Lumbar Spine Areal Bone Mineral Density Research Articles

Bone accrual and structural changes over one year in youth with cystic fibrosis

BackgroundPediatric bone accrual governs peak bone mass and strength. Longitudinal studies of bone health in youth with cystic fibrosis (CF) may provide insight into CF-related bone disease (CFBD), a prevalent co-morbidity in adults with CF. MethodsThis one-year longitudinal study of youth with pancreatic insufficient CF, enrolled in a nutrition intervention study [n = 62 (36 M/26F)] 1) examined dual-energy x-ray absorptiometry (DXA)-defined lumbar spine (LS) and total body less head (TBLH) bone accrual and 2) compared their changes in peripheral quantitative computed tomography (pQCT) cortical and trabecular tibial bone density and geometry to those of a healthy reference group [n = 143 (68 M/75F)].Main outcome measures were 1) DXA: lumbar spine areal bone mineral density (LSaBMD) and total body less head bone mineral content (TBLH-BMC), sex- and pubertal status-specific, height velocity (HV)-adjusted or HV and lean body mass velocity (HV-LBMV)-adjusted annualized velocity-Z scores and 2) pQCT: age, sex, pubertal status and, when appropriate, tibial length adjusted Z-scores for bone architecture measures.DXA velocity-Z were compared to expected mean of 0 and correlations with clinical parameters (age, BMI-Z and FEV1%-predicted) tested. Within-subject comparisons of HV-adjusted and LBMV-HV-adjusted DXA velocity-Z were conducted in CF.pQCT Z-scores were compared between the two groups over one year using longitudinal models. Longitudinal relationships between measures of bone health and clinical parameters (age, BMI-Z and FEV1%-predicted) were examined in individuals with CF. ResultsDXA velocity-Z were higher than normal in females (p < 0.05) but not males with CF. HV-adjusted and LBMV-HV-adjusted velocity-Z did not differ for LSaBMD or TBLH-BMC.In males with CF, both HV-adjusted and LBMV-HV-adjusted LSaBMD velocity-Z scores correlated negatively with age (HV rho: −0.35; p = 0.045 and LBMV-HV rho: −0.47; p = 0.0046). In males with CF BMI-Z correlated positively with HV-adjusted LSaBMD velocity-Z (rho: 0.37; p = 0.034), but this relationship did not persist for LBMV-HV (rho: 0.14; p = 0.42). In females with CF, no correlations between LSaBMD velocity-Z scores and age or BMI-Z were found (all p > 0.05). No correlations between LSaBMD velocity-Z scores and FEV1%-predicted were seen in either sex (all p > 0.12). TBLH-BMC velocity Z-scores were not correlated with clinical parameters in either sex (all p > 0.1).At baseline, multiple pQCT parameters were lower in CF (p < 0.05). pQCT Z-scores did not differ between baseline and one-year in either CF or reference group. In a longitudinal model comparing pQCT-Z changes in CF and reference, multiple pQCT-Z outcomes remained lower in CF, but the changes in parameters did not differ in CF vs reference (all p > 0.26). Lower pQCT outcomes in CF were largely restricted to males (CF group*female sex interaction beta coefficients > 0). In this combined longitudinal model, of both CF and reference, BMI-Z was positively associated with pQCT-Z parameters(p < 0.001).Multiple pQCT-Z outcomes positively correlated with both BMI-Z and FEV1%-predicted in males with CF, and with FEV1%-predicted in females with CF (p < 0.05). Age was negatively associated with section modulus (p = 0.001) in males and with cortical density-Z in females (p < 0.001). ConclusionsWith improved longevity, bone health in CF is of increasing importance. On average, bone accrual was preserved in youth with CF, and while deficits in bone geometry and strength were found, these deficits did not worsen over the one-year study. Lower LS bone accrual with increasing age suggests emerging adulthood is a period of vulnerability in CF while the role of LBM in bone health is underscored by the lack of relationship between LBMV-adjusted accrual and BMI. These findings may be useful in targeting screening practices and interventions.

