Heritability of Bone Mineral Density in a Multivariate Family-Based Study

There is evidence for a genetic contribution to bone mineral density (BMD×). Different loci affecting BMD have been identified by diverse linkage and genome-wide association studies. We studied the heritability of and the correlations among six densitometric phenotypes and four bone mass/fracture phenotypes. For this purpose, we used a family-based study of the genetics of osteoporosis, the Genetic Analysis of Osteoporosis Project. The primary aim of our study was to examine the roles of genetic and environmental factors in determining osteoporosis-related phenotypes. The project consisted of 11 extended families from Spain. All of them were selected through a proband with osteoporosis. BMD was measured using dual-energy X-ray absorptiometry. The proportion of variance of BMD attributable to significant covariates ranged from 25 % (for femoral neck BMD) to 48 % (for whole-body total BMD). The vast majority of the densitometric phenotypes had highly significant heritability, ranging from 0.252 (whole-body total BMD) to 0.537 (trochanteric BMD) after correcting for covariate effects. All of the densitometric phenotypes showed high and significant genetic correlations (from ?0.772 to ?1.000) with a low bone mass/osteopenia condition (Affected 3). Our findings provide additional evidence on the heritability of BMD and a strong genetic correlation between BMD and bone mass/fracture phenotypes in a Spanish population. Our results emphasize the importance of detecting genetic risk factors and the benefit of early diagnosis and especially therapeutic and preventive strategies.     

Effects of age on genetic influence on bone loss over 17 years in women: The Healthy Ageing Twin Study (HATS)

The rate of bone loss varies across the aging period via multiple complex mechanisms. Therefore, the role of genetic factors on bone loss may also change similarly. In this study, we investigated the effect of age on the genetic component of bone loss in a large twin‐based longitudinal study. During 17 years of follow‐up in TwinsUK and Healthy Ageing Twin Study (HATS), 15,491 hip and lumbar spine dual‐energy X‐ray absorptiometry (DXA) scans were performed in 7056 twins. Out of these subjects, 2716 female twins aged >35 years with at least two scans separated for >4 years (mean follow‐up 9.7 years) were included in this analysis. We used a mixed‐effects random‐coefficients regression model to predict hip and spine bone mineral density (BMD) values for exact ages of 40, 45, 50, 55, 60, 65, 70, 75, and 80 years, with adjustment for baseline age, weight, height, and duration of hormone replacement therapy. We then estimated heritability of the changes in BMD measures between these age ranges. Heritability estimates for cross‐sectional hip and spine BMD were high (ranging between 69% and 88%) at different ages. Heritability of change of BMD was lower and more variable, generally ranging from 0% to 40% for hip and 0% to 70% for spine; between age 40 and 45 years genetic factors explained 39.9% (95% confidence interval [CI], 25%–53%) of variance of BMD loss for total hip, 46.4% (95% CI, 32%–58%) for femoral neck, and 69.5% (95% CI, 59%–77%) for lumbar spine. These estimates decreased with increasing age, and there appeared to be no heritability of BMD changes after the age of 65 years. There was some evidence at the spine for shared genetic effects between cross‐sectional and longitudinal BMD. Whereas genetic factors appear to have an important role in bone loss in early postmenopausal women, nongenetic mechanisms become more important determinants of bone loss with advanced age. © 2012 American Society for Bone and Mineral Research.     

An investigation into the relationship between soft tissue body composition and bone mineral density in a young adult twin sample

The purpose of this study was to investigate the relationship of fat mass (FM) and lean mass (LM) with bone mineral density (BMD) independent of genetic effects. We also assessed the extent to which genetic and environmental influences explain the associations between these phenotypes. Body composition and BMD were measured using dual‐energy X‐ray absorptiometry in 57 monozygotic and 92 same‐sex dizygotic twin pairs, aged 23 to 31 years, chosen to represent a wide range of intrapair differences in body mass index (BMI; 0 to 15.2 kg/m²). Heritability estimates were adjusted for height and gender. In multiple linear regression analysis, intrapair differences in both FM and LM were independently associated with intrapair differences in BMD at most skeletal sites after adjustment for gender and differences in height. Within monozygotic and dizygotic pairs, LM was a significantly stronger predictor of whole‐body BMD than FM (p < .01). Additive genetic factors explained 87% [95% confidence interval (CI) 80%–91%), 81% (95% CI 70%–88%), and 61% (95% CI 41%–75%) of the variation in whole‐body BMD, LM, and FM, respectively. Additive genetic factors also accounted for 69% to 88% of the covariance between LM and BMD and for 42% to 72% of the covariance between FM and BMD depending on the skeletal site. The genetic correlation between LM and whole‐body BMD (r_g = 0.46, 95% CI 0.32–0.58) was greater than that of FM and whole‐body BMD (r_g = 0.25, 95% CI 0.05–0.42). In conclusion, our data indicate that peak BMD is influenced by acquired body weight as well as genetic factors. In young adulthood, LM and BMD may have more genes in common than do FM and BMD. © 2011 American Society for Bone and Mineral Research.     

