Patients with high‐bone‐mass phenotype owing to Lrp5‐T253I mutation have low plasma levels of serotonin

The Lrp5 gene is a major determinant of bone mass accrual. It has been demonstrated recently to achieve this function by hampering the synthesis of gut‐derived serotonin, which is a powerful inhibitor of bone formation. In this study we analyzed plasma serotonin levels in patients with a high‐bone‐mass (HBM) phenotype owing to gain‐of‐function mutation of Lrp5 (T253I). A total of 9 HBM patients were compared with 18 sex‐ and age‐matched controls. In HBM patients, the serotonin concentrations in platelet‐poor plasma were significantly lower than in the controls (mean ± SEM: 2.16 ± 0.28 ng/mL versus 3.51 ± 0.49 ng/mL, respectively, p < .05). Our data support the hypothesis that circulating serotonin levels mediate the increased bone mass resulting from gain‐of‐function mutations in Lrp5 in humans. © 2010 American Society for Bone and Mineral Research.     

High Bone Mass–Causing Mutant LRP5 Receptors Are Resistant to Endogenous Inhibitors In Vivo

Certain missense mutations affecting LRP5 cause high bone mass (HBM) in humans. Based on in vitro evidence, HBM LRP5 receptors are thought to exert their effects by providing resistance to binding/inhibition of secreted LRP5 inhibitors such as sclerostin (SOST) and Dickkopf homolog‐1 (DKK1). We previously reported the creation of two Lrp5 HBM knock‐in mouse models, in which the human p.A214V or p.G171V missense mutations were knocked into the endogenous Lrp5 locus. To determine whether HBM knock‐in mice are resistant to SOST‐ or DKK1‐induced osteopenia, we bred Lrp5 HBM mice with transgenic mice that overexpress human SOST in osteocytes (^8kbDmp1‐SOST) or mouse DKK1 in osteoblasts and osteocytes (^2.3kbCol1a1‐Dkk1). We observed that the ^8kbDmp1‐SOST transgene significantly lowered whole‐body bone mineral density (BMD), bone mineral content (BMC), femoral and vertebral trabecular bone volume fraction (BV/TV), and periosteal bone‐formation rate (BFR) in wild‐type mice but not in mice with Lrp5 p.G171V and p.A214V alleles. The ^2.3kbCol1a1‐Dkk1 transgene significantly lowered whole‐body BMD, BMC, and vertebral BV/TV in wild‐type mice and affected p.A214V mice more than p.G171V mice. These in vivo data support in vitro studies regarding the mechanism of HBM‐causing mutations, and imply that HBM LRP5 receptors differ in their relative sensitivity to inhibition by SOST and DKK1. © 2015 American Society for Bone and Mineral Research.     

Van Buchem disease: Clinical,biochemical, and densitometric features of patients and disease carriers

Van Buchem disease (VBD) is a rare bone sclerosing dysplasia caused by the lack of a regulatory element of the SOST gene, which encodes for sclerostin, an osteocyte‐derived negative regulator of bone formation. We studied the demographic, clinical, biochemical, and densitometric features of 15 patients with VBD (12 adults and 3 children) and 28 related carriers of the gene mutation. The most common clinical findings in patients were facial palsy (100%) and various degrees of hearing impairment (93%); raised intracranial pressure had been documented in 20%. The clinical course of the disease appeared to stabilize in adulthood, with the majority of patients reporting no progression of symptoms or development of complications with time. Carriers of the disease had none of the clinical features or complications of the disease. Sclerostin could be detected in the serum in all but 1 VBD patients (mean 8.0 pg/mL; 95% confidence interval [CI], 4.9–11.0 pg/mL), and were lower than those of carriers (mean 28.7 pg/mL; 95% CI, 24.5–32.9 pg/mL; p < 0.001) and healthy controls (mean 40.0 pg/mL; 95% CI, 34.5–41.0 pg/mL; p < 0.). Serum procollagen type 1 amino‐terminal propeptide (P1NP) levels were also significantly higher in adult patients (mean 96.0; 95% CI, 54.6–137.4 ng/mL versus mean 47.8; 95% CI, 39.4–56.2 ng/mL, p = 0.003 in carriers and mean 37.8; 95% CI, 34.5–41.0 ng/mL, p = 0.028 in healthy controls) and declined with age. Bone mineral density (BMD) was markedly increased in all patients (mean Z‐score 8.7 ± 2.1 and 9.5 ± 1.9 at the femoral neck and spine, respectively); BMD of carriers was significantly lower than that of patients but varied widely (mean Z‐scores 0.9 ± 1.0 and 1.3 ± 1.5 at the femoral neck and spine, respectively). Serum sclerostin levels were inversely correlated with serum P1NP levels (r = –0.39, p = 0.018) and BMD values (femoral neck r = –0.69, p < 0.001; lumbar spine r = –0.78, p < 0.001). Our results show that there is a gene‐dose effect of the VBD deletion on circulating sclerostin and provide further in vivo evidence of the role of sclerostin in bone formation in humans. The small amounts of sclerostin produced by patients with VBD may explain their milder phenotype compared to that of patients with sclerosteosis, in whom serum sclerostin is undetectable. © 2013 American Society for Bone and Mineral Research.     