Case Report: Low Bone and Normal Lean Mass in Adolescents With Complete Androgen Insensitivity Syndrome

IntroductionOsteopenia and osteoporosis have been reported in adults with Complete Androgen Insensitivity Syndrome (CAIS). Little is known about changes in bone mineral density (BMD) in adolescents with CAIS and whether it is affected by early gonadectomy. Body composition data have not been reported.MethodsSingle-center, retrospective study of CAIS adolescents who underwent dual-energy x-ray absorptiometry (DXA) (Hologic, Horizon A). Body composition is presented as lean and fat mass indices (LMI, FMI). Z-scores for lumbar spine areal BMD (LBMD), total body less head (TBLH), bone mineral content (BMC), LMI, and FMI were calculated using female normative data. Results are expressed as median and min, max.ResultsSix females with genetically confirmed CAIS were identified—one with intact gonads and five with history of gonadectomy at 2–11 months. In the subject with intact gonads, LBMD-Z and TBLH BMC-Z were −1.56 and −1.26, respectively, at age 16 years. Among those with gonadectomy, LBMD-Z was −1.8 (−3.59 to 0.49) at age 15.6 years (12–16.8) and decreased in all three subjects who had longitudinal follow-up despite hormone replacement therapy (HRT). Adherence to HRT was intermittent. LMI-Z and FMI-Z were 0.1 (−1.39 to 0.7) and 1.0 (0.22 to 1.49), respectively.ConclusionsThese limited data indicate that adolescents with CAIS have bone mass deficit. Further studies are needed to understand the extent of BMD abnormalities and the effect of gonadectomy, especially early in childhood, and to establish the optimal HRT regimen for bone accrual. Data on lean mass are reassuring.

Bone densities and bone geometry in children and adolescents with arthrogryposis.

To describe bone densitometry results using lumbar spine dual-energy X-ray absorptiometry and forearm peripheral quantitative computed tomography (pQCT) in children with arthrogryposis multiplex congenita (AMC). Prospective study. Lumbar spine areal bone mineral density (BMD) was measured in 58 participants (mean age 6.8years, range 1month to 19.7years; 26 males). The diagnostic subgroup was Amyoplasia in 27 participants, distal arthrogryposis (unclassified, n=13; type 2A, n=1; type 2B, n=2; type 8, n=2) in 18 patients, an unclassified form of arthrogryposis in 6 patients, and a syndromic form of arthrogryposis in 7 patients. The mean lumbar spine areal BMD was -0.4 (SD: 1.5) which was significantly below 0 (p<0.05, one-sample t-test). The mean lumbar spine bone mineral apparent density z-score (+0.4 [SD: 1.4]), a measure that is largely independent of bone size, was not significantly different from 0 (P>0.05). A subset of 22 patients aged 6years or older (mean age 10.9years, 11 males) had forearm pQCT analysis. Mean z-scores for trabecular and cortical volumetric BMD at the radius were similar to healthy controls. Radius periosteal bone circumference and bone mineral content were appropriate for height. These densitometric results did not differ between patients with Amyoplasia or individuals with other diagnoses. Low areal BMD in children and adolescents with AMC reflects their smaller bone size rather than a specific bone mass deficit. These data do not suggest that children and adolescents with AMC in general require regular monitoring by bone densitometry unless there are specific clinical concerns.

Vertebral Fracture Risk in Diabetic Elderly Men: The MrOS Study.

Type 2 diabetes (T2DM) is associated with a significant increase in risk of nonvertebral fractures, but information on risk of vertebral fractures (VFs) in subjects with T2DM, particularly among men, is lacking. Furthermore, it is not known whether spine bone mineral density (BMD) can predict the risk of VF in T2DM. We sought to examine the effect of diabetes status on prevalent and incident vertebral fracture, and to estimate the effect of lumbar spine BMD (areal and volumetric) as a risk factor for prevalent and incident morphometric vertebral fracture in T2DM (n = 875) and nondiabetic men (n = 4679). We used data from the Osteoporotic Fractures in Men (MrOS) Study, which enrolled men aged ≥65 years. Lumbar spine areal BMD (aBMD) was measured with dual-energy X-ray absorptiometry (DXA), and volumetric BMD (vBMD) by quantitative computed tomography (QCT). Prevalence (7.0% versus 7.7%) and incidence (4.4% versus 4.5%) of VFs were not higher in T2DM versus nondiabetic men. The risk of prevalent (OR, 1.05; 95% CI, 0.78 to 1.40) or incident vertebral-fracture (OR, 1.28; 95% CI, 0.81 to 2.00) was not higher in T2DM versus nondiabetic men in models adjusted for age, clinic site, race, BMI, and aBMD. Higher spine aBMD was associated with lower risk of prevalent VF in T2DM (OR, 0.55; 95% CI, 0.48 to 0.63) and nondiabetic men (OR, 0.66; 95% CI, 0.5 to 0.88) (p for interaction = 0.24) and of incident VF in T2DM (OR, 0.50; 95% CI, 0.41 to 0.60) and nondiabetic men (OR, 0.54; 95% CI, 0.33 to 0.88) (p for interaction = 0.77). Results were similar for vBMD. In conclusion, T2DM was not associated with higher prevalent or incident VF in older men, even after adjustment for BMI and BMD. Higher spine aBMD and vBMD are associated with lower prevalence and incidence of VF in T2DM as well as nondiabetic men. © 2017 American Society for Bone and Mineral Research.

