This study evaluated racial differences in bone size and volumetric density at the spine and hip in pre-and postmenopausal Chinese American and White women. Compared with White women, Chinese American women have greater cortical volumetric bone density (vBMD) at the hip, congruent with the results at the peripheral skeleton.
Chinese American women have lower rates of fracture than White women despite lower areal bone density. At the forearm and tibia, however, Chinese American women have higher cortical vBMD as well as greater trabecular and cortical thickness, but smaller bone area as measured by high-resolution peripheral quantitative computed tomography (HR-pQCT) compared with White women. Since HR-pQCT data are obtained at peripheral sites, it is unclear whether these differences are relevant to the clinically important lumbar spine and hip. This study assesses racial differences in bone size and vBMD at the spine and hip in Chinese American and White women.
QCT of the spine and hip was measured to assess racial differences in bone size, structure, and vBMD in pre-(n=83) and postmenopausal (n=50) Chinese American and White women. Data were adjusted for weight, height, physical activity, total calcium intake, parathyroid hormone, and 25-hydroxyvitamin D levels.
Among premenopausal women, lumbar spine trabecular vBMD was 5.8% greater in Chinese American versus White women (p=0.01). At the hip, cortical vBMD was 3% greater at the femoral neck (p=0.05) and 3.6% greater at the total hip (p=0.01) in premenopausal Chinese American compared with White women. Among postmenopausal women, there was no difference in lumbar spine trabecular vBMD. Cortical vBMD was 4% greater at the total hip (p= 0.02) and tended to be greater at the femoral neck (p=0.058) in Chinese American versus White women.
Consistent with earlier findings in the peripheral skeleton, cortical vBMD is greater at the hip in Chinese American versus White women.
Central QCT; Chinese American; Race; Volumetric bone density; White
In a prospective cohort study of 5,995 older American men (MrOS), users of angiotensin-converting enzyme (ACE) inhibitors had a small but significant increase in bone loss at the hip over 4 years after adjustment for confounders. Use of angiotensin II AT1 receptor blockers (ARB) was not significantly associated with bone loss.
Experimental evidence suggests that angiotensin II promotes bone loss by its effects on osteoblasts. It is therefore plausible that ACE inhibitor and ARB may reduce rates of bone loss. The objective of this study is to examine the independent effects of ACE inhibitor and ARB on bone loss in older men.
Out of 5,995 American men (87.2%) aged ≥65 years, 5,229 were followed up for an average of 4.6 years in a prospective six-center cohort study—The Osteoporotic Fractures in Men Study (MrOS). Bone mineral densities (BMD) at total hip, femoral neck, and trochanter were measured by Hologic densitometer (QDR 4500) at baseline and year 4.
Out of 3,494 eligible subjects with complete data, 1,166 and 433 subjects reported use of ACE inhibitors and ARBs, respectively. When compared with nonusers, continuous use of ACE inhibitors was associated with a small (0.004 g/cm2) but significant increase in the average rate of BMD loss at total hip and trochanter over 4 years after adjustment for confounders. Use of ARB was not significantly associated with bone loss.
Use of ACE inhibitors but not ARB may marginally increase bone loss in older men.
Angiotensin-converting enzyme inhibitor; Angiotensin receptor blocker; Bone density
Osteocalcin (OC) is a protein constituent of bone matrix and a marker of bone formation. We characterized the heritability of serum OC measures and identified genomic regions potentially involved in the regulation of OC via high-density genome-wide linkage analysis in African ancestry individuals.
African ancestry individuals (n=459) were recruited, without regard to health status, from seven probands (mean family size = 66; 4,373 relative pairs). Residual heritability of serum OC measures was estimated and multipoint quantitative trait linkage analysis was performed using pedigree-based maximum likelihood methods.
Residual heritabilities of total OC, uncarboxylated OC, carboxylated OC and percent uncarboxylated OC were: 0.74±0.10, 0.89±0.08, 0.46±0.10 and 0.41±0.09, respectively. All OC measures were genetically correlated with whole body bone mineral content (BMC). We obtained strong evidence of bivariate linkage for percent uncarboxylated OC and whole body BMC on chromosome 17 (LOD=3.15, 99cM).