Lower fracture risk in older men with higher sclerostin concentration: A prospective analysis from the MINOS study

Sclerostin is synthesized by osteocytes and inhibits bone formation. We measured serum sclerostin levels in 710 men aged 50 years and older. Bone mineral density (BMD) was measured at the lumbar spine, hip, and distal forearm. Serum sclerostin increased with age (unadjusted r = 0.30, p < 0.001). After adjustment for age, weight, and bioavailable 17β‐estradiol, serum sclerostin correlated positively with BMD (r = 0.24 to 0.35, p < 0.001) and negatively with the levels of bone turnover markers (r = ? 0.09 to ? 0.23, p < 0.05 to 0.001). During a 10‐year follow‐up, 75 men sustained fragility fractures. Fracture risk was lower in the two upper quintiles of sclerostin combined versus three lower quintiles combined (6.1 versus 13.5%, p < 0.01). We compared fracture risk in the two highest quintiles combined versus three lower quintiles combined using the Cox model adjusted for age, weight, leisure physical activity, BMD, bone width (tubular bones), prevalent fracture, prevalent falls, ischemic heart disease, and severe abdominal aortic calcification. Men with higher sclerostin concentration had lower fracture risk (adjusted for hip BMD, hazard ratio [HR] = 0.55, 95% confidence interval [CI] 0.31 to 0.96, p < 0.05). The results were similar in 47 men with major fragility fractures (adjusted for lumbar spine BMD: HR = 0.39, 95% CI 0.17 to 0.90, p < 0.05). Men who had higher sclerostin and higher BMD (two highest quintiles) had lower risk of fracture compared with men who had lower BMD and lower sclerostin levels (three lower quintiles) (HR = 0.24, 95% CI 0.10 to 0.62, p < 0.005). Circulating sclerostin was not associated with mortality rate or the incidence of major cardiovascular events. Thus, in older men, higher serum sclerostin levels are associated with lower risk of fracture, higher BMD, and lower bone turnover rate. © 2013 American Society for Bone and Mineral Research.     

Sclerostin antibody inhibits skeletal deterioration due to reduced mechanical loading

Sclerostin, a product of the SOST gene produced mainly by osteocytes, is a potent negative regulator of bone formation that appears to be responsive to mechanical loading, with SOST expression increasing following mechanical unloading. We tested the ability of a murine sclerostin antibody (SclAbII) to prevent bone loss in adult mice subjected to hindlimb unloading (HLU) via tail suspension for 21 days. Mice (n = 11–17/group) were assigned to control (CON, normal weight bearing) or HLU and injected with either SclAbII (subcutaneously, 25 mg/kg) or vehicle (VEH) twice weekly. SclAbII completely inhibited the bone deterioration due to disuse, and induced bone formation such that bone properties in HLU‐SclAbII were at or above values of CON‐VEH mice. For example, hindlimb bone mineral density (BMD) decreased –9.2% ± 1.0% in HLU‐VEH, whereas it increased 4.2% ± 0.7%, 13.1% ± 1.0%, and 30.6% ± 3.0% in CON‐VEH, HLU‐SclAbII, and CON‐SclAbII, respectively (p < 0.0001). Trabecular bone volume, assessed by micro–computed tomography (µCT) imaging of the distal femur, was lower in HLU‐VEH versus CON‐VEH (p < 0.05), and was 2‐ to 3‐fold higher in SclAbII groups versus VEH (p < 0.001). Midshaft femoral strength, assessed by three‐point bending, and distal femoral strength, assessed by micro–finite element analysis (µFEA), were significantly higher in SclAbII versus VEH‐groups in both loading conditions. Serum sclerostin was higher in HLU‐VEH (134 ± 5 pg/mL) compared to CON‐VEH (116 ± 6 pg/mL, p < 0.05). Serum osteocalcin was decreased by hindlimb suspension and increased by SclAbII treatment. Interestingly, the anabolic effects of sclerostin inhibition on some bone outcomes appeared to be enhanced by normal mechanical loading. Altogether, these results confirm the ability of SclAbII to abrogate disuse‐induced bone loss and demonstrate that sclerostin antibody treatment increases bone mass by increasing bone formation in both normally loaded and underloaded environments. © 2013 American Society for Bone and Mineral Research.     

