The effects of menopause on longitudinal bone loss from the spine

Summary Two hundred and thirty women aged 45–66 years were divided into three groups according to their menopausal status and were followed to assess the changes in vertebral bone mineral density (BMD). These included 71 premenopausal, 42 perimenopausal, and 117 postmenopausal women. Menopausal status was assessed through menstrual history and plasma concentrations of 17 estradiol and luteinizing hormone. BMD was measured by dual photon absorptiometry between 2 and 5 times over an average period of 27 months, and annual rates of changes were calculated by linear regression. BMD decreased significantly (P<0.0001) in the three groups during the follow-up. Mean (±SD) annual rate of change was-0.79±1.5% for premenopausal,-2.35±1.5% for perimenopausal, and-1.24±1.5% for postmenopausal women. There was no difference in the rates of bone loss between the perimenopausal group and the postmenopausal group within 3 years after menopause (1–2 years:-2.34±2.1%; 2–3 years:-1.9±1.5%). Thereafter, rates decreased exponentially with time since menopause to fall out at the same level as the premenopausal level. These longitudinal data indicate that vertebral bone loss begins before menopause and accelerates sharply during menopause to decline exponentially with time after 3 years.     

The effect of 1-year transdermal estrogen replacement therapy on bone mineral density and biochemical markers of bone turnover in osteopenic postmenopausal systemic lupus erythematosus patients: a randomized,double-blind,placebo-controlled trial

We studied the effect of 1-year transdermal estrogen replacement therapy (ERT) on bone mineral density (BMD) and biochemical markers of bone turnover in osteopenic postmenopausal systemic lupus erythematosus (SLE) patients in a randomized, double-blind, placebo-controlled trial. SLE patients were randomly allocated to treatment (estradiol; 50 g transdermal 17-estradiol; n=15) or placebo (n=17) group. Both groups received 5 mg continuous oral medroxyprogesterone acetate, 500 mg calcium and 400 IU vitamin D₃. L₁–L₄ spine (LS), left femur and total hip BMD were measured at baseline and at 6 and 12 months. Serum osteocalcin (OC) and degradation products of C-terminal telopeptides of type-I collagen (CTx) levels were measured at baseline and 3, 6, 9, and 12 months. There was a significant difference in the percentage change of LS BMD at 6 months between the two groups (103.24±3.74% (estradiol group) vs 98.99±3.11% (placebo group); P<0.005). There was a significant decrease within the estradiol group in the CTx levels between baseline and all subsequent visits (P<0.05). There was no significant difference in SLE disease activity index, Systemic Lupus International Collaborating Clinics/American College of Rheumatology (ACR) damage index and corticosteroid dose during the study period. Transdermal estradiol may prevent bone loss in postmenopausal SLE women at the lumbar spine and femur, with no increase in disease activity among postmenopausal SLE women receiving transdermal ERT. The high dropout rate (8/15) leads us to the conclusion that efficacy of HRT in a high-risk group such as SLE women can be attained only in a small number of patients, provided all inclusion/exclusion criteria are strictly adhered to.     

Bone mineral density-independent association of quantitative ultrasound measurements and fracture risk in women

Osteoporotic fracture is considered to result from reduced bone strength and to be related to decreased bone mass and impaired bone architecture. Quantitative ultrasound measurements (QUS) of bone, that may reflect certain architectural aspects of bone, have been shown to be associated with fracture, but it is not clear whether the association is independent of bone mineral density (BMD). This study was designed to examine the contributions of cortical QUS and BMD measurements to the prediction of fracture risk in postmenopausal Caucasian women. Speed of sound (SOS) at the distal radius, tibia, and phalanx (Sunlight Omnisense) and BMD at the lumbar spine and femoral neck (GE Lunar) were measured in 549 women, aged 63.2 ± 12.3 years (mean ± SD; range, 49–88 years), including 77 fracture cases. Lower SOS at the distal radius, tibia, and phalanx, which were correlated with each other, were associated with increased risk of fracture. Independent predictors of fracture risk (in multivariate analysis) were distal radius SOS (OR per SD = 1.8; 95% CI, 1.3–2.4), femoral neck BMD (OR per SD = 1.9; 95% CI, 1.4–2.4), and age (OR per 5 years = 1.2; 95% CI, 1.0–1.5). Approximately 30% of the women had distal radius SOS T-scores <–2.5; however, only 6.6% of women had both BMD and SOS T-scores <–2.5. Among the 77 fracture cases, only 14 (18.2%) had both BMD and QUS T-scores below –2.5. These data in postmenopausal women suggest that speed of sound at the distal radius was associated with fracture risk, independent of BMD and age. The combination of QUS and BMD measurements may improve the accuracy of identification of women who will sustain a fracture.     