A protocol for a randomised controlled trial of the bone response to impact loading or resistance training in young women with lower than average bone mass: the OPTIMA-Ex trial

IntroductionThe aim of the Osteoporosis Prevention Through Impact and Muscle-loading Approaches to Exercise trial is to compare the bone response to two known osteogenic stimuli — impact loading exercise and...

The relationship between adiposity and bone density in U.S. children and adolescents.

ObjectiveIn adults, obesity has been associated with several health outcomes including increased bone density. Our objective was to evaluate the association between percent body fat and fat mass with bone mineral density (BMD) in a nationally representative population of children and adolescents.Study designA total of 8,348 participants 8–18 years of age from the National Health and Nutrition Examination Survey (NHANES) 1999–2006 had whole body DXA scans performed. We conducted linear regressions to examine the relationship between percent body fat and fat mass with outcome variables of total body, pelvic and lumbar spine areal BMD (aBMD), controlling for lean body mass and assessing for gender and race/ethnicity interactions.ResultsWe found evidence of gender and race/ethnicity interactions with percent body fat and total fat mass for the different BMD areas. Generally, there were decreases in total body aBMD (p<0.001) and lumbar spine aBMD (p<0.001) with increasing percent body fat and total fat mass, with less consistent patterns for pelvic aBMD.ConclusionOur findings of regional differences in the relationship of adiposity to aBMD in children and adolescents with significant interactions by gender and race/ethnicity emphasizes the need for further investigations to understand the impact of adiposity on bone health outcomes.

Long-term follow-up in osteogenesis imperfecta type VI.

Osteogenesis imperfecta (OI) type VI is an ultra-rare bone fragility disorder caused by recessive mutations in SERPINF1. Here, we describe long-term outcomes in OI type VI and compare the clinical phenotypes caused by different types of SERPINF1 mutations. This study includes a retrospective chart review of 13 individuals with OI type VI. In the absence of therapy, lumbar spine areal bone mineral density (BMD) did not increase during childhood and longitudinal growth seemed to stall after the age of 6 to 8years. The phenotype was similar between individuals with different types of SERPINF1 mutations. Intravenous bisphosphonate treatment was associated with an increase in lumbar spine areal BMD and some reshaping of compressed vertebral bodies. Patients who had started bisphosphonate treatment early (before the age of 6years) were taller than patients who had received bisphosphonate treatment later during their growing years. Lower extremity fractures were frequent despite bisphosphonate treatment and scoliosis was present in all patients who had reached the final height. Most patients had restricted mobility. In four patients, intravenous bisphosphonate treatment was eventually substituted by subcutaneous injections of denosumab, without clear changes in the clinical picture. Patients with OI type VI who received intravenous bisphosphonate treatment during growth had an increase in lumbar spine areal BMD, a higher final height z-score, and presented some reshaping of vertebral bodies. More effective treatment modalities are clearly required in OI type VI.

Effect of high-dose vitamin D supplementation on bone density in youth with osteogenesis imperfecta: A randomized controlled trial