Predictors of Bone Mineral Density Improvement in Patients Undergoing Parathyroidectomy for Primary Hyperparathyroidism

Introduction

Primary hyperparathyroidism (PHPT) results in increased bone turnover, resulting in bone mineral density (BMD) reduction and a predisposition towards fractures. Parathyroidectomy (PTX) is the only definitive cure.

Objective

The primary goals of this study were to investigate the impact of PTX on BMD in patients with PHPT and to identify factors associated with post-operative BMD improvement using a multivariate model.

Methods

Between 1999 and 2010, a total of 757 patients underwent PTX for treatment of PHPT; 123 patients had both a pre- and a post-operative dual-energy X-ray absorptiometry (DEXA) scan. A prospective database was queried to obtain information about patient demographics, medications, comorbidities, and pre- and post-operative laboratory values. A Cox regression model was used to stratify patients and to identify factors that independently predict BMD response following PTX in this patient population.

Results

Overall, mean percent change in BMD was +12.31 % at the spine, +8.9 % at the femoral neck (FN), and +8.5 % at the hip, with a mean follow-up of 2.3 ± 1.5 years. A total of 101 (82.1 %) patients had BMD improvement at their worst pre-operative site. In patients who improved, 69.9 % (n = 86) had >5 % increase. Factors associated with BMD improvement at the worst pre-operative site were as follows: male gender (hazard ratio [HR] 2.29; 95 % confidence interval [CI] 1.54–4.21); pre-operative BMD with T-score less than ?2.0 (HR 1.89; 95 % CI 1.11–2.39); age <55 years (HR 1.74; 95 % CI 1.14–2.25); BMD DEXA scan at >2.5 years post-operatively (HR 1.71; 95 % CI 1.09–2.17); history of previous fracture (HR 1.24; 95 % CI 1.05–1.92); and private insurance (HR 1.18; 95 % CI 1.06–2.1). The use of bisphosphonates, estrogens, vitamin D supplementation, or tobacco; obesity; history of previous PTX, serum calcium or parathyroid hormone levels were not independently associated with post-operative BMD improvement.

Conclusion

Osteoporosis is one of the established National Institutes of Health criteria for PTX in asymptomatic patients with PHPT, but BMD improvement is not consistently seen during the post-operative period. Gender, age, more severe pre-operative bone disease, and insurance status were all predictors for greater BMD improvement following PTX. Further studies with a rigorous post-operative BMD regimen are needed in order to validate these results.     

Incidence and risk factors for osteoporotic vertebral fracture in low-income community-dwelling elderly: a population-based prospective cohort study in Brazil. The São Paulo Ageing & Health (SPAH) Study

Summary

We ascertained the incidence and predictors of radiographic vertebral fracture in a Brazilian elderly cohort, since no data in this field have been reported in low-income countries. This is the first population-based study to demonstrate the high frequency of vertebral fracture in elderly Latin Americans. Age, prior fracture, BMD, and bone turnover were predictors of fracture.

Introduction

Vertebral fractures are associated with increased future fracture risk and mortality. No data on incidence of osteoporotic vertebral fracture have been reported in low-income countries where the population’s aging has been faster. Thus, we sought to describe the incidence and risk factors for radiographic vertebral fracture in a longitudinal prospective Brazilian population-based elderly cohort.

Methods

707 older adults (449 women and 258 men) were evaluated with spinal radiographs obtained at baseline and after a mean follow-up of 4.3?±?0.8 years. New vertebral fracture was defined as distinct alteration in the morphology of vertebrae resulting in higher grade of deformity on the second radiograph when compared to the baseline radiograph. Clinical questionnaire, bone mineral density (BMD), and laboratory tests were performed at baseline. Multivariate Poisson regression models were used to identify independent predictors of fracture.

Results

The age-standardized incidence of vertebral fracture was 40.3/1,000 person-years in women and 30.6/1,000 in men. In women, three models of risk factors for fracture were fitted: (1) age (relative risks (RR) 2.46, 95 % confidence interval (CI) 1.66–3.65), previous osteoporotic fracture (RR 1.65, 95 % CI 1.00–2.71), and lumbar spine BMD (RR 1.21, 95 % CI 1.03–1.41); (2) age (RR 2.25, 95 % CI 1.52–3.34) and femoral neck BMD (RR 1.42, 95 % CI 1.11–1.81); (3) age (RR 2.11, 95 % CI 1.41–3.15) and total hip BMD (RR 1.56, 95 % CI 1.21–2.0). In men, the highest quartile of cross-linked C-telopeptide (CTx) (RR 1.96, 95 % CI 0.98–3.91) and prior fracture (RR 2.10, 95 % CI 1.00–4.39) were predictors of new vertebral fracture.

