assessed for their LS bone mineral content (BMC) and LS aBMD by dual energy x-ray absorptiometry (DXA) and Trab vBMD at distal radius by peripheral quantitative computed tomography (pQCT). Machine generated Z-scores for both LS aBMD and Trab vBMD were used. The retrospective DXA LS scans in children with T1DM (n=137, age 13.1 ± 3.2 years) and controls (n = 68, age 13.0 ± 2.7 years) were analysed with a research trial version of TBS iNsight software (Medimaps Group). The established TBS cut-offs were used to categorize TBS.Results: The mean LS BMC, LS aBMD, TBS and Trab vBMDs were lower in children with T1DM. TBS was positively correlated with LS aBMD but not with Trab vBMD in both groups. Distribution of T1DM and control children was similar in the TBS categories. Over a fourth of the T1DM children with low Trab vBMD (below -2 Z score) had normal TBS, while, in children with LS aBMD Z-score > -2 from both groups, >50% had degraded or partially degraded TBS. Degraded TBS was seen in half the control children although none of them had low Trab vBMD.Conclusion: We found poor correlation between TBS and Trab vBMD in paediatric diabetic and healthy population. Our results also suggest establishing paediatric TBS cut offs in improving the classification of children having degraded trabecular bone.     

Adiponectin and Peak Bone Mass in Men: A Cross-Sectional, Population-Based Study

Adiponectin, a protein classically known to be secreted by adipocytes, is also secreted by bone-forming cells. Results of previous studies have been contradictory as to whether serum adiponectin and bone mineral density (BMD) are associated. The aim of this study was to investigate a possible association between serum adiponectin and BMD in young, healthy men at a time of peak bone mass. BMD in the femoral neck, total hip, and lumbar spine were measured in this population-based cross-sectional study of 700 men aged 20–29 years participating in the Odense Androgen Study. Magnetic resonance imaging of femoral cortical thickness and bone marrow size was performed in a subsample of 363 participants. The associations between serum adiponectin and various bone measures were investigated by means of regression analyses with adjustment for potential confounding variables. An inverse association was found between serum adiponectin and total hip BMD and a direct between adiponectin and femoral bone marrow size (r = −0.092; P = 0.036 and r = 0.164; P = 0.003, respectively). Femoral muscle size may, at least in part, explain the association between adiponectin and total hip BMD. Serum adiponectin was inversely associated with total hip BMD in men at the time of peak bone mass, but this association may be explained by factors related to muscle size and function. The observed association between adiponectin and femoral bone marrow size was retained even after adjustment for potential covariates.     

Increased Bone Mineral Density in Cervical or Thoracic Diffuse Idiopathic Skeletal Hyperostosis (DISH): A Case-Control Study

We aim to compare the bone mineral density (BMD) in a group of patients with cervical or thoracic diffuse idiopathic skeletal hyperostosis (DISH) with that in a matched control group. We also investigated the prevalence of osteoporosis in the two groups and determined the correlation between BMD and the extent of spinal DISH. From 1999 to July 2015, 65 patients with DISH underwent dual-energy X-ray absorptiometry at our institute. The control group was matched with regard to age, sex, and body mass index to the patient group on a 1:1 basis. BMD was measured at the lumbar spine (L1–L4), femur neck, and femur total areas using dual-energy X-ray absorptiometry. The BMDs of the DISH and control groups were significantly different at the lumbar spine (L1–L4) and the femur neck (p?=?0.005, 0.001). The rates of patients with osteopenia and osteoporosis were lower in the DISH than in the control group for the lumbar spine (L1–L4) (p?=?0.05). A positive correlation was observed between the lumbar spine (L1–L4) BMD and the number of spine levels affected by DISH (p?=?0.04). The BMDs of the lumbar spine and femur neck were found to be higher in the DISH group than in a matched control group, when patients with lumbar DISH involvement were excluded. The rates of osteopenia and osteoporosis tended to be lower in the DISH group than in the control group. Lumbar spine BMD is significantly correlated with the number of spine levels affected by DISH.     