Osteogenesis imperfecta (OI) is a heritable condition characterized by fragile bones. Our previous studies indicated that serum 25-hydroxyvitamin D (25OHD) concentrations were positively associated with lumbar spine areal bone mineral density (LS-aBMD) in children and adolescents with OI. Here we assessed whether one year of high-dose vitamin D supplementation results in higher LS-aBMD z-scores in youth with OI. A one-year double-blind randomized controlled trial conducted at a pediatric orthopedic hospital in Montreal, Canada. Sixty patients (age: 6.0 to 18.9years; 35 female) were randomized in equal numbers to receive either 400 or 2000international units (IU) of vitamin D, stratified according to baseline bisphosphonate treatment status and pubertal stage. At baseline, the average serum 25OHD concentration was 65.6nmol/L (SD 20.4) with no difference between treatment groups (p=0.77); 21% of patients had results <50nmol/L. Vitamin D supplementation was associated with higher serum 25OHD concentrations in 90% of participants. The increase in mean 25OHD was significantly higher (p=0.02) in the group receiving 2000IU of vitamin D (mean [95% CI]=30.5nmol/L [21.3; 39.6]) than in the group receiving 400IU (15.2nmol/L [6.4; 24.1]). No significant differences in LS-aBMD z-score changes were detected between treatment groups. Thus, supplementation with vitamin D at 2000IU increased serum 25OHD concentrations in children with OI more than supplementation with 400IU. However, in this study where about 80% of participants had baseline serum 25OHD concentrations ≥50nmol/L, this difference had no detectable effect on LS-aBMD z-scores.

Longitudinal examination of the skeletal effects of selective serotonin reuptake inhibitors and risperidone in boys.

In a previous cross-sectional study, we found lower bone mass during treatment with selective serotonin reuptake inhibitors (SSRIs) and risperidone in youths. Here, we evaluate the skeletal effects of these psychotropics at follow-up. Between April 2005 and July 2011, medically healthy 7- to 17-year-old males treated with risperidone for 6 months or more were enrolled through child psychiatry outpatient clinics and returned for follow-up 1.5 years later. Treatment history was extracted from the medical and pharmacy records. Anthropometric, laboratory, and bone mass measurements were obtained. Multivariable linear regression analyses compared participants who remained on risperidone at follow-up to those who had discontinued risperidone treatment as well as SSRI-treated versus SSRI-unexposed participants. The sample consisted of 94 boys with a mean age of 11.8 ± 2.7 years at study entry. The majority had an externalizing disorder and had received risperidone and SSRIs for 2.5 ± 1.7 years and 1.6 ± 1.9 years, respectively, at study entry. By follow-up, 26% (n = 24) had discontinued risperidone. Compared to discontinuing risperidone, continuing it was associated with a decline in participants' age-sex-height-race-specific areal bone mineral density (BMD) z score at the lumbar spine (P < .04) and failure to increase radius trabecular volumetric BMD (P < .03), after accounting for significant covariates. In addition, receiving an SSRI was associated with reduced lumbar spine areal BMD z score and radius trabecular volumetric BMD at both study entry (P < .02 and P < .03, respectively) and follow-up (P < .06 and P < .03, respectively), but without further decline between the 2 visits. Chronic SSRI treatment in children and adolescents is associated with reduced, albeit stable, bone mass for age, while chronic risperidone treatment is associated with failure to accrue bone mass.

Effect of High‐Dose Vitamin D Supplementation on Bone Density in Youth with Osteogenesis Imperfecta: A Randomized Controlled Trial

Background Osteogenesis imperfecta (OI) is a genetic disease characterized by fragile bones and short stature. Recently, a positive association was found between serum 25-hydroxyvitamin D (25OHD) concentrations and lumbar spine areal bone mineral density (LS-aBMD) z-scores in this population. Objectives: To assess whether high-dose vitamin D supplementation (2000 IU) will result in significantly higher LS-aBMD z-scores after one-year; and to evaluate the effect of vitamin D supplementation on lower limb muscle power. Results: At baseline, average serum 25OHD concentration was 65.6 nmol/L (SD 20.4) with no difference seen between treatment groups (p=0.77). Deficient serum 25OHD concentrations (<50 nmol/L) were measured in only 21% of patients at baseline. Supplementation resulted in higher serum 25OHD concentrations in almost all participants (90%) with significantly higher increases seen with 2000 IU (mean [95% C.I.] = 30.5 nmol/L [21.3; 39.6] vs 15.2 nmol/L [6.4; 24.1], p= 0.02). No significant changes were detected in BMD measurements or in lower limb muscle power between treatment groups from baseline to final visit. Conclusions Supplementation with either 400 or 2000 IU of vitamin D translates into significant increases in serum 25OHD concentrations in children with OI. However, increases in baseline serum 25OHD concentrations already within a healthy range (蠅50 nmol/L) do not translate into increases in BMD z-scores in children with OI. This research was supported by the Shriners Hospital for Children as well as by The Network for Oral and Bone Health Research.