Conclusions

This is the first population-based study to ascertain the incidence of vertebral fracture in elderly Latin Americans, confirming the high frequency of the disorder. Age, prior fracture, BMD, and bone turnover were predictors of the short-term incidence of vertebral fracture.     

Reduced serum osteocalcin concentrations are associated with type 2 diabetes mellitus and the metabolic syndrome components in postmenopausal women: the crosstalk between bone and energy metabolism

Although it has been shown that osteocalcin functions as a hormone in the regulation of glucose metabolism and fat mass, no population-based study to date has addressed serum osteocalcin levels in relation to energy metabolism concurrent with bone metabolism in postmenopausal women. In a population-based study, cardiovascular risk factors, high-sensitivity C-reactive protein (hs-CRP), osteoprotegerin, receptor activator of nuclear factor-??B ligand, osteocalcin, CrossLaps, alkaline phosphatase, and bone mineral density (BMD) at the lumbar spine (L2?CL4) and the proximal femur were measured in 382 Iranian postmenopausal women. In multiple logistic regression analysis, lower osteocalcin and CrossLaps levels were associated with a higher odds ratio (OR) of having type 2 diabetes mellitus when adjustments were made for age, hs-CRP, cardiovascular risk factors, BMD, and markers of bone metabolism [OR 5.17, CI (2.66?C10.04), p?<?0.0001 and OR 2.51, CI (1.37?C4.61), p?=?0.003, respectively]. However, lower alkaline phosphatase levels were associated with a lower OR of having type 2 diabetes mellitus [OR 0.28, CI (0.15?C0.52), p?<?0.0001] in regression analysis. No significant difference was found between serum osteocalcin levels of those with and without metabolic syndrome. Among the metabolic syndrome components, low osteocalcin levels had significant associations with elevated blood glucose [OR 1.89, CI (1.16?C3.07), p?=?0.010] and elevated waist circumference [OR 2.53, CI (1.13?C5.67), p?=?0.024] in multivariate analyses. In conclusion, serum osteocalcin was independently associated with glucose intolerance and abdominal obesity as the components of metabolic syndrome and type 2 diabetes mellitus in postmenopausal women. Since CrossLaps and alkaline phosphatase levels were independently associated with the presence of type 2 diabetes mellitus, the unique contribution of osteocalcin in glucose metabolism could not be concluded.     

Eldecalcitol is more effective for the prevention of osteoporotic fractures than alfacalcidol

Eldecalcitol, a vitamin D₃ analogue, significantly reduces the risk of new vertebral fractures and increases bone mineral density (BMD) more than does alfacalcidol. To determine the effect of eldecalcitol on the incidence of all fragility fractures caused by osteoporosis, we conducted post hoc analyses of the phase III clinical trial to evaluate the incidence of the osteoporotic fractures defined in the World Health Organization (WHO) Technical Report, and, also, the incidence of the major osteoporotic fractures utilized in the WHO Fracture Risk Assessment Tool (FRAX), and compared those in the eldecalcitol group with those in the alfacalcidol group. We also analyzed the incidence of osteoporotic fractures stratified by prespecified risk factors for fractures. Eldecalcitol treatment reduced the incidence of osteoporotic fractures defined by the WHO more than alfacalcidol treatment (18.6 % vs. 25.2 %; hazard ratio, 0.70; 95 % CI, 0.54–0.93). Prevalent vertebral fractures, two or more prevalent vertebral fractures, and total hip BMD T score less than ?2.5 were the risk factors for new osteoporotic fractures with significant differences between the two treatments. Eldecalcitol also decreased the incidence of major osteoporotic fractures in the FRAX more than alfacalcidol (11.1 % vs. 16.3 %; hazard ratio, 0.66; 95 % CI, 0.46–0.94). In conclusion, treatment with eldecalcitol reduced the risk of fragility fractures caused by osteoporosis compared with alfacalcidol administration, which may result from a potent effect of eldecalcitol on BMD, bone structure, and bone turnover.     

Familial resemblance of bone turnover rate in men aged 40 and over—the MINOS study

Familial resemblance of bone mineral density (BMD) is well known in both sexes. Fewer data concern the familial resemblance of bone turnover markers (BTMs) and bone size in men. Our aim was to assess the correlation of BMD, bone size, BTM levels and hormones regulating bone turnover in 50 pairs of brothers aged ≥ 40 and 50 pairs of unrelated men matched for age, weight and height. BMD was measured at the lumbar spine, hip, forearm and whole body. We measured serum osteocalcin (OC), bone-specific alkaline phosphatase (bone ALP), N-terminal propeptide of type I procollagen (PINP) and C-terminal telopeptide of type I collagen (CTX-I) as well as urinary free and total deoxypyridinoline (DPD) and CTX-I. After adjustment for age, weight, bioavailable 17β-estradiol, and parathyroid hormone, all the BTMs (except bone ALP) were significantly correlated in the brothers (ICC = 0.36–0.64). Most of these correlations were significantly stronger than in the unrelated men. Bone size correlated significantly between the brothers (ICC = 0.55–0.65). These correlations were significantly stronger than in the unrelated men. BMD correlated between the brothers at most of the skeletal sites and, for some of them, more strongly than in the unrelated men. Serum levels of LDL-cholesterol and triglycerides were significantly correlated in the brothers, but not more strongly than in the unrelated men. BTM levels correlated independently in the brothers aged ≥ 40, when their shared environment was limited. These data suggest a substantial hereditary determinism of the BTM levels in men.     