Changes in bone density in women starting hormone replacement therapy compared with those in women already established on hormone replacement therapy

It is well established that hormone replacement therapy (HRT) will prevent postmenopausal loss of bone. However, it is not known to what extent HRT will continue to affect bone mineral density (BMD) in women established on HRT compared with those commencing treatment. We recruited 48 healthy early postmenopausal women into a prospective, comparative study. Twenty-nine women had never taken HRT (group A) whilst 19 women were already taking HRT (group B) (conjugated equine oestrogens, 0.625 mg daily; mean (±SD) years of use 2.2 (1.5) years). All of the women were started on, or switched to, micronized 17-oestradiol (2 mg/day) continuously with dydroges-terone (10 mg/day) for the first 14 days of each cycle. BMD measurements were performed at the lumbar spine and proximal femur using dual-energy X-ray absorptiometry (DXA) at baseline and after 12 and 24 months of treatment. Group A showed a significantly greater increase in lumbar spine BMD after 12 months (mean (±SD)=5.3 (4.6)%) compared with group B (mean(±SD)=2.1 (2.1)%) and 24 months of treatment (group A, mean(±SD)=6.4 (5.2)%; group B, mean (±SD)=2.3 (2.6)%; bothp<0.01). Femoral neck and Ward's triangle BMD increased significantly in both groups but there were no significant differences between the groups. Baseline BMD correlated with change in lumbar spine BMD for women in group A after 12 months (r=–0.67,p<0.01) and 24 months of treatment (r=–0.59,p<0.05). These data demonstrate that HRT has the greatest effect on BMD when it is first administered, especially in those women with low BMD, but improvements may still be observed in women continuing HRT in the longer term.     

Association of a single nucleotide polymorphism in the lipoxygenase ALOX15 5′-flanking region (−5229G/A) with bone mineral density

The 12/15-lipoxygenase gene Alox15 has been identified as a susceptibility gene for bone mineral density (BMD) in mice through combined genetic and genomic analyses. Here we studied the association between bone mineral density and an ALOX15 gene single nucleotide polymorphism to assess the potential involvement of the human ALOX15 gene in postmenopausal osteoporosis. Specifically, we examined the association between a single nucleotide polymorphism at –5299G/A in the ALOX15 5-flanking region with BMD in 319 postmenopausal Japanese women (66.7 ± 8.9 years, mean ± SD). We found that subjects bearing at least one variant A allele (GA + AA; n = 273) had significantly lower Z scores for lumbar spine and total body bone mineral density than did subjects with no A allele (GG; n = 46) (lumbar spine, –0.25 ± 1.34 versus 0.48 ± 1.70; P = 0.0014; total body, 0.25 ± 1.01 vs 0.62 ± 1.11; P = 0.048). These findings suggest that the ALOX15 gene is one of the genetic determinants of BMD in postmenopausal women. Accordingly, this polymorphism could be useful as a genetic marker for predicting the risk of osteoporosis.     

Idiopathic osteoporosis in premenopausal women

Although osteoporosis predominantly affects older postmenopausal women, low bone mineral density also occurs in men and younger women. In men, it is often unexplained by recognized secondary causes. These men with idiopathic osteoporosis have reductions in serum IGF-I as well as indices of reduced bone formation. Younger women also experience bone loss of unknown etiology (IOP). Whether premenopausal women with IOP have similar decreases in IGF-I levels and reduced indices of bone formation is unknown. We prospectively evaluated a group of premenopausal women with unexplained low bone mass and compared them to normal premenopausal women with respect to serum concentrations of IGF-I. Thirteen premenopausal women (34.2±2.3 years) with low bone density (mean lumbar spine T-score –2.26±0.20) were compared with 13 premenopausal women (35.7±1.7 years) with normal bone density of similar age, height and ethnic composition. Body mass index (BMI) was lower in subjects than controls (20.5±0.7 versus 25.2±1.1 kg/m², P<0.01). A family history of osteoporosis and a history of fragility fractures were found more frequently in subjects than controls (P0.05). Calciotropic hormones did not differ between the two groups. In contrast to our observations in men with idiopathic osteoporosis, mean serum IGF-I concentrations did not differ between subjects and controls (subjects: 22.5±2.2 nmol/l versus controls: 20.8±1.6 nmol/l; NS). Moreover, serum IGF-I levels did not correlate significantly with serum estradiol or with BMD at either the lumbar spine or femoral neck. However, lower follicular phase serum estradiol levels among non-oral contraceptive users were found in subjects as compared to controls (subjects: 124.1±13 pmol/l versus controls 194.9±24 pmol/l, P=0.06). Calculated free, bioavailable estradiol levels were significantly lower overall in subjects than controls (0.6±0.1 versus 1.2±0.2 pmol/l, P<0.05). Total serum estradiol levels correlated with BMD at the femoral neck (r=+0.50; P<0.05). Free, bioavailable estradiol correlated with BMD and BMAD at the lumbar spine (r=+0.54, P<0.01 and r=+0.54, P<0.05, respectively) and femoral neck (r=+0.60 and r=+0.55 respectively, both P<0.01). Urinary NTX excretion, although within the normal premenopausal range, was 45% higher in subjects than controls (41.6±5.9 nmol BCE/l versus 28.3±2.4 nmol BCE/l; P<0.05). Bone-specific alkaline phosphatase activity was also higher (17.4±1.6 ng/ml versus 14.7±0.8 ng/ml), although the difference was not statistically significant. These results suggest differences in the pathogenesis of idiopathic osteoporosis in women as compared to men with IOP.     