Skeletal effects of bariatric surgery: examining bone loss, potential mechanisms and clinical relevance.

Bariatric surgery is the most effective therapeutic approach to morbid obesity, resulting in substantial weight loss and improved cardiometabolic profiles; however, a growing body of evidence suggests that bariatric procedures increase both skeletal fragility and the risk of related future fracture secondary to excessive bone loss. Prospective evidence shows that areal bone mineral density (BMD) assessed by dual energy X-ray absorptiometry (DXA) declines by as much as 14% in the proximal femoral regions, including the femoral neck and total hip, 12 months postoperatively. Lumbar spine areal BMD outcomes show greater 12-month postoperative variability across surgical procedures (-8 to +6%) and contrast with no change in volumetric BMD outcomes measured by quantitative computed tomography. Diminished mechanical loading, micronutrient deficiency and malabsorption, along with neurohormonal alterations, offer plausible underlying mechanisms to explain these observed post-bariatric bone changes, but most remain largely unsubstantiated in this population. Importantly, DXA-based skeletal imaging may have limited utility in accurately detecting bone change in people undergoing bariatric surgery; partly because excessive tissue overlying bone increases the variability of areal BMD outcomes. Moreover, a paucity of fracture and osteoporosis incidence data raises questions about whether marked post-bariatric surgery bone loss is clinically relevant or a functional adaptation to skeletal unloading. Future studies that use technology which is able to accurately capture the site-specific volumetric BMD and bone architectural changes that underpin bone strength in people undergoing bariatric surgery, that consider mechanical load, and that better quantify long-term fracture and osteoporosis incidence are necessary to understand the actual skeletal effects of bariatric surgery.

Bone mineral density changes following discontinuation of ronacaleret treatment: Off-treatment extension of a randomized, dose-finding phase II trial

ContextParathyroidectomy in patients with hyperparathyroidism can produce subsequent increases in bone mineral density (BMD). Ronacaleret, a selective calcium-sensing receptor antagonist that stimulates endogenous parathyroid hormone release, induced mild hyperparathyroidism. ObjectiveThe aim of this study is to evaluate whether BMD changes after cessation of ronacaleret treatment. DesignObservational, off-treatment, extension of a randomized, placebo-controlled, dose-ranging phase II trial. SettingFifteen academic centers in seven countries. PatientsPostmenopausal women with low BMD; 171 out of 569 women in the parent study were enrolled in the extension study. InterventionsSubjects were treated with ronacaleret 100mg (n=16), 200mg (n=38), 300mg (n=35), or 400mg (n=32) once daily, alendronate 70mg (n=17) once weekly, or matching placebo (n=33) for 10–12months; BMD was measured after discontinuation of ronacaleret or alendronate treatment. Main outcome measureMean percent change in lumbar spine areal BMD by dual-energy X-ray absorptiometry at 6–12months after discontinuing ronacaleret or alendronate compared with the 10- to 12-month BMD measurement of the parent study. ResultsAt the lumbar spine, all doses of ronacaleret resulted in gains in BMD while on treatment. These increases in BMD were maintained or increased after discontinuation of ronacaleret. All doses of ronacaleret caused bone loss at the total hip while on active treatment. However, there was an attenuation of this loss in the off-treatment extension study. ConclusionThe gain in BMD at the lumbar spine was maintained post-treatment and the loss of BMD at the total hip was attenuated. We hypothesize that there may have been some bone remineralization after cessation of ronacaleret.

SIBLING family genes and bone mineral density: Association and allele-specific expression in humans