All forms of OC were highly heritable and genetically correlated with total body BMC in these African ancestry families. The identified linkage region contains several candidate genes for bone and energy metabolism including COL1A1 and TNFRSF11A. Further studies of this genomic region may reveal novel insight into the genetic regulation of OC and bone mineralization.
osteocalcin; genome-wide linkage; African ancestry; bone mineral
Estimates of osteoporosis (OP) prevalence based on bone mineral density testing and fracture occurrence may be imprecise for small demographic groups. Medicare data are a useful supplemental source of information on OP.
We studied people ages ≥65 years covered by Medicare 2005. Cases of presumed OP were beneficiaries with physician services or inpatient claims for OP or for an associated fracture (hip, distal forearm, spine) in 1999–2005.
Among 911,327 beneficiaries with 6 or 7 years of Medicare coverage, the overall prevalence of OP and associated fractures was 29.7%. Prevalence was four times higher for women than men, increased with age, and was two times higher for whites, Hispanic Americans, and Asian Americans than African Americans. Among people with OP-associated fracture claims, the proportion with an OP diagnosis was 49.7% overall (women, 57.1%; men, 21.9%) and was lower for men than women and for African Americans than other ethnic groups.
The low proportion of beneficiaries who had an OP-associated fracture and also had an OP diagnosis, particularly among men and African American women, suggests suboptimal recognition and management of OP. Study limitations included lack of validation of our definition of OP and potential misclassification of race/ethnicity.
Epidemiology; Fracture; Osteoporosis; Prevalence
osteoporosis; evidence implementation; group randomized trial; bone mineral density testing
This study investigates the associations of a history of fracture, comorbid chronic conditions, and demographic characteristics with incident fractures among Medicare beneficiaries. The majority of fracture incidence studies have focused on the hip and on white females. This study examines a greater variety of fracture sites and more population subgroups than prior studies.
We used Medicare claims data to examine the incidence of fracture at six anatomic sites in a random 5% sample of Medicare beneficiaries during the time period 2000 through 2005.
For each type of incident fracture, women had a higher rate than men, and there was a positive association with age and an inverse association with income. Whites had a higher rate than nonwhites. Rates were lowest among African Americans for all sites except ankle and tibia/fibula, which were lowest among Asian Americans. Rates of hip and spine fracture were highest in the South, and fractures of other sites were highest in the Northeast. Fall-related conditions and depressive illnesses were associated with each type of incident fracture, conditions treated with glucocorticoids with hip and spine fractures and diabetes with ankle and humerus fractures. Histories of hip and spine fractures were associated positively with each site of incident fracture except ankle; histories of nonhip, nonspine fractures were associated with most types of incident fracture.
This study confirmed previously established associations for hip and spine fractures and identified several new associations of interest for nonhip, nonspine fractures.
epidemiology; fractures; osteoporosis; incidence; Medicare
National cost estimates of osteoporosis and fractures in the U.S. have been based on diverse sets of provider data or selected commercial insurance claims. We sought to characterize prevalence and costs for osteoporosis using a random population-based sample of older adults.
A cross-sectional estimate of medical cost was made with 2002 data from the Medicare Current Beneficiary Survey (MCBS). MCBS combines health interviews with claims information from all payers to profile a random sample of 12,700 Medicare recipients. Three cohorts aged 65 or over were defined: 1) patients experiencing a fracture-related claim in 2002; 2) patients with a diagnosis, medication, or self-report for osteoporosis or past hip fracture; and 3) non-case controls. The total cost of patient claims was compared to that of controls using multivariate regression.
Of 30.2 million elderly Medicare recipients in 2002, 1.6 million (5%) were treated for a fracture that year and an additional 7.2 million (24%) have osteoporosis without a fracture. The estimated mean impact of fractures on annual medical cost was $8600 (95%CI: $6400 to $10,800), implying a U.S. cost of $14 billion ($10 to $17 billion). Half of the non-fracture osteoporosis patients received drug treatment, averaging $500 per treated patient, or $2 billion nationwide.
The annual cost of osteoporosis and fractures in the U.S. elderly was estimated at $16 billion, using a national 2002 population-based sample. This amount corroborates previous estimates based on substantially different methodologies. Projected to 2008, the national cost of osteoporosis and fractures was $22 billion.
Vitamin D levels ≥30 ng/ml are commonly considered “normal” based upon maximal suppression of intact parathyroid hormone (iPTH); however, this has recently been challenged and the optimal 25(OH)D level among non-Caucasians is unclear. We evaluated the cross-sectional relationship between serum 25(OH)D and iPTH in a sample of Caucasian and African American adults.