Relationship Between Pretreatment Rate of Bone Loss and Bone Density Response to Once‐Yearly ZOL: HORIZON‐PFT Extension Study

Several studies have shown that high bone turnover is associated with greater rates of bone loss and greater bone mineral density (BMD) response to antiresorptive therapy in postmenopausal osteoporosis. However, it is not known whether greater rates of bone loss before therapy are associated with greater BMD response to antiresorptive therapy. In the HORIZON‐PFT study and its extension, one group of women who were randomized to receive placebo for 3 years (years 1, 2, and 3) were then switched to zoledronic acid (ZOL) 5 mg annually for up to three injections (years 4, 5, and 6, P3Z3 arm) (n = 1223). We measured total hip BMD at baseline, 1, 2, and 3 years on placebo and at 4.5 and 6 years on ZOL. The procollagen type I N‐terminal propeptide (PINP) was measured at 3, 4.5, and 6 years. By design, not all subjects were followed for as long as 6 years, so this analysis focused on the results at 4.5 years. Those with the largest loss in total hip BMD on placebo in years 0 to 3 had the largest gain during ZOL (years 3 to 4.5): (r = –0.39, p < 0.0001). The change in total hip BMD in years 0 to 3 on placebo was related to the serum PINP at the end of the 3‐year period (r = –0.24, p < 0.0001). The change in total hip BMD on ZOL from year 3 to 4.5 was related to the serum PINP at the end of the 3‐year period (r = 0.26, p < 0.0001). We conclude that BMD response to ZOL is greater in postmenopausal women who had larger loss before treatment. This association may result from higher bone turnover being associated with both greater bone loss on placebo and greater BMD response to ZOL. © 2014 American Society for Bone and Mineral Research.     

A comparison of bone quality at the distal radius between Asian and white adolescents and young adults: An HR‐pQCT study

Paradoxically, Asians have lower areal bone mineral density (aBMD), but their rates of hip and wrist fractures are lower than whites. Therefore, we used high‐resolution pQCT (HR‐pQCT) to determine whether differences in bone macrostructure and microstructure, BMD, and bone strength at the distal radius were apparent in Asian (n = 91, 53 males, 38 females, [mean ± SD] 17.3 ± 1.5 years) and white (n = 89, 46 males, 43 females, 18.1 ± 1.8 years) adolescents and young adults. HR‐pQCT outcomes included total BMD (Tt.BMD), trabecular bone volume fraction (BV/TV), and trabecular number (Tb.N), thickness (Tb.Th), and separation (Tb.Sp). We used an automated segmentation algorithm to determine total bone area (Tt.Ar), and cortical BMD (Ct.BMD), porosity (Ct.Po), and thickness (Ct.Th), and we applied finite element (FE) analysis to HR‐pQCT scans to estimate bone strength. We fit sex‐specific multivariable regression models to compare bone outcomes between Asians and whites, adjusting for age, age at menarche (girls), lean mass, ulnar length, dietary calcium intake, and physical activity. In males, after adjusting for covariates, Asians had 11% greater Tt.BMD, 8% greater Ct.BMD, and 25% lower Ct.Po than whites (p < 0.05). Also, Asians had 9% smaller Tt.Ar and 27% greater Ct.Th (p < 0.01). In females, Asians had smaller Tt.Ar than whites (16%, p < 0.001), but this difference was not significant after adjusting for covariates. Asian females had 5% greater Ct.BMD, 12% greater Ct.Th, and 11% lower Tb.Sp than whites after adjusting for covariates (p < 0.05). Estimated bone strength did not differ between Asian and white males or females. Our study supports the notion of compensatory elements of bone structure that sustain bone strength; smaller bones as observed between those of Asian origin compared with white origin have, on average, more dense, less porous, and thicker cortices. Longitudinal studies are needed to determine whether ethnic differences in bone structure exist in childhood, persist into old age, and whether they influence fracture risk.     

Effect of Two‐Year Caloric Restriction on Bone Metabolism and Bone Mineral Density in Non‐Obese Younger Adults: A Randomized Clinical Trial