Age-related changes in os calcis ultrasonic indices: A 2-year prospective study

We performed repeated ultrasound measurements approximately 2 years apart (average 23 months ±3 months) on the os calcis of 113 healthy postmeno-pausal women recruited from two large prospective cohort studies named OFELY and EPIDOS. Group A (from OFELY) consisted of 88 women aged 52–72 (63±5) years, randomly selected from a large insurance company, and group B (from EPIDOS) consisted of 25 women aged 75–88 (80±4) years, randomly selected from the voting lists. We obtained broadband ultrasonic attenuation (BUA) and speed of sound (SOS) measurements, as well as the Stiffness index, with a Lunar Achilles ultrasound machine. We performed dual energy X-ray absorptiometry (DXA) measurements of femoral neck bone mineral density (neck BMD) with a Hologic QDR 2000 for group A and with a Lunar DPX Plus for group B. The decrease that we observed over 2 years was on average ±1 SD: –1.01±4.6 dB/MHz (p=0.02) for BUA (which is approximately equal to the long-term precision error in vitro), –11.3±9.2 m/s (p=0.0001) for SOS (approximately 5 times the precision error), –3.8±4.2 %YA (p=0.0001) for Stiffness (2.5 times the precision error) and –0.01±0.03 g/cm2 (p=0.0001) for neck BMD (approximately equal to the precision error). In terms of percentage change this represents: –1.0%±4.3% for BUA, –0.8%±0.6% for SOS and –1.85%±4.4% for neck BMD. At the individual level, most SOS and Stiffness values were consistent with a decrease, whereas BUA and neck BMD values were spread out above and below the zero line of no change. The decreases in SOS and Stiffness were significantly larger in the early postmenopause (20 years since menopause [YSM]) than in the late postmenopause (>20 YSM). We observed a similar trend for BUA and BMD but this did not reach statistical significance. We found a weak but significant correlation between changes in ultrasound variables and changes in neck BMD. However, the 2-year changes observed in SOS were not significantly correlated with changes in BUA. This study suggests that the heel ultrasound measurements of SOS and Stiffness are valuable indices of postmenopausal bone loss, and could be used for follow-up in therapeutic trials.     

Relationship Between Lipids and Bone Mass in 2 Cohorts of Healthy Women and Men

A number of recent findings seem to indicate that fat and bone metabolism are strictly connected. We investigated the relationship between lipid profile and bone mineral density (BMD) in 236 either pre- or postmenopausal women, aged 35–81 years, attending our osteoporosis center (clinic group). In order to verify the consistency of the results, 265 men and 481 women aged 68–75, participating in a population-based epidemiological investigation (community cohort), were also studied. Lumbar spine, femoral neck, total hip and total body BMD, total body fat, % fat mass and lean mass were measured using dual energy X-ray absorptiometry (DXA). In the clinic group, lumbar spine and hip BMD Z score values were both strongly related to all measured serum lipids: the relationship was negative for HDL cholesterol (P < 0.05) and Apo A lipoprotein (P < 0.000) and positive for LDL cholesterol (P < 0.05), Apo B lipoprotein (P < 0.001) and triglycerides (P < 0.05). When BMD values were adjusted for body weight and BMI, most relationships remained statistically significant. In the community cohort, total body and hip BMD values were strongly related in both men and women to age, body weight, height, BMI, fat mass, lean mass, % fat mass. Total body and hip BMD were significantly related to serum lipids in both women and men. The relationship was negative for HDL cholesterol and positive for total cholesterol, triglycerides and LDL cholesterol. Most of these relationships (triglycerides, HDL cholesterol, LDL/HDL cholesterol ratio in women, and all measured lipids in men) remained statistically significant (P values ranging from 0.000 to 0.03) when the BMD values were adjusted also for anthropometric measures (body weight, height, fat mass). This study demonstrates for the first time that the lipid profile is strictly related to bone mass in both men and women. The interpretation of this association remains hypothetical but it might open new perspectives for understanding the mechanisms controlling bone metabolism.     