We used baseline serum samples of participants from the Multicenter Osteoarthritis Study (MOST) for this analysis, and used three methods to model the relationship between 25(OH)D and iPTH: ordinary least squares regression (OLS), segmented regression, and Helmert contrasts.
Among Caucasians (n=1,258), 25(OH)D and iPTH ranged from 4-51 ng/ml and 2-120 pg/ml and from 3-32 ng/ml and 3-119 pg/ml in African Americans (n=423). We observed different thresholds between African Americans and Caucasians using each analytic technique. Using 25(OH)D as a categorical variable in OLS, iPTH was statistically higher at lower 25(OH)D categories than the 24-32 ng/ml referent group among Caucasians. However, in African Americans, the mean iPTH was only significantly higher at 25(OH)D levels below 15 ng/ml. Using segmented regression, iPTH appeared to stabilize at a lower 25(OH)D level in African Americans (19-23 ng/ml) compared to in Caucasians (>32 ng/ml). Helmert contrasts also revealed a lower threshold in African Americans than Caucasians.
Among MOST participants, the 25(OH)D thresholds at which no further change in iPTH was observed was approximately 20 ng/ml in African Americans versus approximately 30 ng/ml in Caucasians, suggesting optimal vitamin D levels in Caucasians may not be applicable to African Americans.
vitamin D; parathyroid hormone; racial differences; African American; thresholds; osteoporosis
People with spinal cord injury (SCI) lose bone and muscle integrity after their injury. Early doses of stress, applied through electrically induced muscle contractions, preserved bone density at high-risk sites. Appropriately prescribed stress early after the injury may be an important consideration to prevent bone loss after SCI.
Skeletal muscle force can deliver high compressive loads to bones of people with spinal cord injury (SCI). The effective osteogenic dose of load for the distal femur, a chief site of fracture, is unknown. The purpose of this study is to compare three doses of bone compressive loads at the distal femur in individuals with complete SCI who receive a novel stand training intervention.
Seven participants performed unilateral quadriceps stimulation in supported stance [150% body weight (BW) compressive load—“High Dose” while opposite leg received 40% BW—“Low Dose”]. Five participants stood passively without applying quadriceps electrical stimulation to either leg (40% BW load—“Low Dose”). Fifteen participants performed no standing (0% BW load—“Untrained”) and 14 individuals without SCI provided normative data. Participants underwent bone mineral density (BMD) assessment between one and six times over a 3-year training protocol.
BMD for the High Dose group significantly exceeded BMD for both the Low Dose and the Untrained groups (p<0.05). No significant difference existed between the Low Dose and Untrained groups (p>0.05), indicating that BMD for participants performing passive stance did not differ from individuals who performed no standing. High-resolution CT imaging of one High Dose participant revealed 86% higher BMD and 67% higher trabecular width in the High Dose limb.
Over 3 years of training, 150% BW compressive load in upright stance significantly attenuated BMD decline when compared to passive standing or to no standing. High-resolution CT indicated that trabecular architecture was preserved by the 150% BW dose of load.
Bone density; Electrical stimulation; Muscle physiology; Quadriceps femoris; Spinal cord injury; Weight-bearing strengthening program
The relationship between bone marrow adipose tissue and bone mineral density is different between African Americans and Caucasians as well as between men and women. This suggests that the mechanisms that regulate the differentiation and proliferation of bone marrow stromal cells may differ in these populations.
It has long been established that there are ethnic and sex differences in bone mineral density (BMD) and fracture risk. Recent studies suggest that bone marrow adipose tissue (BMAT) may play a role in the pathogenesis of osteoporosis. It is unknown whether ethnic and sex differences exist in the relationship between BMAT and BMD.
Pelvic BMAT was evaluated in 455 healthy African American and Caucasian men and women (age 18–88 years) using whole-body T1-weighted magnetic resonance imaging. BMD was measured using whole-body dual-energy X-ray absorptiometry.
A negative correlation was observed between pelvic BMAT and total body BMD or pelvic BMD (r=−0.533, −0.576, respectively; P<0.001). In multiple regression analyses with BMD as the dependent variable, ethnicity significantly entered the regression models as either an individual term or an interaction with BMAT. Menopausal status significantly entered the regression model with total body BMD as the dependent variable. African Americans had higher total body BMD than Caucasians for the same amount of BMAT, and the ethnic difference for pelvic BMD was greater in those participants with a higher BMAT. Men and premeno-pausal women had higher total body BMD levels than postmenopausal women for the same amount of BMAT.