The clinical utility of FRAX to discriminate fracture status in men and women with chronic kidney disease

Summary

We assessed the ability of the World Health Organization’s fracture risk assessment tool (FRAX), bone mineral density (BMD), and age to discriminate fracture status in adults with pre-dialysis chronic kidney disease (CKD). In adults with CKD, FRAX was able to discriminate fracture status but performed no better than BMD alone.

Introduction

Patients with CKD are at increased risk for fracture but the best method to assess fracture risk is not known.

Methods

We assessed the ability of the World Health Organization’s FRAX, compared with BMD at the femoral neck (FN), and age to discriminate fracture status (prevalent clinical nonspine and/or morphometric vertebral) in men and women, 18 years and older with pre-dialysis CKD. Results are presented as area under receiver operator characteristic curves (AUC) with 95 % confidence intervals (CI).

Results

We enrolled 353 subjects; mean age was 65?±?14 years; weight was 79?±?18 kg, and estimated glomerular filtration rate was 28 ml/min/1.73 m². About one third of the subjects had a prevalent clinical nonspine and/or morphometric vertebral fracture. FRAX was able to discriminate among those with prevalent clinical nonspine fractures (AUC, 0.72; 95 % CI, 0.65–0.78), morphometric vertebral fractures (AUC, 0.66; 95 % CI, 0.59–0.73), and any fracture (AUC, 0.71; 95 % CI, 0.65–0.77). The discriminative ability of BMD at the FN alone was similar to FRAX for morphometric vertebral and any fractures; FRAX performed better than BMD for prevalent clinical nonspine fractures (AUC for BMD alone, 0.66; 95 % CI, 0.60–0.73). Compared to FRAX, the AUC for age alone was lower for all fracture types.

Conclusions

Among men and women with CKD, FRAX is able to discriminate fracture status but performs no better than BMD alone.     

Does Diet‐Induced Weight Loss Lead to Bone Loss in Overweight or Obese Adults? A Systematic Review and Meta‐Analysis of Clinical Trials

Diet‐induced weight loss has been suggested to be harmful to bone health. We conducted a systematic review and meta‐analysis (using a random‐effects model) to quantify the effect of diet‐induced weight loss on bone. We included 41 publications involving overweight or obese but otherwise healthy adults who followed a dietary weight‐loss intervention. The primary outcomes examined were changes from baseline in total hip, lumbar spine, and total body bone mineral density (BMD), as assessed by dual‐energy X‐ray absorptiometry (DXA). Secondary outcomes were markers of bone turnover. Diet‐induced weight loss was associated with significant decreases of 0.010 to 0.015 g/cm² in total hip BMD for interventions of 6, 12, or 24 (but not 3) months' duration (95% confidence intervals [CIs], –0.014 to –0.005, –0.021 to –0.008, and –0.024 to –0.000 g/cm², at 6, 12, and 24 months, respectively). There was, however, no statistically significant effect of diet‐induced weight loss on lumbar spine or whole‐body BMD for interventions of 3 to 24 months' duration, except for a significant decrease in total body BMD (–0.011 g/cm²; 95% CI, –0.018 to –0.003 g/cm²) after 6 months. Although no statistically significant changes occurred in serum concentrations of N‐terminal propeptide of type I procollagen (P1NP), interventions of 2 or 3 months in duration (but not of 6, 12, or 24 months' duration) induced significant increases in serum concentrations of osteocalcin (0.26 nmol/L; 95% CI, 0.13 to 0.39 nmol/L), C‐terminal telopeptide of type I collagen (CTX) (4.72 nmol/L; 95% CI, 2.12 to 7.30 nmol/L) or N‐terminal telopeptide of type I collagen (NTX) (3.70 nmol/L; 95% CI, 0.90 to 6.50 nmol/L bone collagen equivalents [BCEs]), indicating an early effect of diet‐induced weight loss to promote bone breakdown. These data show that in overweight and obese individuals, a single diet‐induced weight‐loss intervention induces a small decrease in total hip BMD, but not lumbar spine BMD. This decrease is small in comparison to known metabolic benefits of losing excess weight. © 2015 American Society for Bone and Mineral Research     

Heritability of scoliosis

Purpose

To estimate the heritability of scoliosis in the Swedish Twin Registry.