Plasma Fluorescent Oxidation Products and Bone Mineral Density Among Male Veterans: A Cross-Sectional Study

In vitro and vivo studies indicate that oxidative stress contributes to bone loss. Fluorescent oxidation products (FlOPs) are novel biomarkers of oxidative stress; they reflect global oxidative damage of lipids, proteins, carbohydrates, and DNA. However, whether FlOPs are associated with bone mineral density (BMD) is still unclear. In the present study, we examined the association between FlOPs and BMD among male veterans. This cross-sectional study was conducted among participants recruited from the Department of Medical Examination, The Second Hospital of Jilin University in Jilin, China. We identified male veterans who were at least 50 y old between June and October of 2019. Plasma FlOPs were measured with a fluorescent microplate reader (excitation/emission wavelength: 320/420 nm). BMD were measured by dual-energy X-ray absorptiometry (DXA). The association between FlOPs and BMD was tested by multivariable linear regression models. A total of 164 male veterans were enrolled in the study, the average age was 56.6 y. After adjusting for covariates, veterans who had FlOP levels in the highest tertile had a statistically significant lower femoral neck (β = -0.044; p = 0.007) and total hip BMD (β = -0.045; p = 0.020) as compared to those with FlOP levels in the lowest tertile. Similar results were found when FlOPs were treated as a continuous variable (per 1-SD increase, β = -0.014 and p = 0.033 for femoral neck BMD; β = -0.016 and p = 0.047 for total hip BMD). Higher FlOP levels were associated with lower BMD among male veterans.     

Bone Microarchitecture in Transgender Adults: A Cross-Sectional Study

Gender-affirming hormone therapy aligns physical characteristics with an individual's gender identity, but sex hormones regulate bone remodeling and influence bone morphology. We hypothesized that trans men receiving testosterone have compromised bone morphology because of suppression of ovarian estradiol production, whereas trans women receiving estradiol, with or without anti-androgen therapy, have preserved bone microarchitecture. We compared distal radial and tibial microarchitecture using high-resolution peripheral quantitative computed tomography images in a cross-sectional study of 41 trans men with 71 cis female controls, and 40 trans women with 51 cis male controls. Between-group differences were expressed as standardized deviations (SD) from the mean in age-matched cisgender controls with 98% confidence intervals adjusted for cross-sectional area (CSA) and multiple comparisons. Relative to cis women, trans men had 0.63 SD higher total volumetric bone mineral density (vBMD; both p = 0.01). Cortical vBMD and cortical porosity did not differ, but cortices were 1.11 SD thicker (p < 0.01). Trabeculae were 0.38 SD thicker (p = 0.05) but otherwise no different. Compared with cis men, trans women had 0.68 SD lower total vBMD (p = 0.01). Cortical vBMD was 0.70 SD lower (p < 0.01), cortical thickness was 0.51 SD lower (p = 0.04), and cortical porosity was 0.70 SD higher (p < 0.01). Trabecular bone volume (BV/TV) was 0.77 SD lower (p < 0.01), with 0.57 SD fewer (p < 0.01) and 0.30 SD thicker trabeculae (p = 0.02). There was 0.56 SD greater trabecular separation (p = 0.01). Findings at the distal radius were similar. Contrary to each hypothesis, bone microarchitecture was not compromised in trans men, perhaps because aromatization of administered testosterone prevented bone loss. Trans women had deteriorated bone microarchitecture either because of deficits in microstructure before treatment or because the estradiol dosage was insufficient to offset reduced aromatizable testosterone. Prospective studies are needed to confirm these findings. © 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).     

Intensive Insulin Therapy and Bone Mineral Density in Type 1 Diabetes Mellitus: A Prospective Study