An inverse relationship exists between BMAT and BMD in African American and Caucasian men and women. The observed ethnic and sex differences between BMAT and BMD in the present study suggest the possibility that the mechanisms regulating the differentiation and proliferation of bone marrow stromal cells may differ in these populations.
Body composition; Bone marrow; Bone mineral density; Dual-energy X-ray absorptiometry; Ethnicity; Magnetic resonance imaging; Sex
Many determinants of parathyroid hormone (PTH) are unknown. In the National Health and Nutrition Examination Survey (NHANES), numerous factors not classically associated with calcium–phosphorus homeostasis, such as uric acid and smoking, are independently associated with PTH in adults without chronic kidney disease. Associations between serum phosphorus and PTH may vary by race.
Although PTH may be an important biomarker for osteoporosis and cardiovascular disease, many determinants of PTH are unknown. We investigated associations between demographic, dietary, and serum factors and PTH level.
We studied 4,026 white, 1,792 black, and 1,834 Mexican-American adult participants without chronic kidney disease from the 2003–2004 and 2005–2006 NHANES.
The mean serum PTH level was 38.3 pg/ml for whites, 42.6 pg/ml for blacks, and 41.3 pg/ml for Mexican-Americans. After adjusting for diet, body mass index, serum levels of calcium, phosphorus, 25-hydroxyvitamin D, creatinine, and other factors, smokers compared to non-smokers had lower PTH, ranging from −4.2 pg/ml (95% confidence interval (CI) −7.3 to −1.1) in Mexican-Americans to −6.1 pg/ml (95% CI −8.7 to −3.5) in blacks. After multivariate adjustment, PTH was higher in females compared to males, ranging from 1.1 pg/ml (95% CI −1.2 to 3.4) in Mexican-Americans to 4.5 pg/ml (95% CI 1.9 to 7.0) in blacks, and in older (>60 years) compared to younger participants (<30 years), ranging from 3.7 pg/ml (95% CI 1.3 to 6.1) in Mexican-Americans to 8.0 pg/ml (95% CI 5.4 to 10.7) in blacks. Higher uric acid was associated with higher PTH. In whites only, lower serum phosphorus and lower serum retinol were associated with higher PTH.
Numerous factors not classically associated with calcium–phosphorus homeostasis are independently associated with PTH and should be considered in future studies of PTH and chronic disease. Additional research is needed to elucidate mechanisms underlying identified associations with PTH and to explore possible racial differences in phosphorus handling.
CDC; Centers for Disease Control and Prevention; National Health and Nutrition Examination Survey; NHANES; Parathyroid hormone
To study the effects of age and dose of selective serotonin reuptake inhibitors (SSRI), trycyclic antidepressants (TCA) and anxiolytics/sedatives on fracture risk.
Subjects and methods
Case control study. From the Danish National Health Service, we identified 124,655 fracture cases and 373,962 age- and gender-matched controls. Crude odds ratios (OR) were estimated, and propensity score adjustment was used to minimize confounding by indication.
A higher risk of fractures was associated with an increasing dose of anxiolytics and sedatives; the highest excess risk was present in the age stratum below 40 years of age (p<0.01), and thereafter the excess risk of fractures declined with age. For SSRI, a growing excess risk of fractures was seen with both increasing dose and age. Regarding TCA, no particular trend with age was present. However, an increasing risk of fractures was associated with increasing TCA dose in the age group above 60 years. Finally, for other antidepressants no particular trend with age or dose was observed. In our data, a hospital diagnosis of depression or manic-depression was associated with fewer fractures.
Caution should be shown upon prescription of SSRI to older subjects. A hospital diagnosis of depression or manic-depression and thus potentially more severe disease was not a risk factor for fractures.
Selective serotonin reuptake inhibitors; tricyclic antidepressants; antidepressant; fracture
Osteogenesis imperfecta (OI), Ehlers-Danlos syndrome (EDS), and osteopetrosis (OPT)are collectively common inherited skeletal diseases. Evaluation of subjects with these conditions often includes molecular testing which has important counseling, therapeutic and sometimes legal implications. Since several different genes have been implicated in these conditions, Sanger sequencing of each gene can be a prohibitively expensive and time consuming way to reach a molecular diagnosis.
In order to circumvent these problems, we have designed and tested a NGS platform that would allow simultaneous sequencing on a single diagnostic platform of different genes implicated in OI, OPT, EDS, and other inherited conditions leading to low or high bone mineral density. We used a liquid-phase probe library that captures 602 exons (~100 kb) of 34 selected genes and have applied it to test clinical samples from patients with bone disorders.