Effects of physical activity and dietary calcium intake on bone mineral density and osteoporosis risk in a rural Thai population

The objective of the study was to determine the effects of modifiable risk factors on bone mineral density in postmenopausal Thai women. Dietary calcium intake (g/day), energy expenditure (kcal/day), and sunlight exposure (h/day) were assessed in 129 rural Thai women aged 63 years (range 50 to 84 years). Bone mineral density (BMD) at the femoral neck, lumbar spine, and distal radius were measured by dual-energy X-ray absorptiometry (DXA). The average dietary calcium intake was 236 ± 188 g/day (mean ± SD), while the energy expenditure was 2,118 ± 656 kcal/day with 1.1 ± 1.7 h of sunlight exposure. In multiple linear regression analysis, dietary calcium intake, energy expenditure, and years since menopause were significant and independent predictors of BMD at various sites. The three factors together accounted for between 35% and 45% of the variance of BMD. The prevalence of osteoporosis (defined as BMD T-scores –2.5) was 33% at the femoral neck, 42% at the lumbar spine, and 35% at the distal radius. The risk of osteoporosis was higher in women with lower dietary calcium intake (138 mg/day; prevalence rate ratio [PRR], 1.4; 95% confidence interval [CI], 1.0 to 1.9), lower energy expenditure (1,682 kcal; PRR, 1.7; 95% CI, 1.2 to 2.3), and greater years since menopause (6 years; PRR, 2.6; 95% CI, 1.2 to 5.8). The population attributable risk fraction of osteoporosis risk due to the three factors was 70%. These results suggest that in the Thai population, low dietary calcium intake and low physical activity together with advancing years since menopause were independent risk factors for low BMD.     

Bone loss is more severe in primary adrenal than in pituitary-dependent Cushing’s syndrome

Either exogenous or endogenous glucocorticoid excess is an established cause of osteoporosis and fractures. Glucocorticoids exert their negative effects on bone through mechanisms that are not yet completely elucidated; however, as many as 50% of patients with Cushings syndrome suffer from osteoporosis. Bone loss induced by glucocorticoids is potentially reversible after resolution of glucocorticoid excess. It is presently unknown if Cushings disease (CD) sustained by a pituitary ACTH-producing adenoma and adrenal-dependent Cushings syndrome (ACS) sustained by an adrenocortical adenoma have a different potential of inducing osteopenia. The aim of the present study was to retrospectively analyze bone mineral density (BMD) in 26 patients with CD (4 men, 22 women, aged 14–79 years), 12 patients with ACS (4 men, 8 women, aged 32–79 years) and 38 healthy subjects carefully matched for sex, age and body mass index (BMI). Measurement of BMD was performed by dual-energy X-ray absorptiometry (DXA) using the Hologic QDR 4500 W instrument. Data were analyzed using absolute BMD values (g/cm²), T-score and Z-score referred to the manufacturers normative data for the lumbar spine and to the NHANES III dataset for the hip. The patients with CD and ACS were comparable for age, BMI, estimated duration of disease, urinary free cortisol (UFC) levels, midnight serum cortisol and gonadal function. The analysis of variance demonstrated that lumbar bone densitometric parameters were significantly different among the three groups. They were more reduced in patients with ACS (BMD, 0.76±0.03 g/cm²; T-score, –2.78±0.28; Z-score, –2.25±0.30) while patients with CD (BMD, 0.87±0.02 g/cm²; T-score, –1.74±0.24; Z-score, –0.99±0.32) showed DXA values between the first group and controls (BMD, 1.02±0.02 g/cm²; T-score, –0.35±0.19; Z-score, 0.33±0.16). The difference in BMD at the spine remained statistically significant (P=0.04) after adjustment for the non-significant differences in age, UFC and fat mass between CD and ACS. Conversely, femoral bone densitometric parameters were not significantly different between patients with ACS and CD, even if they were more reduced than in controls. In patients with ACS, we observed a reduction of DHEA-S levels, expressed as standard score (Z-score) values referred to a group of 180 healthy subjects stratified by sex and different age groups (<40 years, between 40 and 60 years, >60 years) to circumvent the pronounced effect of gender and age on such hormone (ACS DHEA-S Z-score -0.88±1.4 versus CD DHEA-S Z-score 2.25±2.35, P=0.0001). DHEA-S Z-score values were significantly correlated with lumbar BMD (r=0.41, P=0.02) and femoral BMD (r=0.43, P=0.01). DHEA-S Z-score values were also significantly correlated with osteocalcin levels (r=0.45, P=0.01). Our data suggest that bone loss is greater in ACS than in CD. A plausible explanation comes from the reduced DHEA-S level in ACS since DHEA-S has well known anabolic actions on bone. However, this hypothesis needs to be confirmed in large, prospective series of patients with Cushings syndrome of different etiology.     