Although caloric restriction (CR) could delay biologic aging in humans, it is unclear if this would occur at the cost of significant bone loss. We evaluated the effect of prolonged CR on bone metabolism and bone mineral density (BMD) in healthy younger adults. Two‐hundred eighteen non‐obese (body mass index [BMI] 25.1 ± 1.7 kg/m²), younger (age 37.9 ± 7.2 years) adults were randomly assigned to 25% CR (CR group, n = 143) or ad libitum (AL group, n = 75) for 2 years. Main outcomes were BMD and markers of bone turnover. Other outcomes included body composition, bone‐active hormones, nutrient intake, and physical activity. Body weight (–7.5 ± 0.4 versus 0.1 ± 0.5 kg), fat mass (–5.3 ± 0.3 versus 0.4 ± 0.4 kg), and fat‐free mass (–2.2 ± 0.2 versus –0.2 ± 0.2 kg) decreased in the CR group compared with AL (all between group p < 0.001). Compared with AL, the CR group had greater changes in BMD at 24 months: lumbar spine (–0.013 ± 0.003 versus 0.007 ± 0.004 g/cm²; p < 0.001), total hip (–0.017 ± 0.002 versus 0.001 ± 0.003 g/cm²; p < 0.001), and femoral neck (–0.015 ± 0.003 versus –0.005 ± 0.004 g/cm²; p = 0.03). Changes in bone markers were greater at 12 months for C‐telopeptide (0.098 ± 0.012 versus 0.025 ± 0.015 μg/L; p < 0.001), tartrate‐resistant acid phosphatase (0.4 ± 0.1 versus 0.2 ± 0.1 U/L; p = 0.004), and bone‐specific alkaline phosphatase (BSAP) (–1.4 ± 0.4 versus –0.3 ± 0.5 U/L; p = 0.047) but not procollagen type 1 N‐propeptide; at 24 months, only BSAP differed between groups (–1.5 ± 0.4 versus 0.9 ± 0.6 U/L; p = 0.001). The CR group had larger increases in 25‐hydroxyvitamin D, cortisol, and adiponectin and decreases in leptin and insulin compared with AL. However, parathyroid hormone and IGF‐1 levels did not differ between groups. The CR group also had lower levels of physical activity. Multiple regression analyses revealed that body composition, hormones, nutrients, and physical activity changes explained ～31% of the variance in BMD and bone marker changes in the CR group. Therefore, bone loss at clinically important sites of osteoporotic fractures represents a potential limitation of prolonged CR for extending life span. Further long‐term studies are needed to determine if CR‐induced bone loss in healthy adults contributes to fracture risk and if bone loss can be prevented with exercise. © 2015 American Society for Bone and Mineral Research.     

Sclerostin Expression in Bile Ducts of Patients With Chronic Cholestasis May Influence the Bone Disease in Primary Biliary Cirrhosis

Sclerostin is involved in the regulation of osteoblastogenesis and little is known about its role in the development of bone disease in primary biliary cirrhosis (PBC), characterized by low bone formation. Therefore, we have assessed the circulating levels and the liver expression of sclerostin in this cholestatic disease. Serum sclerostin levels were measured in 79 women with PBC (mean age 60.6 ± 1.2 years) and in 80 control women. Lumbar and femoral bone mineral density (BMD), as well as parameters of mineral metabolism and bone remodeling, were measured. Moreover, sclerostin gene (SOST) expression in the liver was assessed by real‐time PCR in samples of liver tissue taken by biopsy in 11 PBC patients and in 5 normal liver specimens. Presence and distribution of sclerostin was evaluated in liver slices from 11 patients by immunohistochemistry. The severity of histologic lesions was assessed semiquantitatively in the same liver samples. PBC patients had higher sclerostin levels than controls (75.6 ± 3.9 versus 31.7 ± 1.6 pmol/L, p < 0.001). Serum sclerostin correlated inversely with markers of bone formation and resorption. Sclerostin mRNA in the liver was overexpressed compared with control samples (2.7‐fold versus healthy liver). Sclerostin was detected by immunohistochemistry in 7 of the 11 liver samples, mainly located in the bile ducts. Liver sclerostin was associated with the severity of cholangitis (p = 0.02) and indirectly with the degree of lobular inflammation (p = 0.03). Sclerostin mRNA expression was higher in samples that tested positive by immunohistochemistry and particularly in those with lobular granuloma (p = 0.02). The increased expression of sclerostin in the liver and the association with histologic cholangitis may explain the high serum levels of this protein in patients with PBC, thus suggesting that sclerostin may influence the decreased bone formation in this cholestatic disease. © 2016 American Society for Bone and Mineral Research.     

Application of High‐Resolution Skeletal Imaging to Measurements of Volumetric BMD and Skeletal Microarchitecture in Chinese‐American and White Women: Explanation of a Paradox