Osteoporosis is a common complex disorder with reduced bone mineral density (BMD) and increased susceptibility to fracture. Peak BMD is one of the primary determinants of osteoporotic fracture risk, and is under substantial genetic control. Extracellular matrix, a major component of the bone, influences BMD by regulating mineral deposition and maintaining cellular activity. It contains several SIBLING family proteins, null mutations of which cause mineralization defects in humans. In this study, we tested 59 single-nucleotide polymorphisms (SNPs) located in the 5 SIBLING family genes (DSPP, DMP1, IBSP, MEPE and SPP1) for association with normal variation in peak BMD in healthy men and women. We measured femoral neck (FN) and lumbar spine (LS) areal BMD by dual energy x-ray absorptiometry (DXA) in 1692 premenopausal European-American women, 512 premenopausal African-American women and 715 European-American men. SNPs were tested for association with FN and LS-BMD in the 3 subsamples. In the European-American women, we observed association (p≤0.005) with LS-BMD for SNPs in DSPP, IBSP and MEPE, and for FN-BMD with SNPs in DMP1 and IBSP. Allele-specific regulation of gene expression (ASE) is an important mechanism in which an allele giving rise to modest influence in transcript abundance might result in a predisposition to disease. To identify whether there was ASE of SIBLING family genes at these SNPs, we examined 52 human bone samples obtained from the femoral neck during surgical hip replacement (27 female, 25 male; 44 European-American and 8 African-American). We observed unidirectional ASE for the IBSP gene, with lower expression of the G allele compared to the A allele for SNP rs17013181. Our data suggest that SNPs within the SIBLING genes may contribute to normal variation of peak BMD. Further studies are necessary to identify the functional variants and to determine the mechanisms underlying the differences in ASE and how these differences relate to the pathophysiology of osteoporosis.

Osteoporosis Caused by Mutations in PLS3: Clinical and Bone Tissue Characteristics

Mutations in PLS3 have been identified as a cause of bone fragility in children, but the bone phenotype associated with PLS3 mutations has not been reported in detail. PLS3 is located on the X chromosome and encodes the actin-binding protein plastin 3. Here we describe skeletal findings in 4 boys from 2 families with mutations in PLS3 (c.994_995delGA; p.Asp332* in family 1; c.1433T > C; p.Leu478Pro in family 2). When first evaluated between 4 and 8 years of age, these boys had a history of one to four long-bone fractures. Mild vertebral compression fractures were identified in each boy. No obvious extraskeletal disease manifestations were present. Lumbar spine areal bone mineral density (LS-aBMD) Z-scores ranged from -1.7 to -3.5, but height was normal. Iliac bone histomorphometry in 2 patients showed low trabecular bone volume and a low osteoid maturation time but normal bone formation rate and osteoclast surface. Quantitative backscattered electron imaging (qBEI) did not reveal a major abnormality in bone mineralization density distribution. The 2 boys from family 1 received oral alendronate for 6 years, which normalized LS-aBMD. The mothers of the 4 boys did not have a history of fractures and had normal LS-aBMD. However, one of these mothers had low bone mass at the distal radius, as measured by peripheral quantitative computed tomography (pQCT). In conclusion, hemizygous mutations in PLS3 are associated with osteoporosis and bone fragility in childhood, but in contrast to bone fragility caused by mutations in collagen type I encoding genes, there is no hypermineralization of mineralized bone matrix.

Circulating Sclerostin in Children and Young Adults with Heritable Bone Disorders

Sclerostin is an inhibitor of bone formation and is an important determinant of bone mass. The role of sclerostin in heritable metabolic bone disorders has not been studied in detail. We evaluated serum sclerostin levels in patients with X-linked hypophosphatemic rickets (XLH) and osteogenesis imperfecta (OI) and analyzed the relationship of circulating sclerostin concentrations with lumbar spine areal bone mineral density (LS-aBMD). The study was conducted in the metabolic bone clinic of a pediatric orthopedic hospital. Participants were 128 individuals, including 30 patients with XLH, 76 patients with OI types I, III, and IV, and 22 healthy subjects. Sclerostin was quantified in serum samples. Patients with XLH had higher circulating sclerostin concentrations (mean [SD]: 30.2 [16.7] pmol/L) than healthy control subjects (21.4 [9.2] ng/mL) (P = .02), as well as relatively high LS-aBMD Z-scores (+1.1 [1.7]). In the XLH cohort, serum sclerostin levels were positively associated with the LS-aBMD Z-score (r = 0.56; P < .002) and with alkaline phosphatase (r = 0.45; P = .01). In patients with OI, sclerostin serum levels were similar to those of healthy control subjects despite low LS-aBMD. The elevated sclerostin serum levels in XLH and the normal concentrations in OI suggest that the bone mass abnormalities in these disorders are not caused by primary sclerostin dysregulation.