Prediction of incident osteoporotic fractures in elderly women using the free estradiol index

A decline in postmenopausal estrogen concentration accelerates postmenopausal bone loss. We have examined the predictive power of endogenous estrogen production, DXA hip bone density (BMD), and heel quantitative ultrasound (QUS) on incident clinical fracture in a prospective 3-year population based, randomised controlled trial of calcium supplementation. Baseline blood testing on 1499 women mean (SD) age 75 (3) years for estradiol and sex hormone binding globulin measurements and ankle QUS measurements (Lunar Achilles) was undertaken. Bone density was measured using DXA (Hologic 4500A) at 1 year. Incident clinical fractures were confirmed by X-ray. At 3 years, 10% had sustained more than one incident fracture. The fracture group had significantly lower levels of free estradiol index (FEI) (0.40±0.44 versus 0.49±0.54 pmol/nmol), hip BMD (0.776±0.129 versus 0.815±0.124 g/cm²) and measures of QUS (BUA 98±8 versus 101±8 db/Hz, SOS 1504±22 versus 1514 ±26 m/s; stiffness 67±11 versus 71±11 % mean young adult), respectively, than the non-fracture group. After adjustment for age, weight, use of topical estrogen, calcium supplementation and prevalent fracture, incident fracture was predicted by free estradiol index (HR per SD: 1.43:95%CI: 1.08–1.91, P=0.013). After adjustment for BMD, SOS or stiffness, the free estradiol index no longer predicted fracture. When examined separately, the presence of a vertebral or an appendicular fracture was associated with an 18% lower free estradiol index compared with no fracture. The risk of vertebral fracture increased with decreased free estradiol index (HR per SD reduction: 1.63:95% CI: 0.91–2.92); the risk of appendicular fracture also increased with decreased free estradiol index (HR per SD reduction: 1.45:95% CI: 1.05–2.01) after adjustment for age, weight, use of topical estrogen, calcium supplementation and prevalent fracture. After further adjustment for hip BMD or QUS measures, the effect of free estradiol index was no longer significant for vertebral or appendicular fractures. Therefore, a low free estradiol index increases the probability of having an incident fracture as a result of decreased BMD. These data confirm the importance of postmenopausal estrogen concentration in the pathogenesis of osteoporosis in elderly women.     

Bone mineral density and bone turnover markers in children with chronic renal failure

Bone mineral density (BMD) at lumbar spine (L₂-L₄) was measured by dual-energy X-ray absorptiometry (DEXA) in 21 children with predialysis chronic renal failure (CRF) and 44 children with end-stage renal failure (ESRF) on regular hemodialysis. BMD results were expressed as Z-scores. Osteopenia was documented in 13 predialysis patients (61.9%) and 26 patients (59.1%) with ESRF. No significant correlation was observed between Z-scores and the duration of CRF or estimated creatinine clearance. In osteopenic children there was a negative correlation between Z-scores and serum phosphorus (r=–0.61, P=0.004), intact parathyroid hormone (iPTH) (r=–0.47, P=0.03), and bone-specific alkaline phosphatase (r=–0.52, P=0.02) and a positive correlation with total calcium (r=0.41, P=0.07) and 25-hydroxycholecalciferol (r=0.53, P=0.02). Osteopenic children who had iPTH values 200 pg/ml were more osteopenic than those who had lower iPTH levels (P=0.006). In conclusion, osteopenia, assessed by DEXA, is frequent in children with CRF. It occurs early irrespective of the duration or the severity of CRF. In children with ESRF the degree of osteopenia is correlated with laboratory markers of renal osteodystrophy and patients with biochemical findings of secondary hyperparathyroidism are more osteopenic than the others.     

Calcaneal ultrasound predicts early postmenopausal fractures as well as axial BMD. A prospective study of 422 women

Low calcaneal ultrasound measurement (quantitative ultrasound, QUS) has been shown to predict fractures in elderly women. However, only a few studies have examined its ability to predict perimenopausal and early postmenopausal fractures. We conducted a prospective population-based cohort study to assess the capability of QUS as compared to axial BMD measurement to predict early postmenopausal fractures at that age. Four hundred and twenty-two women (mean age 59.6, range 53.7–65.3) from the Kuopio Osteoporosis Risk Factor and Prevention Study (OSTPRE) were randomly chosen to undergo a calcaneal ultrasound measurement. In all, 9.4% of these women were premenopausal at the time of measurement. Thirty-two follow-up fractures were reported during the mean follow-up of 2.6 years (SD 0.7). These were validated with patient record perusal. Broadband ultrasound attenuation (BUA), speed of sound (SOS) and stiffness index (SI) were significantly lower among women with than without fracture (P-values 0.028, 0.001 and 0.001, respectively). Mean T-score adapted from SI was –1.5 (95% CI –1.7 to –1.2) for fracture group and –1.0 (95% CI –1.1 to –0.9) for the non-fracture group. All QUS measurements predicted fractures even after adjusting for age, weight, height, previous fracture history, femoral neck BMD and use of hormone replacement therapy according to Cox regression. The adjusted hazard ratios (HR, 95% confidence interval) of a follow-up fracture for a 1 SD decrease were 1.80 (1.27–2.56), 1.72 (1.21–2.45) and 1.43 (1.01–2.03) for SOS, SI and BUA, respectively. Similarly, the adjusted HR for a 1 SD decrease of spinal BMD was 1.27 (0.85–1.94) and for that of femoral neck BMD 1.14 (0.78–1.70). In receiver operator analyses, the area under the curve (AUC) was greatest for QUS measurements: SOS (AUC=0.68), stiffness (AUC=0.67), BUA (AUC=0.62) and least for lumbar BMD (AUC=0.56), while and femoral neck BMD (AUC=0.59). The difference between AUCs was statistically significant between SI and lumbar BMD (P=0.02, Duncans P=0.07). We conclude that low calcaneal QUS predicts early postmenopausal fractures as well as or even better than axial BMD.     