Asian women have lower rates of hip and forearm fractures despite lower areal BMD (aBMD) by DXA compared with white women and other racial groups. We hypothesized that the lower fracture rates may be explained by more favorable measurements of volumetric BMD (vBMD) and microarchitectural properties, despite lower areal BMD. To address this hypothesis, we used high‐resolution pQCT (HRpQCT), a new method that can provide this information noninvasively. We studied 63 premenopausal Chinese‐American (n = 31) and white (n = 32) women with DXA and HRpQCT. aBMD by DXA did not differ between groups for the lumbar spine (1.017 ± 0.108 versus 1.028 ± 0.152 g/cm²; p = 0.7), total hip (0.910 ± 0.093 versus 0.932 ± 0.134 g/cm²; p = 0.5), femoral neck (0.788 ± 0.083 versus 0.809 ± 0.129 g/cm²; p = 0.4), or one‐third radius (0.691 ± 0.052 versus 0.708 ± 0.047 g/cm²; p = 0.2). HRpQCT at the radius indicated greater trabecular (168 ± 41 versus 137 ± 33 mg HA/cm³; p = <0.01) and cortical (963 ± 46 versus 915 ± 42 mg HA/cm³; p < 0.0001) density; trabecular bone to tissue volume (0.140 ± 0.034 versus 0.114 ± 0.028; p = <0.01); trabecular (0.075 ± 0.013 versus 0.062 ± 0.009 mm; p < 0.0001) and cortical thickness (0.98 ± 0.16 versus 0.80 ± 0.14 mm; p < 0.0001); and lower total bone area (197 ± 34 versus 232 ± 33 mm²; p = <0.001) in the Chinese versus white women and no difference in trabecular number, spacing, or inhomogeneity before adjustment for covariates. Similar results were observed at the weight‐bearing tibia. At the radius, adjustment for covariates did not change the direction or significance of differences except for bone, which became similar between the groups. However, at the tibia, adjustment for covariates attenuated differences in cortical BMD and bone area and accentuated differences in trabecular microarchitecture such that Chinese women additionally had higher trabecular number and lower trabecular spacing, as well as inhomogeneity after adjustment. Using the high‐resolution technology, the results provide a mechanistic explanation for why Chinese women have fewer hip and forearm fractures than white women.     

Antiresorptives overlapping ongoing teriparatide treatment result in additional increases in bone mineral density

During teriparatide (TPTD) treatment, high levels of bone formation are accompanied by an increase in bone resorption. The aim of this work was to test if coadministration of raloxifene (RAL) or alendronate (ALN) following 9 months of ongoing TPTD therapy would reopen the anabolic window, thereby exerting additional benefit on bone mineral density (BMD). Postmenopausal women (n = 125) with severe osteoporosis on TPTD treatment for 9 months were randomized into three open‐label groups for a further 9 months: ALN (70 mg/week) in addition to TPTD; RAL (60 mg/d) in addition to TPTD; or no medication in addition to TPTD. Amino‐terminal propeptide of type I procollagen (P1NP) and cross‐linked C‐telopeptide (CTX), and areal and volumetric BMD at the lumbar spine and hip were assessed. During the combination period, P1NP concentrations did not change on TPTD monotherapy (693% ± 371%, p < 0.0001) and decreased in the ALN (360% ± 153%, p < 0.0001) and RAL (482% ± 243%, p < 0.0001) combination groups; whereas CTX did not change on TPTD monotherapy (283% ± 215%, p < 0.0001), decreased to the starting level in the ALN combination group (17% ± 72%, p = 0.39), and remained elevated in the RAL combination group (179% ± 341%, p < 0.0001). The increase in lumbar spine BMD was 5% ± 6.3% in the ALN and 6% ± 5.2% in the RAL combination groups compared with 2.8% ± 9.3% in the TPTD monotherapy group (p = 0.085 and p = 0.033, respectively). The increase of trabecular lumbar spine BMD for both the ALN and RAL combination groups was superior to TPTD monotherapy. Total hip BMD changes were 4% ± 5.3% for the ALN combination group and 1.4% ± 5.1% for the TPTD monotherapy (p = 0.032), and 1.4% ± 3.4% (p = 0.02) for the RAL combination group. With the exception of no differences in the trabecular compartment of femoral neck, volumetric BMD changes in the ALN combination group for all other comparisons were significantly superior to the two other groups. Our data suggest that ALN when added to TPTD 9 months after initiation of TPTD monotherapy results in a more robust increase in BMD, probably due to a reopening of the anabolic window. The clinical relevance of the BMD increase is unknown. © 2013 American Society for Bone and Mineral Research     

Correlates of bone microarchitectural parameters and serum sclerostin levels in men: The STRAMBO study