Methods

Self-reported data on scoliosis from 64,578 twins in the Swedish Twin Registry were analysed. Prevalence, pair- and probandwise concordances and tetrachoric correlations in mono- and dizygotic same-sex twins were calculated. The relative importance of genetic variance, i.e. the heritability, and unique and shared environmental variance was estimated using structural equation modelling in Mx software. In addition, all twins in the twin registry were matched against the Swedish Inpatient Register on the primary diagnosis idiopathic scoliosis.

Results

The prevalence of scoliosis was 4%. Pair- and probandwise concordance was 0.11/0.17 for mono- and 0.04/0.08 for same-sex dizygotic twins. The tetrachoric correlation (95% CI) was 0.41 (0.33–0.49) in mono- and 0.18 (0.09–0.29) in dizygotic twins. The most favourable model in the Mx analyses estimated the additive genetic effects (95% CI) to 0.38 (0.18–0.46) and the unique environmental effects to 0.62 (0.54–0.70). Shared environmental effects were not significant. The pairwise/probandwise concordance for idiopathic scoliosis in the Swedish Inpatient Register was 0.08/0.15 for monozygotic and zero/zero for same-sex dizygotic twins.

Conclusion

Using self-reported data on scoliosis from the Swedish Twin Registry, we estimate that 38% of the variance in the liability to develop scoliosis is due to additive genetic effects and 62% to unique environmental effects. This is the first study of sufficient size to make heritability estimates of scoliosis.     

High Bone Turnover is Associated with Low Bone Mass and Spinal Fracture in Postmenopausal Women

A group of 366 healthy, white postmenopausal women, aged 50–81 years, mean age 66 years, were selected from the screened population of Scandinavians who were part of a multicenter study of the efficacy of tiludronate, a new bisphosphonate, in established postmenopausal osteoporosis. Eighty-eight women had a lumbar spine bone mineral density (BMD) above 0.860 g/cm², and 278 women had a BMD below 0.860 g/cm². Spinal fracture was diagnosed from lateral spine X-ray studies and defined as at least 20% height reduction (wedge, compression, or endplate fracture) in at least one vertebra (T4–L4). Bone resorption was assessed by measurement of the urinary excretion of type I collagen degradation products by the CrossLaps™ enzyme-linked immunoassay (ELISA). Bone formation was assessed by ELISA measurement of the N-terminal-mid-fragment as well as the intact serum osteocalcin (OC_N-MID), thus omitting the influence of the instability of osteocalcin caused by the labile 6 amino acid C-terminal sequence. The women were divided into groups with high or low bone turnover according to the concentrations of urinary CrossLaps™ or OC_N-MID. Women in the quartiles with the highest concentrations of CrossLaps [519 ± 119 μg/mmol (SD)] or OC_N-MID [44.6 ± 7.5 ng/ml (SD)] had 10–16% lower spinal BMD compared with women in the lowest quartiles (CrossLaps 170 ± 48 μg/mmol (SD), and OC_N-MID [22.1 ± 3.0 ng/ml (SD)] (P < 0.0004). The prevalences of spinal fracture were 25 to 29% in the lowest quartiles, whereas the prevalences in the highest quartiles were almost double—53–54% (P < 0.006). If the women were subgrouped according to spinal BMD and prevalence of spinal fracture, corresponding results were found. Women with a BMD less than 0.860 g/cm², without or with spinal fracture (n = 136 and n = 142), had 36–43% higher concentration of CrossLaps (P= 0.0001) and 11–15% higher concentration of OC_N-MID (P < 0.02), as compared with women with a BMD above 0.860 g/cm² and no spinal fracture (n = 84). In conclusion, the results indicate a strong association among high bone turnover, low bone mass, and prevalence of spinal fracture, which supports the theory that high bone turnover is a risk factor for spinal fracture and osteoporosis. Received: 29 February 1996 / Accepted: 9 August 1996     

Individual site-specific bone mineral density gain in normocalcemic primary hyperparathyroidism

Summary

In this study, we show that successful parathyroidectomy is followed at 1 year by a significant individual bone mineral density (BMD) gain in nearly half of normocalcemic PHPT patients with reduced bone mass. Alkaline phosphatase levels above median were identified as an independent predictor of individual BMD gain in normocalcemic PHPT patients.

Introduction

The aims of this study were to assess bone mineral density (BMD) gains after parathyroidectomy (PTX) in normocalcemic primary hyperparathyroidism (PHPT) at the individual level and to identify predictors of BMD gain after PTX in this context.

Methods

Longitudinal cohort study of 55 PHPT patients referred for low bone mass and mild abnormalities of calcium/phosphorus metabolism, and successfully treated by PTX. BMD gain at 1 year was considered significant if ≥0.030 g/cm² at one site or more, without any equivalent BMD loss at another site. A logistic regression analysis was performed to identify predictive factors of individual BMD gain.