To determine the effect of metabolic control on bone mineral density (BMD) in type 1 diabetes mellitus (type 1 DM), we studied BMD (by dual-energy X-ray energy absorptiometry) and bone remodeling parameters in 62 patients with type 1 DM both before and 7 years after commencement of intensive insulin therapy. Overall outcomes after the 7-year treatment included the stabilization of BMD at all sites, as well as a significant decrease in tartrate-resistant acid phosphatase (TRAP) (4.302 ± 2.62 vs 2.65 ± 0.97 IU/l; p = 0.0001) and increase in intact parathyroid hormone (PTHi) (28.05 ± 15.7 vs 39.78 ± 22.41 ng/l; p = 0.005). Presence of diabetic retinopathy (RTP) versus its absence (non-RTP) was associated with lower BMD in femoral neck (FN) (0.831 ± 0.142 vs 0.756 ± 0.153 mg/cm²; p = 0.03) and Ward’s triangle (WT) (0.736 ± 0.165 vs 0.632 ± 0.172 mg/cm²; p = 0.03), and with a lower T-score in FN (–0.93 ± 1.34 vs –1.70 ± 1.46; p = 0.04) and WT (–0.72 ± 1.42 vs –1.540 ± 1.55; p = 0.04) and Z-score in FN (–0.591 ± 1.23 vs –1.132 ± 1.46; p = 0.01). The percentage of patients with osteopenia or osteoporosis in the RTP group was significantly higher than in the non-RTP group (72% vs 53%, p = 0.05; RR= 3.2) and the glycosylated hemoglobin (HbA1c) levels of the RTP group were also higher (8.53 ± 1.6% vs 7.1 ± 1.1%; p = 0.05). The improvement in metabolic control, increase in body mass index and decrease in resorption parameters could contribute to the stabilization of bone mass in type 1 DM but the presence of retinopathy is a critical factor in the progression of diabetic osteopenia. Received: 4 June 1999 / Accepted: 16 November 1999     

Bone Microarchitecture,Volumetric or Areal Bone Mineral Density for Discrimination of Vertebral Deformity in Adults: A Cross-sectional Study

Introduction/Background: Both areal bone mineral density (aBMD) and bone microarchitecture have been associated with vertebral deformity (VD), but there are limited data on the utility of bone microarchitecture measures in combination with aBMD in discriminating VD. This study aimed to describe whether radial bone microarchitecture measures alone or in combinations with radial volumetric bone mineral density (vBMD) or spine aBMD can improve discrimination of VD in adults.Methods: Data on 196 subjects (mean age (standard deviation, SD) = 72 (7) years, female 46%) were utilized. VD of T4-L4 and spine aBMD were measured using dual-energy X-ray absorptiometry. VD was defined if anterior to posterior height ratio was more than 3-SD, 4-SD below, or >25% decrease compared with the sex-matched normal means. Bone microarchitecture parameters at distal radius were collected using high-resolution peripheral quantitative computed tomography and analyzed using StrAx.Results: The strongest associations were seen for the cortical thickness (odds ratios (ORs): 2.63/SD decrease for 25% and 2.38/SD decrease for 3-SD criterion) and compact cortical area (OR: 3.33/SD decrease for 4-SD criterion). The area under the receiver operating characteristic curve (AUC) for spine aBMD for VD was 0.594, 0.597, and 0.634 for 25%, 3-SD and 4-SD criteria, respectively (all p < 0.05). Compact cortical area, cortical thickness and compact cortical thickness alone had the largest AUCs for VD (0.680–0.685 for 25% criterion, 0.659–0.674 for 3-SD criterion, and 0.699–0.707 for 4-SD criterion). Adding spine aBMD or radial vBMD to each cortical measure did not improve VD discrimination (? AUC 0.8%–2.1%).Conclusions: Cortical measures had the best utility for discriminating VD when used alone. Adding either spine aBMD or radial vBMD did not improve the utility of cortical measures.     

Influence of Grip Strength on Metacarpal Bone Mineral Density in Postmenopausal Japanese Women: A Cross-Sectional Study

Most published studies on the role of muscle strength in the maintenance of bone mineral density (BMD) focused on the relationship between specific muscle groups and adjacent bones, mostly in young and premenopausal women. This study examined the influence of grip strength on BMD of the metacarpal index in postmenopausal Japanese women. Subjects included 1168 postmenopausal women aged 40–70 years. BMD measurement was done with computed X-ray densitometry (CXD) by analyzing X-ray films of the right second metacarpal index. Grip strength was measured in both the dominant and nondominant hands using a squeeze dynamometer. Grip strength (r = 0.2474; P= 0.0001) and age (r =−0.5443; P= 0.0001) significantly correlated positively and negatively, respectively, with BMD. Physical activity (r = 0.1318; P= 0.0001) also correlated positively with BMD. Breastfeeding (r =−0.1658; P= 0.0001), however, correlated negatively with BMD. Subjects with a history of regular physical activity had higher grip strengths and BMD, than those with no physical activity. Adjustment for age, physical activity, calcium intake, BMI, breastfeeding, testing site, and menopausal type indicated a significant (P for trend = 0.0013) positive association of grip strength with BMD. Subjects with stronger grip strengths had a decreased risk for low BMD. Received: 24 February 1998 / Accepted: 7 August 1998     