NGS of the captured exons by Illumina HiSeq2000 resulted in an average coverage of over 900X. The platform was successfully validated by identifying mutations in 6 patients with known mutations. Moreover, in 4 patients with OI or OPT without a prior molecular diagnosis, the assay was able to detect the causative mutations.
In conclusion, our NGS panel provides a fast and accurate method to arrive at a molecular diagnosis in most patients with inherited high or low bone mineral density disorders.
Few studies exist for bone densitometry of the whole foot. A phantom study demonstrated the sources of error and necessary controls for accurate quantitative computed tomography of the foot. A loss in bone mineral density in the small foot bones may be an early indicator of diabetic foot complications.
Volumetric quantitative computed tomography (vQCT) facilitates assessment of pedal bone osteopenia, which in the presence of peripheral neuropathy may well be an early sign of diabetic foot deformity. To date, sources and magnitudes of error in foot vQCT measurements have not been reported.
Foot phantoms were scanned using a 64-slice CT scanner. Energy (kVp), table height, phantom size and orientation, location of “bone” inserts, insert material, location of calibration phantom, and reconstruction kernel were systematically varied during scan acquisition.
Energy (kVp) and distance from the isocenter (table height) resulted in relative attenuation changes from −5% to 22% and −5% to 0%, respectively, and average bone mineral density (BMD) changes from −0.9% to 0.0% and −1.1% to 0.3%, respectively, compared to a baseline 120 kVp scan performed at the isocenter. BMD compared to manufacturer specified values ranged on average from −2.2% to 0.9%. Phantom size and location of bone-equivalent material inserts resulted in relative attenuation changes of −1.2% to 1.4% compared to the medium sized phantom.
This study demonstrated that variations in kVp and table height can be controlled using a calibration phantom scanned at the same energy and height as a foot phantom; however, error due to soft tissue thickness and location of bones within a foot cannot be controlled using a calibration phantom alone.
Foot; Bone Mineral Density; Quantitative Computed Tomography; Diabetes; Neuropathic Charcot's Arthropathy; Phantom
This study illustrates how network meta-analysis techniques (meta-analysis, adjusted indirect comparison, mixed treatment comparison [MTC]) can provide comparisons of the relative efficacy of postmenopausal osteoporosis therapies in the absence of comprehensive head-to-head trials.
Source articles were identified in MEDLINE; EMBASE; Cochrane Central Register of Controlled Trials (CENTRAL) via Wiley Interscience; and Cumulative Index to Nursing and Allied Health Literature (CINAHL) between April 28, 2009 and November 4, 2009. Two reviewers identified English-language articles reporting randomized controlled trials (RCTs) with on-label dosing of marketed osteoporosis agents and fracture endpoints. Trial design, population characteristics, intervention and comparator, fracture outcomes and adverse events were abstracted for analysis. Primary analyses included data from RCTs with fracture endpoints. Sensitivity analyses also included studies with fractures reported through adverse event reports. Meta-analysis compared fracture outcomes for pharmacologic therapies versus placebo (fixed and random effects models); adjusted indirect comparisons and MTC assessed fracture risk in postmenopausal women treated with denosumab versus other agents.
Using data from 33 studies, random effects meta-analysis showed that all agents except etidronate significantly reduced risk of new vertebral fractures compared with placebo; denosumab, risedronate, and zoledronic acid significantly reduced non-vertebral and hip fracture while alendronate, strontium ranelate, and teriparatide significantly reduced risk for non-vertebral fractures. MTC showed denosumab as more effective than strontium ranelate, raloxifene, alendronate, and risedronate in preventing new vertebral fractures.
The conditional estimates of relative treatment efficacy indicate that there are important differences in fracture risk reduction profiles for marketed pharmacologic therapies for postmenopausal osteoporosis.
osteoporosis; treatment efficacy; postmenopausal women; meta-analysis; mixed treatment comparison
To estimate the cost-effectiveness of Balloon Kyphoplasty (BKP) for the treatment of patients hospitalised with acute Osteoporotic Vertebral Compression Fracture (OVCF) compared to Percutaneous Vertebroplasty (PVP) and Non-Surgical Management (NSM) in the UK.