Results

Among the 55 PHPT patients included, 29 patients with hypercalcemia, 36 patients with normocalcemic PHPT, defined by normal pre-PTX serum total (albumin-corrected) calcium (tCa), including 15 patients with normal ionized calcium (iCa), were identified. At 1 year of PTX, an individual BMD gain was observed in 73.7 % of hypercalcemic, 44.4 % of normocalcemic, and 46 % of PHPT patients with both normal tCa and iCa. Site-specific BMD gains were most important at the spine and hip in all subgroups including patients with normal iCa. Alkaline phosphatase activity above median, which reflects high bone turnover, was predictive of individual BMD gain, both in the overall cohort (OR?=?4.9, 95 % CI 1.3–18.9), and in the normocalcemic group: OR?=?8.4, 95 % CI 1.4–56.6.

Conclusions

Successful PTX is followed at 1 year by a significant individual BMD gain in nearly half of normocalcemic PHPT patients with osteoporosis. ALP levels above median could contribute to the therapeutic decision in this context.     

Genetic and environmental determinants on bone loss in postmenopausal Caucasian women: a 14-year longitudinal twin study

Summary  This longitudinal twin study documented that genetic factors explain 44–56% of the between-individual variance in bone loss at femoral neck, lumbar spine, and forearm in postmenopausal Caucasian women, providing a rationale for identifying the specific genes involved. Introduction  Although there is a significant genetic effect on peak BMD, until recently, no substantive studies on heritability of bone loss in human were available. The aim of the study was to estimate the heritability of the bone loss at multiple sites in postmenopausal Caucasian women. Methods  Postmenopausal female monozygotic (MZ) and dizygotic (DZ) twins aged 40 or above at baseline were selected from the TwinsUK registry and followed up for an average of 8 years (range 5–14 years). All twins were noncurrent hormone replacement therapy users and not on any osteoporosis treatment. They had dual-energy X-ray absorptiometry (DXA) scans of their hip, lumbar spine, and forearm several times (range 2–9) during the follow-up period. Individual bone losses at femoral neck, lumbar spine, and forearm were estimated by linear regression modeling. Structural equation modeling was utilized to estimate the heritability of the bone loss. Results  A total of 712 postmenopausal Caucasian female twins (152 MZ and 204 DZ pairs) were included. MZ twins were older and had slightly lower BMD at all sites than DZ twins. DZ twins had slightly higher bone loss at lumbar spine, but similar at femoral neck and forearm compared to MZ twins. Intraclass correlation coefficients (ICC) for the bone loss at all sites were significantly higher in MZ than DZ twin pairs (p = 0.0045, 0.0003, and 0.0007 for femoral neck, lumbar spine, and forearm, respectively), indicating a significant genetic influence on bone loss at these sites. After adjustment for age at baseline and weight change during the follow-up, the heritability estimate was 47% (95% CI 27–63%) for bone loss at femoral neck, 44% (95% CI 27–58%) for lumbar spine, and 56% (95% CI 44–65%) for forearm. Conclusions  Our data suggest that up to 56% of the between-individual variance in bone loss is due to genes, providing a rationale to identify specific genetic factors for bone loss.     

Vitamin D Status and Bone Mineral Density Changes During Alendronate Treatment in Postmenopausal Osteoporosis

Vitamin D supplementation is recommended for women with osteoporosis. In the FOCUS-D trial comparing the combination tablet alendronate plus vitamin D₃ 5,600 IU (ALN/D) with standard care (SC) prescribed by patients’ personal physicians, ALN/D was more effective in improving serum 25(OH)D and bone turnover markers by 6 months and increasing spine and hip bone mineral density (BMD) after 1 year than SC. This post hoc analysis examined the relationship between BMD gain and 25(OH)D in women in SC receiving alendronate (SC/ALN, n = 134, 52 % of the SC group) and in the ALN/D group (n = 257). At baseline, participants were of mean age 73 years and 72 % were Caucasian, with a mean 25(OH)D of 14.9 ng/mL. In the SC/ALN group, most received vitamin D, although intake of vitamin D varied extensively (51 % received <400 μg/day). In this group, end-of-study 25(OH)D correlated positively with mean percent increases from baseline in lumbar spine and femoral neck BMD [Pearson correlation coefficients (95 % CI) = 0.23 (0.02–0.41) and 0.24 (0.03–0.41), respectively]. Baseline 25(OH)D correlated with increases in only lumbar spine BMD [Pearson correlation coefficient (95 % CI) = 0.22 (0.01–0.40)]. No correlations between mean BMD change and 25(OH)D were seen with ALN/D. In conclusion, in postmenopausal women with osteoporosis and low 25(OH)D receiving alendronate and a wide range of vitamin D doses, the increase in lumbar spine and femoral neck BMD was positively correlated with serum 25(OH)D achieved by the end of the study and, to some extent, with 25(OH)D concentrations at baseline. The degree of success of alendronate therapy for osteoporosis may depend on the vitamin D status of patients.     