The influence of Lys3Asn polymorphism in the osteoprotegerin gene on bone mineral density in Chinese postmenopausal women

The objective was to identify single nucleotide polymorphisms (SNPs) in exons of the osteoprotegerin gene and to analyze the relationship between the SNPs and bone mineral density in postmenopausal women. We used polymerase chain reaction (PCR) and direct sequencing methods to identify SNPs and genotypes in 205 postmenopausal women. BMD at the lumbar spine (L_2–4) and femoral neck (FN) were measured by dual-energy X-ray absorptiometry (DEXA). Serum osteocalcin (OC), osteoprotegerin (OPG), receptor activator of nuclear factor B ligand (RANKL) and urinary N-telopeptide of type I collagen (NTx) were also measured. In exon 1 of the OPG gene, we found the Lys3Asn SNP. In 205 postmenopausal women, the Asn-allele frequency was 26.0%, and the distribution of Lys3Asn genotypes was Lys-Lys 56.6%, Lys-Asn 34.6% and Asn-Asn 8.8%, respectively. BMD at the lumbar spine (L_2–4) of the Asn-Asn genotype was significantly higher (9.5–12.6%) than Lys-Asn and Lys-Lys genotypes ( P =0.012), with evidence for an allele dose effect ( P =0.008). Results remained similar after adjustment for age and body mass index. The Lys3Asn polymorphism of the OPG gene alone accounted for 7.7% of the variance of the L_2–4 BMD in a multiple regression model. Logistic regression analysis revealed that the OPG genotype Lys-Lys had a 2.7 times (95% CI: 0.83–9.11) greater risk for osteopenia/osteoporosis than the Asn-Asn genotype. The Lys3Asn polymorphism in the OPG gene is associated with L_2–4 BMD in postmenopausal women. The Lys-allele is associated with lower BMD and an increased risk for osteoporosis.     

The relationship between sex steroids, bone turnover and vertebral fracture prevalence in asymptomatic men

Objective

To examine the association between oestradiol (E2), testosterone (T), SHBG levels and vertebral fractures' (VFs) prevalence in asymptomatic men.

Methods

The study cohort consists of a population of 112 consecutive men (mean ± SD (range) age, weight and BMI were 62.9 ± 9.2 (41–84) years, 75.0 ± 13.8 (45–120) kgs and 26.4 ± 4.7 (18.0–39.6) kg/m², respectively). Lateral vertebral fracture assessment (VFA) images and scans of the lumbar spine and proximal femur were obtained using a GE Healthcare Lunar Prodigy densitometer. VFs were defined using a combination of Genant semiquantitative approach and morphometry. Serum levels of T, E2, CTx and osteocalcine were measured. Free androgen index (FAI) and free estradiol index (FEI) were calculated respectively from the ratio of serum T and E2 to SHBG.

Results

Among the 112 men, 38 (33.9%) had densitometric osteoporosis, and on VFA, VFs were identified in 60 (53.5%): 24 men had grade 1 and 36 had grade 2 or 3 VFs (32.1%). Men with VFs weighted less and had a statistically significant lower lumbar spine and total hip BMD and T-scores than those without a VFA-identified vertebral fracture. Levels of osteocalcine, CTx, and SHBG were statistically higher in men with grades 2 and 3 VFs than men with grade 1 VFs and those without VFs whereas FAI and FEI levels were significantly lower. Comparison of patients according to quartiles of SHBG levels showed that men in the highest quartile were older, had a lower lumbar spine and total hip BMD and a higher prevalence of osteoporosis and VFs. They had also higher levels of CTx. Stepwise regression analysis showed that the osteoporotic status and SHBG was independently associated to the presence of VFs.

Conclusion

Men with asymptomatic densitometric VFs have lower BMD than subjects without VFs. They have evidence of higher SHBG levels and hence lower free sex steroids as well as increased bone resorption. This study confirms that BMD and CTx are the most important determinant of asymptomatic VFs, and that SHBG is an independent risk factor that must be taken into account.     