Sclerostin is predominantly expressed by osteocytes. Serum sclerostin levels are positively correlated with areal bone mineral density (aBMD) measured by dual‐energy X‐ray absorptiometry (DXA) and bone microarchitecture assessed by high‐resolution peripheral quantitative computed tomography (HR‐pQCT) in small studies. We assessed the relation of serum sclerostin levels with aBMD and microarchitectural parameters based on HR‐pQCT in 1134 men aged 20 to 87 years using multivariable models adjusted for confounders (age, body size, lifestyle, comorbidities, hormones regulating bone metabolism, muscle mass and strength). The apparent age‐related increase in serum sclerostin levels was faster before the age of 63 years than afterward (0.43 SD versus 0.20 SD per decade). In 446 men aged ≤63 years, aBMD (spine, hip, whole body), trabecular volumetric BMD (Tb.vBMD), and trabecular number (Tb.N) at the distal radius and tibia were higher in the highest sclerostin quartile versus the three lower quartiles combined. After adjustment for aBMD, men in the highest sclerostin quartile had higher Tb.vBMD (mainly in the central compartment) and Tb.N at both skeletal sites (p < 0.05 to 0.001). In 688 men aged >63 years, aBMD was positively associated with serum sclerostin levels at all skeletal sites. Cortical vBMD (Ct.vBMD) and cortical thickness (Ct.Th) were lower in the first sclerostin quartile versus the three higher quartiles combined. Tb.vBMD increased across the sclerostin quartiles, and was associated with lower Tb.N and more heterogeneous trabecular distribution (higher Tb.Sp.SD) in men in the lowest sclerostin quartile. After adjustment for aBMD, men in the lowest sclerostin quartile had lower Tb.vBMD and Tb.N, but higher Tb.Sp.SD (p < 0.05 to 0.001) at both the skeletal sites. In conclusion, serum sclerostin levels in men are strongly positively associated with better bone microarchitectural parameters, mainly trabecular architecture, regardless of the potential confounders.     

Bone quality, as measured by trabecular bone score in patients with adrenal incidentalomas with and without subclinical hypercortisolism

Patients with adrenal incidentalomas (AIs) and subclinical hypercortisolism (SH) have increased risk of fracture independent of bone mineral density (BMD) and possibly due to reduced bone quality. The trabecular bone score (TBS) has been proposed as a index of bone microarchitecture. The aim of the study was to investigate TBS in AI. In 102 AI patients, SH was diagnosed in the presence of at least two of the following: (1) urinary free cortisol >70 µg/24 h (193.1 nmol/L); (2) cortisol after 1‐mg dexamethasone suppression test (1‐mg DST) >3.0 µg/dL (82.8 nmol/L); or (3) adrenocorticotropic hormone (ACTH) <10 pg/mL (<2.2 pmol/L). In patients and in 70 matched controls, BMD was measured at lumbar spine (LS) and femur (neck [FN] and total [FT]) by dual X‐ray absorptiometry and TBS was assessed in the region of LS‐BMD; BMD and TBS data were reported as Z‐scores. In patients, vertebral deformities were assessed by radiograph. Patients with SH (n = 34) had lower LS‐BMD (?0.31 ± 1.17), FT‐BMD (?0.29 ± 0.91), and TBS (?3.18 ± 1.21) than patients without SH (n = 68, 0.31 ± 1.42, p = 0.03; 0.19 ± 0.97, p = 0.01; ?1.70 ± 1.54, p < 0.0001, respectively) and controls (0.42 ± 1.52, p = 0.02; 0.14 ± 0.76, p = 0.02; ?1.19 ± 0.99, p < 0.0001, respectively). TBS was inversely correlated with 1‐mg DST (β = ?0.26, t = ?2.79, p = 0.006) regardless of age, LS‐BMD, body mass index (BMI), and gender. The presence of fracture was associated with low TBS alone (odds ratio [OR], 4.8; 95% confidence interval [CI], 1.85–12.42, p = 0.001) and with the cluster low TBS plus low LS‐BMD (OR, 4.37; 95% CI, 1.71–11.4, p = 0.002), after adjustment for age, BMI, and gender. Low TBS plus low LS‐BMD showed a good specificity (79%) for predicting fractures, whereas normal TBS (ie, > ?1.5) plus normal LS‐BMD high specificity (88.1%) for excluding fractures. Finally, TBS predicted the occurrence of a new fracture in 40 patients followed for 24 months (OR, 11.2; 95%CI, 1.71–71.41, p = 0.012) regardless of LS‐BMD, BMI, and age. In SH, bone quality, as measured by TBS, is altered. TBS is useful in detecting AI patients at risk of fractures. © 2012 American Society for Bone and Mineral Research.     