Circulating amounts of osteoprotegerin and RANK ligand: genetic influence and relationship with BMD assessed in female twins

Osteoprotegerin (OPG) is a circulating receptor that inhibits osteoclastogenesis by binding to RANK ligand (RANKL). OPG knock-out animals develop severe osteoporosis. Treatment with OPG lowers bone resorption and increases BMD. OPG production is influenced by a wide range of hormones and cytokines. The influence of genetic factors on circulating amounts of OPG and RANKL is not known. BMD has been demonstrated to have a high heritability and there is evidence also that bone turnover and bone loss rates are controlled at least in part by genetic factors. OBJECTIVE: Assessing the genetic impact on serum OPG and RANKL in women and estimation of the relative contribution of this inheritance to the total heritability of BMD. METHODS: 188 female twins (52 DZ and 42 MZ pairs) from the Danish Twin Registry were included in the study. Mean age was 35 years (range 19-64 years), average spine BMD was 1.04 +/- 0.11 g/cm2. Serum levels of OPG and RANKL were measured by ELISA (Biomedica, Vienna, Austria). This register covers twins born in Denmark since 1870. Heritability and environmental influence was assessed using a maximum-likelihood model for genetic pleiotropy. RESULTS: RANKL levels showed a negative correlation with age and lower values in smokers. OPG levels were higher in postmenopausal women. Heritability (h(2)) was 85% for spine BMD and 52% for serum RANKL after adjustment for age, smoking and BMI. By contrast, there was no significant genetic influence on OPG levels (h(2) = 0, 95% CI: 0 to 0.31). Serum OPG was determined almost exclusively by individual environment (e(2) = 0.79), with a small, non-significant contribution from shared environment (c(2) = 0.21). Restricting analyses to the 158 premenopausal twins did not alter the findings. CONCLUSIONS: Serum OPG and RANKL levels have only a weak relation to BMD in healthy women. Phenotype correlations indicate that the genes that contribute to twin similarity for BMD are not genes regulating serum levels of RANKL or OPG. The weak correlation with BMD appears to consist in shared environmental factors.     

High prevalence of spine–femur bone mineral density discordance and comparison of vertebral fracture risk assessment using femoral neck and lumbar spine bone density in Korean patients

The aim of this study was to evaluate the prevalence of spine–femur discordance, and to compare the effectiveness of femoral neck (FN) and lumbar spine (LS) bone mineral density (BMD) for estimation of the risk of vertebral fractures. Women who were evaluated with dual energy X-ray absorptiometry between January 2001 and December 2005 were enrolled in this study. Vertebral fracture risk was calculated using initial FN and LS BMD. The follow-up vertebral X-rays from all subjects were reviewed, and the calculated estimated risk using the Fracture Risk Assessment Tool (FRAX^®) was compared with the actual prevalence of vertebral fractures during the follow-up period. Among a total of 443 women with a mean age of 58.5 years, 130 women (29.3 %) demonstrated femur–spine discordance (i.e., a difference between FN and LS BMD of >1 SD). Most subjects having discordance showed lower LS BMD (73.1 %) compared to FN BMD. During the mean 7-year follow-up period, 12 (2.7 %) vertebral fractures occurred. In cases with high estimated fracture risk (>20 % for estimated fracture risk), using LS BMD significantly reflected the actual vertebral fracture in total subjects [odds ratio (OR) 19.29, 95 % confidence interval (CI) 4.21–88.46], in subjects with spine–femur discordance (OR 16.00, 95 % CI 1.91–134.16), and in subjects with spine–femur discordance having lower LS BMD (OR 20.67, 95 % CI 1.63–262.71). In comparison, the estimated risk using FN BMD did not reflect the actual occurrence of vertebral fractures. In conclusion, a significant number of Korean subjects exhibited spine–femur discordance, and LS BMD might be more appropriate for estimation of vertebral fracture risk.     

The relationship between vitamin D and parathyroid hormone: calcium homeostasis, bone turnover, and bone mineral density in postmenopausal women with established osteoporosis