A Markov simulation model was developed to evaluate treatment with BKP, NSM and PVP in patients with symptomatic OVCF. Data on health related quality of life (HRQoL) with acute OVCF were derived from the FREE and VERTOS II Randomised Clinical Trials (RCTs) and normalized to the NSM arm in the FREE trial. Estimated differences in mortality among the treatments and costs for NSM were obtained from the literature whereas procedure costs for BKP and PVP were obtained from three NHS hospitals. It was assumed that BKP and PVP reduced hospital length of stay by six days compared to NSM.
The incremental cost-effectiveness ratio (ICER) was estimated at GBP 2,706 per QALY and GBP 15,982 per QALY compared to NSM and PVP respectively. Sensitivity analysis showed that the cost-effectiveness of BKP vs. NSM was robust when mortality and HRQoL benefits with BKP were varied. The cost-effectiveness of BKP compared to PVP was particularly sensitive to changes in the mortality benefit.
BKP may be a cost-effective strategy for the treatment of patients hospitalised with acute OVCF in the UK compared to NSM and PVP. Additional RCT data on the benefits of BKP and PVP compared to simulated sham-surgery and further data on the mortality benefits with BKP compared to NSM and PVP would reduce uncertainty.
HTA; Markov; Osteoporosis; QALY; United Kingdom; Spinal Fracture
We compared skeletal parameters in type 2 diabetic (T2DM) and non-diabetic postmenopausal women. Bone structure by dual energy x-ray absorptiometry (DXA) and HR-pQCT was not different, although procollagen type 1 amino-terminal propeptide (P1NP) and osteocalcin levels were lower in T2DM.
T2DM is associated with increased fracture risk, but, paradoxically, with higher cross-sectional bone density (BMD) as measured by DXA. We sought explanations to this puzzle by investigating detailed structural and biochemical skeletal parameters in T2DM.
Cross-sectional comparison of 25 postmenopausal T2DM women and 25 matched controls using DXA, high-resolution peripheral quantitative computed tomography (HR-pQCT) and biochemical bone turnover markers.
BMD by DXA did not differ between T2DM and controls. HR-pQCT assessment also did not differ, with the exception of cortical area at the tibia, which tended to be lower in the diabetics (difference of 12±6 [mean ± SD] mm, p=0.06). P1NP and osteocalcin levels were lower in T2DM as compared to controls (P1NP, 34.3±16 vs. 57.3±28 ng/ml; p=0.005; osteocalcin, 4.5±2 vs. 6.2±2 nmol/L; p=0.001).
Postmenopausal women with T2DM had lower levels of bone formation markers as compared to controls. Aside from a possible decrease in cortical bone area at a weight-bearing site, bone structure was not altered in T2DM. Lower bone turnover may be a skeletal parameter that is present in T2DM.
Bone quality; HR-pQCT; Osteocalcin; P1NP; Type 2 diabetes mellitus
Vertebral bone mineral density (BMD) and cross-sectional area (CSA) are important determinants of vertebral bone strength. Little is known about the specific genetic variants that influence these phenotypes in humans. We investigated the potential genetic variants associated with vertebral trabecular volumetric BMD (vBMD) and CSA measured by quantitative computed tomography (QCT). We initially tested for association between these phenotypes and 4608 tagging and potentially functional single nucleotide polymorphisms (SNPs) in 383 candidate genes in 862 community-dwelling Caucasian men aged ≥65 years in the Osteoporotic Fractures in Men Study (MrOS). The most promising SNP associations (P<0.01) were then validated by genotyping an additional 1,156 randomly sampled men from the same cohort. We identified 11 SNPs in 10 genes (TGFBR3, SOST, KL, CALCR, LEP, CSF1R, PTN, GNRH2, FGFR2, MEPE) that were consistently associated with trabecular vBMD and 5 SNPs in 5 genes (CYP11B1, DVL2, DLX5, WNT4, PAX7) that were consistently associated with CSA in both samples (p<0.005). None of the SNPs associated with trabecular vBMD were associated with CSA. Our findings raise the possibility that at least some of the loci for vertebral trabecular BMD and bone size may be distinct.
Osteoporosis; Genetics; BMD; men; QCT; Polymorphism
We examined the relationships between childhood physical activity (PA), dietary calcium intake and bone size and density.
Subjects and methods
Children aged 4 years were recruited from the Southampton Women’s Survey. They underwent measurement of bone mass by DXA (Hologic, QDR 4000). Physical activity was assessed by accelerometry (Actiheart, Cambridge Neurotechnology Ltd, Cambridge, UK) for 7 continuous days.