Insulin-Like Growth Factor I Is a Determinant of Hip Bone Mineral Density in Men Less Than 60 years of Age: MINOS Study

Several studies show that in elderly men bone mineral density (BMD) is not correlated with the insulin-like growth factor (IGF-I) level, but data are scanty in young men. Results of studies correlating insulin-like growth factor binding protein 3 (IGFBP-3) and BMD in men are discordant. As different hypotheses can explain the discordant results, we evaluated the correlation of BMD with serum IGF-I, IGFBP-3, and IGF-I/IGFBP-3 index in a large cohort of 721 men aged 19–85 years taking into account age, body weight, 17-estradiol, free testosterone, and parathyroid hormone. Serum IGF-I and IGFBP-3 decreased with age (r = –0.44 and r = –0.36, P = 0.0001). After adjustment for confounding variables, IGF-I correlated weakly positively with BMD and with bone mineral apparent density (BMAD) of hip as well as with cortical thickness of femoral neck, both of which are determined mainly by bone resorption, but not with bone size determined by periosteal apposition. IGF-I correlated weakly positively with BMD at the whole body and at the third lumbar vertebra IGFBP-3 and IGF-I/IGFBP-3 index did not correlate with densitometric parameters. In men aged 19–60 years, IGF-I correlated with BMD and BMAD of total hip and with cortical thickness of femoral neck positively and more strongly than in the entire cohort but not with the size of proximal femur. BMD of total hip was 6% higher in men in the highest quartile of IGF-I than in men in the lowest quartile. IGF-I, IGFBP-3, and IGF-I/IGFBP-3 index did not correlate with densitometric parameters of other sites. In the men aged more than 60 years, neither IGF-I nor IGFBP-3 nor IGF-I/IGFBP-3 index correlated with BMD, BMAD, or bone size. In men aged 19–60 years, the most significant hormonal determinants of BMD and BMAD of the hip and of the cortical thickness of femoral neck were 17-estradiol and IGF-I (P < 0.05–0.0001). In men aged more than 60 years, the most significant determinants of hip BMD were 17-estradiol and PTH. In conclusion, IGF-I seems to contribute to the inhibition of bone resorption and to maintaining bone mass of the proximal femur during the phase of slow bone loss in men aged less than 60 years. IGFBP-3 and IGF-I/IGFBP-3 index were not correlated with BMD or bone size. Supported by a contract with INSERM/Merck Sharp & Dohme Chibret, Paris, France     

Association between bone mineral densities and serum lipid profiles of pre- and post-menopausal rural women in South Korea

The objectives of this population-based study were to investigate the potential association between bone mineral density (BMD) and serum lipid profiles and to compare the effects of serum lipids on BMD at various skeletal sites in pre- and post-menopausal women. In July and August of 2004, BMD was measured at a variety of skeletal sites [lumbar spine (L_1–4), femoral neck, trochanter, Wards triangle, shaft and proximal total hip] using the GE/Bravo Lunar DPX dual-energy X-ray absorptiometer in a South Korean population-based sample of 375 pre-menopausal and 355 post-menopausal rural women aged 19–80 years. The levels of serum total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) were inversely associated with BMD in both pre- and post-menopausal women. In the pre-menopausal women, correlations were shown only for lumbar 1–4 (TC: r =–0.12, P <0.05; LDL-C: r =–0.12, P <0.05), whereas in the post-menopausal women, no correlation was evident for the lumbar sites. In the post-menopausal subjects, the TC levels showed significant correlations with the BMD values at the trochanter ( r =–0.15, P <0.01), shaft ( r =–0.16, P <0.001) and proximal total hip ( r =–0.15, P <0.01) sites, while the LDL-C levels showed significant correlations with the BMD values at the neck ( r =–0.13, P <0.05), trochanter ( r =–0.21, P <0.001), shaft ( r =–0.20, P <0.001) and proximal total hip ( r =–0.20, P <0.001) sites. The levels of triglyceride (TG) were shown to have a significant positive correlation with BMD values at the trochanter site ( r =0.11, P =0.05) in the post-menopausal women; by contrast, subjects in a higher quartile of TG levels show lower lumbar BMD values in the pre-menopausal women. The levels of high-density lipoprotein cholesterol (HDL-C) were not associated with BMD values at any of the sites in the pre- and post-menopausal subjects. Our data indicate a relationship between BMD values and serum lipid levels and suggest differences between pre- and post-menopausal women in terms of the effects of serum lipids on BMD at various skeletal sites.     

Early changes in urinary cross-linked N-terminal telopeptides of type I collagen level correlate with 1-year response of lumbar bone mineral density to alendronate in postmenopausal Japanese women with osteoporosis