Volumetric bone mineral density and bone structure in childhood chronic kidney disease

Chronic kidney disease (CKD) is associated with increased fracture risk and skeletal deformities. The impact of CKD on volumetric bone mineral density (vBMD) and cortical dimensions during growth is unknown. Tibia quantitative computed tomographic scans were obtained in 156 children with CKD [69 stages 2 to 3, 51 stages 4 to 5, and 36 stage 5D (dialysis)] and 831 healthy participants aged 5 to 21 years. Sex‐, race‐, and age‐ or tibia length–specific Z‐scores were generated for trabecular BMD (TrabBMD), cortical BMD (CortBMD), cortical area (CortArea) and endosteal circumference (EndoC). Greater CKD severity was associated with a higher TrabBMD Z‐score in younger participants (p < .001) compared with healthy children; this association was attenuated in older participants (interaction p < .001). Mean CortArea Z‐score was lower (p < .01) in CKD 4–5 [?0.49, 95% confidence interval (CI) ?0.80, ?0.18)] and CKD 5D (?0.49, 95% CI ?0.83, ?0.15) compared with healthy children. Among CKD participants, parathyroid hormone (PTH) levels were positively associated with TrabBMD Z‐score (p < .01), and this association was significantly attenuated in older participants (interaction p < .05). Higher levels of PTH and biomarkers of bone formation (bone‐specific alkaline phosphatase) and resorption (serum C‐terminal telopeptide of type 1 collagen) were associated with lower CortBMD and CortArea Z‐scores and greater EndoC Z‐score (r = 0.18–0.36, all p ≤ .02). CortBMD Z‐score was significantly lower in CKD participants with PTH levels above versus below the upper limit of the Kidney Disease Outcome Quality Initiative (KDOQI) CKD stage‐specific target range: ?0.46 ± 1.29 versus 0.12 ± 1.14 (p < .01). In summary, childhood CKD and secondary hyperparathyroidism were associated with significant reductions in cortical area and CortBMD and greater TrabBMD in younger children. Future studies are needed to establish the fracture implications of these alterations and to determine if cortical and trabecular abnormalities are reversible. © 2011 American Society for Bone and Mineral Research     

Bone Geometry,Volumetric Density,Microarchitecture, and Estimated Bone Strength Assessed by HR‐pQCT in Adult Patients With Hypophosphatemic Rickets

Hypophosphatemic rickets (HR) is characterized by a generalized mineralization defect. Although densitometric studies have found the patients to have an elevated bone mineral density (BMD), data on bone geometry and microstructure are scarce. The aim of this cross‐sectional in vivo study was to assess bone geometry, volumetric BMD (vBMD), microarchitecture, and estimated bone strength in adult patients with HR using high‐resolution peripheral quantitative computed tomography (HR‐pQCT). Twenty‐nine patients (aged 19 to 79 years; 21 female, 8 male patients), 26 of whom had genetically proven X‐linked HR, were matched with respect to age and sex with 29 healthy subjects. Eleven patients were currently receiving therapy with calcitriol and phosphate for a median duration of 29.1 years (12.0 to 43.0 years). Because of the disproportionate short stature in HR, the region of interest in HR‐pQCT images at the distal radius and tibia were placed in a constant proportion to the entire length of the bone in both patients and healthy volunteers. In age‐ and weight‐adjusted models, HR patients had significantly higher total bone cross‐sectional areas (radius 36%, tibia 20%; both p < 0.001) with significantly higher trabecular bone areas (radius 49%, tibia 14%; both p < 0.001) compared with controls. In addition, HR patients had lower total vBMD (radius ?20%, tibia ?14%; both p < 0.01), cortical vBMD (radius ?5%, p < 0.001), trabecular number (radius ?13%, tibia ?14%; both p < 0.01), and cortical thickness (radius ?19%; p < 0.01) compared with controls, whereas trabecular spacing (radius 18%, tibia 23%; p < 0.01) and trabecular network inhomogeneity (radius 29%, tibia 40%; both p < 0.01) were higher. Estimated bone strength was similar between the groups. In conclusion, in patients with HR, the negative impact of lower vBMD and trabecular number on bone strength seems to be compensated by an increase in bone diameter, resulting in HR patients having normal estimates of bone strength. © 2014 American Society for Bone and Mineral Research.     

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/m²; 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. © 2013 American Society for Bone and Mineral Research.     

Simulated increases in body fat and errors in bone mineral density measurements by DXA and QCT