422 children (212 boys) participated. After adjusting for gender, daily mean time (min/day) spent in moderate to very vigorous activity (MVPA) was positively related to hip bone area (p<0.001), mineral content (p<0.001), mineral density (p=0.001) and estimated volumetric density (p=0.01). Mean daily calcium intake positively predicted bone indices (p=0.002 with BMC) in those with a low calcium intake (<800 mg/day), but there was a much attenuated relationship in those above this threshold (p=0.229 with BMC). The relationships between MVPA and bone indices were stronger in children with higher calcium intakes (> 800mg/day) (For BMC and MVPA, p=0.121 below and p<0.001 above).
These results support the notion that adequate calcium intake may be required for optimal action of physical activity on bone development and that improving levels of physical activity and calcium intake in childhood may help to optimise accrual of bone mass.
We tested whether two genetic variants were associated with BMD at multiple clinically relevant skeletal sites in Caucasians. We found that variant rs7776725 is consistently associated with hip, spine, wrist and whole-body BMD, which highlights the potential importance of this variant or linked variants for osteoporosis.
A recent genome-wide association study identified two single nucleotide polymorphisms (SNPs), rs7776725 and rs1721400, that were associated with bone mineral density (BMD) variation at the radius, tibia and calcaneus in a Korean population. In this study, we aimed to test whether the association of these two genetic variants can be replicated in Caucasians and whether their association with BMD can be extended to other clinically relevant skeletal sites.
We performed this study in two large cohorts of unrelated US Caucasians. Area BMD at the hip, spine, wrist (ultra-distal radius) and whole body were measured with Hologic dual-energy X-ray absorptiometer. SNPs were genotyped with Affymetrix human genome-wide genotyping arrays. Association analyses were performed using PLINK.
We detected highly significant association (combined p=1.42×10−16) of rs7776725 with wrist BMD but only borderline association signal (combined p=0.017) for rs1721400 with wrist BMD. In addition, we found that rs7776725 was associated with BMD at the hip, spine and whole body. At the FAM3C gene locus where rs7776725 was located, we identified several other SNPs (rs4727922, rs1803389, rs718766 and rs7793554) that were also associated with BMD.
This is the first follow-up association study of rs7776725 and rs1721400 with BMD. The rs7776725 showed consistent association with BMD at multiple clinically important skeletal sites, which highlighted the potential importance of rs7776725 or linked SNPs for risk of osteoporosis. Further in-depth re-sequencing studies and functional assays are necessary to elucidate the underlying mechanisms.
Bone mineral density; FAM3C; Osteoporosis; Single nucleotide polymorphisms
Maternal diet in pregnancy has been linked to childhood bone mass, but the mechanisms and nutrients involved are uncertain. Long-chain polyunsaturated fatty acids (LCPUFAs) have been shown to affect bone metabolism, but the relationship between maternal fatty acid status and bone mass in the offspring remains unknown.
We evaluated the association between maternal LCPUFA status in late pregnancy (34 weeks gestation) and bone density in their children at age four years, within 727 mother-child pairs taking part in the Southampton Women’s Survey.
Concentrations of the n-3 LCPUFA component of maternal plasma phosphatidylcholine were positively associated with a number of bone mineral measures at the age of 4 years; these associations persisted after adjustment for maternal body build, walking speed and infant feeding. Relationships were most evident for eicosapentaenoic acid (r=0.09, p=0.02 for whole body areal bone mineral density [aBMD] and r=0.1, p=0.008 for lumbar spine aBMD) and for docosapentaenoic acid (r=0.09, p=0.02 for whole body aBMD and r=0.12, p=0.002 for lumbar spine aBMD).
These findings suggest that variation in early exposure to n-3 and n-6 LCPUFA may have potential consequences for bone development and that the effects appear to persist into early childhood.
Epidemiology; osteoporosis; development; nutrition; bone mass
The incidence of non-hip femur fractures increased between 1984 and 2007, with an increase in the rates for women after 1996.
Recent reports have suggested that non-hip femur fractures may be decreasing over time, similar to proximal femur fractures.
Incidence rates for non-hip femur fractures among Olmsted County, Minnesota, residents were assessed before and after 1995 when the oral bisphosphonate, alendronate, was approved in the USA.