Risedronate in children with osteogenesis imperfecta: a randomised, double-blind, placebo-controlled trial

Children with osteogenesis imperfecta are often treated with intravenous bisphosphonates. We aimed to assess the safety and efficacy of risedronate, an orally administered third-generation bisphosphonate, in children with the disease. In this multicentre, randomised, parallel, double-blind, placebo-controlled trial, children aged 4-15 years with osteogenesis imperfecta and increased fracture risk were randomly assigned by telephone randomisation system in a 2:1 ratio to receive either daily risedronate (2·5 or 5 mg) or placebo for 1 year. Study treatment was masked from patients, investigators, and study centre personnel. Thereafter, all children received risedronate for 2 additional years in an open-label extension. The primary efficacy endpoint was percentage change in lumbar spine areal bone mineral density (BMD) at 1 year. The primary efficacy analysis was done by ANCOVA, with treatment, age group, and pooled centre as fixed effects, and baseline as covariate. Analyses were based on the intention-to-treat population, which included all patients who were randomly assigned and took at least one dose of assigned study treatment. The trial is registered with ClinicalTrials.gov, number NCT00106028. Of 147 patients, 97 were randomly assigned to the risedronate group and 50 to the placebo group. Three patients from the risedronate group and one from the placebo group did not receive study treatment, leaving 94 and 49 in the intention-to-treat population, respectively. The mean increase in lumbar spine areal BMD after 1 year was 16·3% in the risedronate group and 7·6% in the placebo group (difference 8·7%, 95% CI 5·7-11·7; p<0·0001). After 1 year, clinical fractures had occurred in 29 (31%) of 94 patients in the risedronate group and 24 (49%) of 49 patients in the placebo group (p=0·0446). During years 2 and 3 (open-label phase), clinical fractures were reported in 46 (53%) of 87 patients in the group that had received risedronate since the start of the study, and 32 (65%) of 49 patients in the group that had been given placebo during the first year. Adverse event profiles were otherwise similar between the two groups, including frequencies of reported upper-gastrointestinal and selected musculoskeletal adverse events. Oral risedronate increased areal BMD and reduced the risk of first and recurrent clinical fractures in children with osteogenesis imperfecta, and the drug was generally well tolerated. Risedronate should be regarded as a treatment option for children with osteogenesis imperfecta. Alliance for Better Bone Health (Warner Chilcott and Sanofi).

Bone Density, Turnover, and Estimated Strength in Postmenopausal Women Treated With Odanacatib: A Randomized Trial

Odanacatib, a cathepsin K inhibitor, increases spine and hip areal bone mineral density (BMD) in postmenopausal women with low BMD and cortical thickness in ovariectomized monkeys. The objective of the study was to examine the impact of odanacatib on the trabecular and cortical bone compartments and estimated strength at the hip and spine. This was a randomized, double-blind, 2-year trial. The study was conducted at a private or institutional practice. PARTICIPANTS included 214 postmenopausal women with low areal BMD. The intervention included odanacatib 50 mg or placebo weekly. Changes in areal BMD by dual-energy x-ray absorptiometry (primary end point, 1 year areal BMD change at lumbar spine), bone turnover markers, volumetric BMD by quantitative computed tomography (QCT), and bone strength estimated by finite element analysis were measured. Year 1 lumbar spine areal BMD percent change from baseline was 3.5% greater with odanacatib than placebo (P < .001). Bone-resorption marker C-telopeptide of type 1 collagen was significantly lower with odanacatib vs placebo at 6 months and 2 years (P < .001). Bone-formation marker procollagen I N-terminal peptide initially decreased with odanacatib but by 2 years did not differ from placebo. After 6 months, odanacatib-treated women had greater increases in trabecular volumetric BMD and estimated compressive strength at the spine and integral and trabecular volumetric BMD and estimated strength at the hip (P < .001). At the cortical envelope of the femoral neck, bone mineral content, thickness, volume, and cross-sectional area also increased from baseline with odanacatib vs placebo (P < .001 at 24 months). Adverse experiences were similar between groups. Over 2 years, odanacatib decreased bone resorption, maintained bone formation, increased areal and volumetric BMD, and increased estimated bone strength at both the hip and spine.