Trabecular Bone Score Is Associated With Volumetric Bone Density and Microarchitecture as Assessed by Central QCT and HRpQCT in Chinese American and White Women

Although high-resolution peripheral quantitative computed tomography (HRpQCT) and central quantitative computed tomography (QCT) studies have shown bone structural differences between Chinese American (CH) and white (WH) women, these techniques are not readily available in the clinical setting. The trabecular bone score (TBS) estimates trabecular microarchitecture from dual-energy X-ray absorptiometry spine images. We assessed TBS in CH and WH women and investigated whether TBS is associated with QCT and HRpQCT indices. Areal bone mineral density (aBMD) by dual-energy X-ray absorptiometry, lumbar spine (LS) TBS, QCT of the LS and hip, and HRpQCT of the radius and tibia were performed in 71 pre- (37 WH and 34 CH) and 44 postmenopausal (21 WH and 23 CH) women. TBS did not differ by race in either pre- or postmenopausal women. In the entire cohort, TBS positively correlated with LS trabecular volumetric bone mineral density (vBMD) (r = 0.664), femoral neck integral (r = 0.651), trabecular (r = 0.641) and cortical vBMD (r = 0.346), and cortical thickness (C/I; r = 0.540) by QCT (p < 0.001 for all). TBS also correlated with integral (r = 0.643), trabecular (r = 0.574) and cortical vBMD (r = 0.491), and C/I (r = 0.541) at the total hip (p < 0.001 for all). The combination of TBS and LS aBMD predicted more of the variance in QCT measures than aBMD alone. TBS was associated with all HRpQCT indices (r = 0.20–0.52) except radial cortical thickness and tibial trabecular thickness. Significant associations between TBS and measures of HRpQCT and QCT in WH and CH pre- and postmenopausal women demonstrated here suggest that TBS may be a useful adjunct to aBMD for assessing bone quality.     

Deficits in Trabecular Bone Microarchitecture in Young Women With Type 1 Diabetes Mellitus

The pathophysiological mechanism of increased fractures in young adults with type 1 diabetes mellitus (T1DM) is unclear. We conducted a case‐control study of trabecular bone microarchitecture and vertebral marrow adiposity in young women with T1DM. Thirty women with T1DM with a median age (range) age of 22.0 years (16.9, 36.1) attending one outpatient clinic with a median age at diagnosis of 9.7 years (0.46, 14.8) were compared with 28 age‐matched healthy women who acted as controls. Measurements included MRI‐based assessment of proximal tibial bone volume/total volume (appBV/TV), trabecular separation (appTb.Sp), vertebral bone marrow adiposity (BMA), and abdominal adipose tissue and biochemical markers of GH/IGF‐1 axis (IGF‐1, IGFBP3, ALS) and bone turnover. Median appBV/TV in cases and controls was 0.3 (0.22, 0.37) and 0.33 (0.26, 0.4), respectively (p = 0.018) and median appTb.Sp in T1DM was 2.59 (2.24, 3.38) and 2.32 (2.03, 2.97), respectively (p = 0.012). The median appBV/TV was 0.28 (0.22, 0.33) in those cases with retinopathy (n = 15) compared with 0.33 (0.25, 0.37) in those without retinopathy (p = 0.02). Although median visceral adipose tissue in cases was higher than in controls at 5733 mm³ (2030, 11,144) and 3460 mm³ (1808, 6832), respectively (p = 0.012), there was no difference in median BMA, which was 31.1% (9.9, 59.9) and 26.3% (8.5, 49.8) in cases and controls, respectively (p = 0.2). Serum IGF‐1 and ALS were also lower in cases, and the latter showed an inverse association to appTbSp (r = –0.30, p = 0.04). Detailed MRI studies in young women with childhood‐onset T1DM have shown clear deficits in trabecular microarchitecture of the tibia. Underlying pathophysiological mechanisms may include a microvasculopathy. © 2015 American Society for Bone and Mineral Research.     