From 1984 to 2007, 727 non-hip femur fractures were observed in 690 Olmsted County residents (51% female [median age, 71.6 years] and 49% male [21.4 years]). Altogether, 20% of the fractures were subtrochanteric, 51% were diaphyseal, and 29% involved the distal femur. Causes included severe trauma in 51%, minimal to moderate trauma in 34%, and pathologic causes in 15%. The overall age- and sex-adjusted annual incidence of first non-hip femur fracture was 26.7 per 100,000 (25.0 per 100,000 for women and 26.6 per 100,000 for men). Incidence rates increased with age and were greater in women than men. Between 1984–1995 and 1996–2007, age-adjusted rates increased significantly for women (20.4 vs. 28.7 per 100,000; p=0.002) but not for men (22.4 vs. 29.5 per 100,000; p=0.202).
The incidence of first non-hip femur fractures rose between 1984 and 2007, with an increase in the rates for women after 1995.
Aging; Incidence; Non-hip femoral fracture; Population-based study; Subtrochanteric fracture
To determine whether dysregulation of circulating concentrations of undercarboxylated osteocalcin (UC-OC) or GLA-carboxylated osteocalcin (GLA-OC) occurs in patients with type 1 diabetes, a condition of insulin deficiency without insulin resistance.
We measured serum concentrations of UC-OC and GLA-OC in 115 subjects with type 1 diabetes (T1D), ages 14–40 years, and in 55 age-matched healthy control subjects. Relationships between UC-OC and GLA-OC concentrations and patient characteristics (gender, age), indices of glycemic control (HbA1c, fasting plasma glucose, C-peptide concentration, 3-day average glucose measured by a continuous glucose sensor, total daily insulin dose) and circulating indices of skeletal homeostasis [Total calcium, 25-OH vitamin D, parathyroid hormone, IGF-I, type 1 collagen degradation fragments (CTX), adiponectin, leptin] were examined. Between group differences in the concentrations of UC-OC and GLA-OC were the main outcome measures.
Although adiponectin levels were higher in the T1D group, between-group comparisons did not reveal statistically significant differences in concentration of UC-OC, GLA-OC, CTX or leptin between the T1D and control populations. Instead, by multivariate regression modeling, UC-OC was correlated with younger age (p<0.001), higher CTX (p<0.001), lower HbA1c (p=0.013) and higher IGF-I (p=0.086). Moreover, within the T1D subgroup, UC-OC was positively correlated with C-peptide: Glucose ratio (reflecting endogenous insulin secretion); with IGF-I (reflecting intra-portal insulin sufficiency); and with total daily insulin dose.
In T1D, UC-OC appears to correlate positively with markers of insulin exposure, either endogenously produced or exogenously administered.
Adiponectin; Leptin; IGF-I; insulin; osteoporosis
In older men, severe abdominal aortic calcification and vertebral fracture (both assessed using dual-energy X-ray absorptiometry) were positively associated after adjustment for confounders including bone mineral density.
Abdominal aortic calcification (AAC) is associated with higher fracture risk, independently of low bone mineral density (BMD). Dual-energy X-ray absorptiometry (DXA) can be used to assess both vertebral fracture and AAC and requires less time, cost, and radiation exposure.
We conducted a cross-sectional study of the association between AAC and prevalent vertebral fractures in 901 men ≥50 years old. We used DXA (vertebral fracture assessment) to evaluate BMD, vertebral fracture, and AAC.
Prevalence of vertebral fracture was 11 %. Median AAC score was 1 and 12 % of men had AAC score >6. After adjustment for age, weight, femoral neck BMD, smoking, ischemic heart disease, diabetes, and hypertension, AAC score >6 (vs ≤6) was associated with 2.5 (95 % CI, 1.4–4.5) higher odds of vertebral fracture. Odds of vertebral fracture for AAC score >6 increased with vertebral fracture severity (grade 1, OR=1.8; grade 2, OR=2.4; grade 3, OR=4.4; trend p<0.01) and with the number of vertebral fractures (1 fracture, OR=2.0, >1 fracture, OR=3.5). Prevalence of vertebral fracture was twice as high in men having both a T-score<−2.0 and an AAC score>6 compared with men having only one of these characteristics.
Men with greater severity AAC had greater severity and greater number of vertebral fractures, independently of BMD and co-morbidities. DXA can be used to assess vertebral fracture and AAC. It can provide a rapid, safe, and less expensive alternative to radiography. DXA may be an important clinical tool to identify men at high risk of adverse outcomes from osteoporosis and cardiovascular disease.
Aortic calcification; DXA; Men; Vertebral fracture; Vertebral fracture assessment