Major alterations in body composition, such as with obesity and weight loss, have complex effects on the measurement of bone mineral density (BMD) by dual‐energy X‐ray absorptiometry (DXA). The effects of altered body fat on quantitative computed tomography (QCT) measurements are unknown. We scanned a spine phantom by DXA and QCT before and after surrounding with sequential fat layers (up to 12 kg). In addition, we measured lumbar spine and proximal femur BMD by DXA and trabecular spine BMD by QCT in 13 adult volunteers before and after a simulated 7.5 kg increase in body fat. With the spine phantom, DXA BMD increased linearly with sequential fat layering at the normal (p < 0.01) and osteopenic (p < 0.01) levels, but QCT BMD did not change significantly. In humans, fat layering significantly reduced DXA spine BMD values (mean ± SD: ?2.2 ± 3.7%, p = 0.05) and increased the variability of measurements. In contrast, fat layering increased QCT spine BMD in humans (mean ± SD: 1.5 ± 2.5%, p = 0.05). Fat layering did not change mean DXA BMD of the femoral neck or total hip in humans significantly, but measurements became less precise. Associations between baseline and fat‐simulation scans were stronger for QCT of the spine (r² = 0.97) than for DXA of the spine (r² = 0.87), total hip (r² = 0.80), or femoral neck (r² = 0.75). Bland‐Altman plots revealed that fat‐associated errors were greater for DXA spine and hip BMD than for QCT trabecular spine BMD. Fat layering introduces error and decreases the reproducibility of DXA spine and hip BMD measurements in human volunteers. Although overlying fat also affects QCT BMD measurements, the error is smaller and more uniform than with DXA BMD. Caution must be used when interpreting BMD changes in humans whose body composition is changing. © 2012 American Society for Bone and Mineral Research     

Methylation of Bone SOST,Its mRNA,and Serum Sclerostin Levels Correlate Strongly With Fracture Risk in Postmenopausal Women

Inhibition of sclerostin, a glycoprotein secreted by osteocytes, offers a new therapeutic paradigm for treatment of osteoporosis (OP) through its critical role as Wnt/catenin signaling regulator. This study describes the epigenetic regulation of SOST expression in bone biopsies of postmenopausal women. We correlated serum sclerostin to bone mineral density (BMD), fractures, and bone remodeling parameters, and related these findings to epigenetic and genetic disease mechanisms. Serum sclerostin and bone remodeling biomarkers were measured in two postmenopausal groups: healthy (BMD T‐score > –1) and established OP (BMD T‐score < –2.5, with at least one low‐energy fracture). Bone specimens were used to analyze SOST mRNAs, single nucleotide polymorphisms (SNPs), and DNA methylation changes. The SOST gene promoter region showed increased CpG methylation in OP patients (n = 4) compared to age and body mass index (BMI) balanced controls (n = 4) (80.5% versus 63.2%, p = 0.0001) with replication in independent cohorts (n = 27 and n = 36, respectively). Serum sclerostin and bone SOST mRNA expression correlated positively with age‐adjusted and BMI‐adjusted total hip BMD (r = 0.47 and r = 0.43, respectively; both p < 0.0005), and inversely to serum bone turnover markers. Five SNPs, one of which replicates in an independent population‐based genomewide association study (GWAS), showed association with serum sclerostin or SOST mRNA levels under an additive model (p = 0.0016 to 0.0079). Genetic and epigenetic changes in SOST influence its bone mRNA expression and serum sclerostin levels in postmenopausal women. The observations suggest that increased SOST promoter methylation seen in OP is a compensatory counteracting mechanism, which lowers serum sclerostin concentrations and reduces inhibition of Wnt signaling in an attempt to promote bone formation. © 2014 American Society for Bone and Mineral Research.     

Iron overload accelerates bone loss in healthy postmenopausal women and middle‐aged men: A 3‐year retrospective longitudinal study

Despite extensive experimental and animal evidence about the detrimental effects of iron and its overload on bone metabolism, there have been no clinical studies relating iron stores to bone loss, especially in nonpathologic conditions. In the present study, we performed a large longitudinal study to evaluate serum ferritin concentrations in relation to annualized changes in bone mineral density (BMD) in healthy Koreans. A total of 1729 subjects (940 postmenopausal women and 789 middle‐aged men) aged 40 years or older who had undergone comprehensive routine health examinations with an average 3 years of follow‐up were enrolled. BMD in proximal femur sites (ie, the total femur, femur neck, and trochanter) was measured with dual‐energy X‐ray absorptiometry using the same equipment at baseline and follow‐up. The mean age of women and men in this study was 55.8 ± 6.0 years and 55.5 ± 7.8 years, respectively, and serum ferritin levels were significantly higher in men than in women (p < 0.001). The overall mean annualized rates of bone loss in the total femur, femur neck, and trochanter were ?1.14%/year, ?1.17%/year, and ?1.51%/year, respectively, in women, and ?0.27%/year, ?0.34%/year, and ?0.41%/year, respectively, in men. After adjustment for potential confounders, the rates of bone loss in all proximal femur sites in both genders were significantly accelerated in a dose‐response fashion across increasing ferritin quartile categories (p for trend = 0.043 to <0.001). Consistently, compared with subjects in the lowest ferritin quartile category, those in the third and/or highest ferritin quartile category showed significantly faster bone loss in the total femur and femur neck in both genders (p = 0.023 to <0.001). In conclusion, these data provide the first clinical evidence that increased total body iron stores could be an independent risk factor for accelerated bone loss, even in healthy populations. © 2012 American Society for Bone and Mineral Research.