Relationship between Vitamin D Metabolites and Bone Mineral Density in Young Males: A Cross-Sectional and Longitudinal Study

The purpose of this study was to investigate the association between vitamin D analogs and peak bone mineral density (BMD, g/cm²) in young men. The cohort consisted of 78 healthy young males with a mean age of 22.6 years at baseline. BMD of the total body, hip, and spine and lean body mass were measured at baseline and at follow-up 2 years later. Blood samples were assayed for 25−hydroxyvitamin D₂ (25OHD₂), 25-hydroxyvitamin D₃ (25OHD₃), and 25-hydroxyvitamin D (25OHD) at baseline using high-performance liquid chromatography. Levels of 25OHD₃ significantly correlated to BMD at all sites and to lean body mass (r = 0.23–0.35, P < 0.05). In contrast, levels of 25OHD₂ significantly negatively correlated with BMD of the total body (r = −0.28, P = 0.01) and spine (r = −0.27, P = 0.02). BMD was then adjusted for the influence of age, body weight, body height, and physical activity (hours/week). Level of 25OHD₃ was then found to be an independent predictor of BMD of the total body (beta = 0.24, P = 0.03) and spine (beta = 0.25, P = 0.03), while level of 25OHD₂ was an independent negative predictor at the same sites (beta = −0.23 for both, P = 0.03). There was a negative association between levels of 25OHD₃ and 25OHD₂ (r = −0.31, P = 0.006). In summary, our novel results suggest an inverse relationship between 25OHD₃ and 25OHD₂ and an opposite relationship of these vitamin D analogs to BMD in young men.     

QCT Volumetric Bone Mineral Density and Vascular and Valvular Calcification: The Framingham Study

There is increasing evidence that bone and vascular calcification share common pathogenesis. Little is known about potential links between bone and valvular calcification. The purpose of this study was to determine the association between spine bone mineral density (BMD) and vascular and valvular calcification. Participants included 1317 participants (689 women, 628 men) in the Framingham Offspring Study (mean age 60 years). Integral, trabecular, and cortical volumetric bone density (vBMD) and arterial and valvular calcification were measured from computed tomography (CT) scans and categorized by sex‐specific quartiles (Q4 = high vBMD). Calcification of the coronary arteries (CAC), abdominal aorta (AAC), aortic valve (AVC), and mitral valve (MVC) were quantified using the Agatston Score (AS). Prevalence of any calcium (AS >0) was 69% for CAC, 81% for AAC, 39% for AVC, and 20% for MVC. In women, CAC increased with decreasing quartile of trabecular vBMD: adjusted mean CAC = 2.1 (Q4), 2.2 (Q3), 2.5 (Q2), 2.6 (Q1); trend p = 0.04. However, there was no inverse trend between CAC and trabecular vBMD in men: CAC = 4.3 (Q4), 4.3 (Q3), 4.2 (Q2), 4.3 (Q1); trend p = 0.92. AAC increased with decreasing quartile of trabecular vBMD in both women (AAC = 4.5 [Q4], 4.8 [Q3], 5.4 [Q2], 5.1 [Q1]; trend p = 0.01) and men (AAC = 5.5 [Q4], 5.8 [Q3], 5.9 [Q2], 6.2 [Q1]; trend p = 0.01). We observed no association between trabecular vBMD and AVC or MVC in women or men. Finally, cortical vBMD was unrelated to vascular calcification and valvular calcification in women and men. Women and men with low spine vBMD have greater severity of vascular calcification, particularly at the abdominal aorta. The inverse relation between AAC and spine vBMD in women and men may be attributable to shared etiology and may be an important link on which to focus treatment efforts that can target individuals at high risk of both fracture and cardiovascular events. © 2015 American Society for Bone and Mineral Research.     