It is evident from several studies that not all patients with hypovitaminosis D develop secondary hyperparathyroidism. What this means for bone biochemistry and bone mineral density (BMD) remains unclear. The aim of this study was to investigate the effects of hypovitaminosis D (defined as a 25OHD < or = 30 nmol/l) and patients with a blunted PTH response (defined arbitrarily as a PTH within the standard laboratory reference range in the presence of a 25OHD < or = 30 nmol/l) in comparison to patients with hypovitaminosis D and secondary hyperparathyroidism (defined arbitrarily as a PTH above the standard laboratory reference range in the presence of a 25OHD < or = 30 nmol/l) and vitamin D-replete subjects (25OHD > 30 nmol/l). Four hundred twenty-one postmenopausal women (mean age: 71.2 years) with established vertebral osteoporosis were evaluated by assessing mean serum calcium, 25OHD, 1,25(OH)2D, bone turnover markers, and BMD. The prevalence of hypovitaminosis D was 39%. Secondary hyperparathyroidism was found in only one-third of these patients who maintained calcium homeostasis at the expense of increased bone turnover relative to the vitamin D-replete subjects (bone ALP mean difference: 43.9 IU/l [95% CI: 24.8, 59.1], osteocalcin: 1.3 ng/ml [95% CI: 1.1, 2.5], free deoxypyridinoline mean difference: 2.6 nmol/nmol creatinine [95% CI: 2.5, 4.8]) and bone loss (total hip BMD mean difference: 0.11 g/cm2 [95% CI: 0.09, 0.12]). Patients with hypovitaminosis D and a blunted PTH response were characterized by a lower serum calcium (mean difference: 0.07 mmol/l [95% CI: 0.08, 0.2]), a reduction in bone turnover (bone ALP mean difference: 42.4 IU/l [95% CI: 27.8, 61.9], osteocalcin: 1.6 ng/ml [95% CI: 0.3, 3.1], free-deoxypyridinoline mean difference: 3.0 nmol/nmol creatinine [95% CI: 1.9, 5.9]), but protection in bone density (total hip BMD mean difference: 0.10 g/cm2, [95% CI: 0.08, 0.11]) as compared to those with hypovitaminosis D and secondary hyperparathyroidism. This study identifies a distinct group of patients with hypovitaminosis D and a blunted PTH response who show a disruption in calcium homeostasis but protected against PTH-mediated bone loss. This has clinical implications with respect to disease definition and may be important in deciding the optimal replacement therapy in patients with hypovitaminosis D but a blunted PTH response.     

Association of IL-6 G-174C polymorphism with bone mineral density

Functional polymorphisms in the promoter region of interleukin-6 (IL-6) are known to be involved in bone mineral density (BMD) and the development of osteoporosis, but the reported results have been inconsistent. Using the meta-analysis approach, the present study is designed to provide a relatively comprehensive picture of the relationship between bone mineral density (BMD) or osteoporosis and polymorphisms in the promoter region of IL-6 (rs1800795 and rs1800796). The difference of bone mineral density (BMD) values between genotypes was examined by mean difference and 95 % confidence intervals (CIs). Association between IL-6 polymorphism and clinical osteoporosis was evaluated by pooled odds ratios (ORs) and 95 % CIs. A total of 13 articles with 11,499 subjects were included in the present study. For ?174 (rs1800795), we found that individuals with the G/G genotype had a significantly lower BMD value than those with C/C genotype at femoral neck (0.02 g/cm², 95 % CI 0.00–0.03) (p = 0.04) and distal radius (0.01 g/cm², 95 %CI 0.01–0.01) (p < 0.0001). However, we did not find a statistically significant difference of BMD at the spine. When analysis was limited to postmenopausal women, similar results were obtained. We further found that the C/C genotype was associated with a reduced risk of osteoporosis compared to G/G genotype, and the pooled OR was 0.72 (95 % CI 0.54–0.95, p = 0.02). In addition, a significant relationship was found between G-634C (rs1800796) polymorphism and distal radius BMD (CC vs. GG: 0.02 g/cm², 95 % CI 0.01–0.03; GC vs. GG: 0.02 g/cm², 95 % CI 0.00–0.03) in the Asian population. These findings suggest that the CC genotype of IL-6 G-174C polymorphism may be associated with high BMD at femoral neck and distal radius and decreased risk of osteoporosis in the Caucasian population whereas G-634C polymorphism was associated with distal radius BMD in Asians.     

Effect of Intermittent and Daily Regimens of Minodronic Acid on Bone Metabolism in an Ovariectomized Rat Model of Osteoporosis

The goal of the study was to compare the effects of minodronic acid on bone mineral density (BMD) and bone turnover in a rat ovariectomized (OVX) osteoporosis model, using two intermittent treatment regimens (weekly and 4 continuous days every 4 weeks) and a daily regimen. Female F344 rats (age 14 weeks) underwent ovariectomy or a sham operation. Minodronic acid was orally administered at 0.042, 0.21, and 1.05 mg/kg in the intermittent regimens, and at 0.03 and 0.15 mg/kg in the daily regimen for 12 weeks from the day after surgery. Minodronic acid dose-dependently ameliorated the decreases in areal BMD of the lumbar vertebrae and femur, and volumetric BMD of total and trabecular bone in the distal femur. Minodronic acid also suppressed the increase in urinary deoxypyridinoline levels and reduced serum osteocalcin levels. In bone histomorphometry, all three minodronic acid regimens suppressed OVX-induced increases in bone turnover at the tissue level and ameliorated all structural indices, except that an effect on trabecular thickness only occurred with daily treatment. In conclusion, minodronic acid administered weekly or for 4 continuous days every 4 weeks suppressed increased bone resorption and BMD to a similar extent to that of a similar total dose given daily in a rat OVX model.