Predictors and Correlates of Vitamin D Status in Children and Adolescents with Osteogenesis Imperfecta

The prevalence of vitamin D deficiency and its consequences on bone in pediatric bone fragility disorders is not well characterized. In the present study, we evaluated determinants of vitamin D status in children and adolescents with osteogenesis imperfecta (OI) and assessed the relationship between 25-hydroxyvitamin D (25OH D) serum concentrations and lumbar spine areal bone mineral density (LS-aBMD). This retrospective cross-sectional study comprised 315 patients with a diagnosis of OI type I, III, or IV (aged 1.1-17.9 yr; 161 girls) who had not received bisphosphonate treatment at the time of 25OH D analysis. In 282 patients (90%), LS-aBMD measurements were available at the same time. Serum concentrations of 25OH D ranged from 14 to 133 nmol/liter and were less than 50 nmol/liter in 86 patients (27%). Regression analysis revealed that age (P < 0.001), season (P < 0.001), and OI severity (P = 0.048), but not gender, were significant independent predictive factors of 25OH D levels. Serum 25OH D concentrations were negatively correlated with serum PTH levels (P = 0.003) and urinary cross-linked N-telopeptides of type I collagen to creatinine ratios (P = 0.005). Serum 25OH D levels were positively associated (P = 0.02) with LS-aBMD z-scores after accounting for OI severity, age, and gender. Serum 25OH D levels are positively associated with LS-aBMD z-scores in children and adolescents with OI types I, III, and IV.

Skeletal findings in children recently initiating glucocorticoids for the treatment of nephrotic syndrome

Eighty children with nephrotic syndrome underwent lumbar spine densitometry and vertebral morphometry soon after glucocorticoid initiation. We found an inverse relationship between glucocorticoid exposure and spine areal bone mineral density (BMD) Z-score and a low rate of vertebral deformities (8%). Vertebral fractures are an under-recognized complication of childhood glucocorticoid-treated illnesses. Our goal was to study the relationships among glucocorticoid exposure, lumbar spine areal BMD (LS BMD), and vertebral shape in glucocorticoid-treated children with new-onset nephrotic syndrome. Lateral thoracolumbar spine radiography and LS BMD were performed in 80 children with nephrotic syndrome (median age 4.4 years; 46 boys) within the first 37 days of glucocorticoid therapy. Genant semiquantitative grading was used as the primary method for vertebral morphometry; the algorithm-based qualitative (ABQ) method was used for secondary vertebral deformity analysis. Six of the 78 children with usable radiographs (8%; 95% confidence interval 4 to 16%) manifested a single Genant grade 1 deformity each. All deformities were mild anterior wedging (two at each of T6, T7, and T8). Four of the 78 children (5%; 95% confidence interval 2 to 13%) showed one ABQ sign of fracture each (loss of endplate parallelism; two children at T6 and two at T8). Two of the children with ABQ signs also had a Genant grade 1 deformity in the same vertebral body. None of the children with a Genant or ABQ deformity reported back pain. An inverse relationship was identified between LS BMD Z-score and glucocorticoid exposure. Although we identified an inverse relationship between steroid exposure and LS BMD soon after glucocorticoid initiation for childhood nephrotic syndrome, there was only a low rate of vertebral deformities. The clinical significance of these findings requires further study.

Osteosclerosis in two brothers with autosomal dominant pseudohypoparathyroidism type 1b: bone histomorphometric analysis

Pseudohypoparathyroidism (PHP) is a heterogeneous disorder characterized by hypocalcemia and hyperphosphatemia resulting from selective renal resistance to parathyroid hormone (PTH). One autosomal dominant form of PHP type 1b (PHP-Ib) is most frequently caused by a maternally inherited 3-kb deletion within STX16, the gene encoding syntaxin 16. To date, increased bone mineral density (BMD) has been described only in PHP type 1a, and there is a lack of detailed information on bone histomorphometry in PHP-Ib. The objective of this report was to present trans-iliac static and dynamic histomorphometry in two brothers with the 3-kb deletion in the STX16 region and elevated BMD. Observational study of two brothers (age 18.0 and 22.7 years) with the 3-kb STX16 deletion and increased BMD. The brothers had elevated PTH (146 pg/ml (15.6 pmol/l) and 102 pg/ml (10.9 pmol/l); normal: 10-64 pg/ml (1.1-6.8 pmol/l)) and striking osteosclerosis (lumbar spine areal BMD Z-scores: +5.4 and +4.9). Bone histomorphometry showed marked elevations in cortical width for both brothers (241 and 209% of the mean result expected for age), with elevations in the bone formation rate on the endocortical (119 and 260% of the healthy mean) and trabecular (220 and 190% of mean) surfaces. Our findings suggest that PTH in this PHP-Ib genotype can increase cortical thickness due to its anabolic effect on endocortical bone, and underscore the heterogeneity in the skeletal phenotype among patients with PHP-Ib.