Poor Trabecular Microarchitecture in Male Current Smokers: The Cross-Sectional STRAMBO Study

Current smoking (but not past smoking) is associated with higher risk of fracture independent of areal bone mineral density (aBMD); however, the pathophysiologic mechanism underlying this association is not clear. In 810 men aged 60–87, aBMD was measured by dual-energy X-ray absorptiometry. Bone microarchitecture at the distal radius and distal tibia was assessed by high-resolution peripheral quantitative computed tomography using the Xtreme CT Scanco device. Current smokers (n = 47) had lower trabecular volumetric density (Dtrab), lower trabecular number (TbN), more heterogenous trabecular network (higher trabecular spacing standard deviation [TbSpSD]), as well as higher urinary deoxypyridinoline and higher C-reactive protein levels in comparison with 261 men who never smoked (adjusted for age, weight, height, time spent outdoors, physical activity, and intake of alcohol, caffeine, and calcium). Abnormal values (lower Dtrab and TbN, higher TbSpSD, deoxypyridinoline, and C-reactive protein) were found mainly in 21 current smokers who smoked eight or more cigarettes per day. Cortical parameters and aBMD did not differ from the never-smokers. In 502 former smokers, aBMD and all bone microarchitectural parameters did not differ from the never-smokers. At the tibia (not radius), Dtrab decreased, whereas TbSpSD slightly increased across quartiles of smoking intensity (number of pack-years). In conclusion, older men who are moderate current smokers have poor trabecular (but not cortical) microarchitecture, which is not reflected by a decrease in aBMD.     

Increased Bone Mineral Density in Patients With Ossification of the Ligamentum Flavum: A Case-Control Study

The present study investigated the bone mineral density (BMD) and the prevalence of osteoporosis in an ossification of the ligamentum flavum (OLF) patient group and a matched control group. We also investigated the correlation of BMD with the number of spine levels exhibiting OLF. From January 1999 to August 2012, 120 patients with spinal OLF underwent dual-energy X-ray absorptiometry at our institute, and 102 of those were included in our study. Control group members were age, sex, and body mass index (BMI) matched to OLF group members on a 1:1 basis. Age, sex, and BMI were similar in the OLF and control groups. BMDs of the OLF and control groups were significantly different in the lumbar spine (mean T-scores: −0.2 ± 1.5 and −0.7 ± 1.5, respectively; p = 0.03). The prevalences of osteopenia and osteoporosis tended to be lower in the OLF group (28.3% and 4.0%, respectively) than those in the control group (31.3% and 9.1%, respectively); however, the differences were not statistically significant (p = 0.41). A significant positive correlation was detected between the lumbar spine BMD and the number of spine levels exhibiting OLF (p = 0.03).     

Bone Density in Patients With Berardinelli-Seip Congenital Lipodystrophy Is Higher in Trabecular Sites and in Type 2 Patients

Berardinelli-Seip congenital lipodystrophy (BSCL) is a rare autosomal recessive syndrome characterized by a difficulty storing lipid in adipocytes, low body fat, hypoleptinemia, and hyperinsulinemia. We report here laboratory, bone mineral density (BMD), and bone mineral content findings of 21 patients (24.1?±?8.4?yr old, 14 females, 18 diabetics, 5.3% total body fat) with BSCL. The mean leptin was very low (0.91?±?0.42 ng/mL), and the mean values of the Z-scores for all studied sites were positive, except for the 33% radius (Z-score ?0.5?standard deviation [SD]). Twelve patients (57.1%) had a BMD Z-score higher than +2.5?SD in at least 1 site. There was no significant difference in the Z-scores between males and females. None of type 1 (AGPAT2) patients had Z-scores higher than +2.5?SD, and these patients had a smaller Z-score of BMD total body (0.26?SD vs 1.90?SD, p?=?0.022) and of bone mineral content (1.59?SD vs 3.3?SD, p?=?0.032) than type 2 (seipin) patients. Insulin, as well as HOMA_IR (homeostasis model assessment), correlated positively with the BMD of all sites, except for the 33% radius. Z-Scores on this site (33% radius) were the smallest of all. More than half of our patients with BSCL have BMD Z-scores higher than +2.5?SD on at least 1 site, and this increase is more pronounced in the trabecular sites and in type 2 patients.