The purpose of this study was to determine whether early changes in the urinary levels of cross-linked N-terminal telopeptides of type I collagen (NTX) during alendronate treatment would be correlated with the 1-year response of lumbar bone mineral density (BMD) in postmenopausal Japanese women with osteoporosis. One hundred five postmenopausal women with osteoporosis, aged 54–88 years, were treated with alendronate (5mg daily) for 12 months. The urinary NTX levels were measured by enzyme-linked immunosorbent assay at the baseline and at 3, 6, and 12 months, and lumbar (L1–L4) BMD was measured by dual-energy X-ray absorptiometry using the Hologic QDR 1500W equipment at the baseline and at 12 months. The mean percent reduction in urinary NTX level at 3, 6, and 12 months was 36.8%, 49.5%, and 49.0%, respectively, the extent of reduction at 6 and 12 months being greater than that at 3 months, and the mean percent increase of the lumbar BMD at 12 months was 8.2%. Single regression analysis showed a significant correlation between the percent reductions in the urinary NTX level at 3, 6, and 12 months of treatment and the percent increase of the lumbar BMD at 12 months (r = 0.200, P < 0.05; r = 0.341, P < 0.001; and r = 0.338, P < 0.001, respectively). Thirty percent of the patients were labeled as poor responders at 3 months, with the reduction in the urinary NTX level being less than the minimum significant change (MSC); 61% of these patients showed a greater reduction in the urinary NTX level, exceeding the MSC, at 6 months. These results suggest that the changes in the urinary NTX levels at 3 and 6 months after the start of alendronate treatment at the dose of 5mg daily may be correlated with the 1-year response of the lumbar BMD in postmenopausal Japanese women with osteoporosis. In other words, the greater the reduction of the urinary NTX level at 3 and 6 months after the start of alendronate treatment, the greater can be the expected increase of the lumbar BMD after 12 months of treatment. In this study, 70% of the patients were good responders, who showed a reduction of the urinary NTX level exceeding the MSC at 3 months. Among the remaining 30% poor responders, about 60% showed satisfactory reduction of the urinary NTX level, exceeding the MSC, at 6 months after the start of treatment with alendronate.     

New biochemical markers of bone resorption derived from collagen breakdown in the study of postmenopausal osteoporosis

The aim of this work was to perform a comparative study between three recently developed biochemical markers of bone resorption derived from collagen metabolism — (1) total urinary free pyridinolines (Pyr), (2) serum pyridinoline cross-linked carboxy-terminal telopeptides of type I collagen (ICTP) and (3) a urinary-specific sequence for a part of the C-telopeptide of the ₁ chain of type I collagen (CTX) — in the diagnosis and follow-up of postmenopausal osteoporosis. Results were also evaluated relative to the classical biochemical marker urinary hydroxyproline (Hyp). The study included 20 untreated osteoporotic postmenopausal women (OSP), age 60 ±6 years, range 46–69 years; 27 osteoporotic postmenopausal women treated (OSP-T) by cyclic therapy with disodium etidronate, 25-hydroxyvitamin D and calcium for a period between 3 months and 4 years (25±15 months), age 59±7 years, range 41–67 years; 17 osteopenic postmenopausal women, age 57±6 years, range 46±68 years; and 29 healthy control postmenopausal women, age 56±7 years, range 41–70 years. The diagnostic criterion for postmenopausal osteoporosis was a bone mineral density (BMD) (Hologic QDR-1000) in lumbar spine and/or femoral neck more than 2 SD below the mean value corresponding to an age- and sex-matched healthy control group. For inclusion in the osteopenic group BMD values had to be between 1 and 2 SD below the mean BMD value corresponding to the control group. We found a significant increase (p<0.01) in the levels of Pyr/Cr and CTX/Cr (Cr=creatinine) in OSP patients with respect to the control group and we did not obeserve any significant difference between control and OSP-T or osteopenic women. It is interesting to note that there was a mean increase in CTX/Cr in OSP patients of 101% of the control values, while the mean increase found in Pyr/Cr concentration was only 33%. However, we did not find significant differences in the concentrations of ICTP and Hyp/Cr between groups. In a comparison of Pyr/Cr and CTX/Cr, urinary CTX showed the higher diagnostic accuracy, as can be deduced from the receiver operating characteristic (ROC) curves. CTX sensitivity was 40% with a specificity of 100%, whereas the sensitivity was 25% for urinary Pyr/Cr. In conclusion, the results of the present work suggest that in osteoporotic women CTX has the highest diagnostic accuracy among the markers of bone resporption studied.     

Role of oral pamidronate in preventing bone loss in postmenopausal women

We have performed a 2-year prospective double-masked study to determine whether the bisphosphonate pamidronate can prevent bone loss in postmenopausal women and its optimal dosage regimen. One hundred and twenty-one such women (mean ± SD age 57.6±3.4 years; mean ± SD time since menopause 7.5±3.5 years) were randomized to receive either oral pamidronate (300 mg/day) for 4 weeks every 4 months (group A), oral pamidronate (150 mg/day) for 4 weeks every 2 months (group B) or identical placebo capsules (group C). Bone mineral density (BMD) measurements at the lumbar spine and proximal femur were performed at baseline and at 6-month intervals for 2 years using dual-energy X-ray absorptiometry. BMD at the lumbar spine (L2–4) increased significantly in groups A and B after 2 years of treatment (mean ± SD 2.8±2.1% and 3.0±2.9% respectively, bothp<0.001) but decreased in the placebo group (–1.6±3.1%,p<0.01). Identical results were seen for BMD at the femoral neck, which increased significantly in groups A and B after 2 years of treatment (1.2±2.3% and 1.3±2.9% respectively, bothp<0.05) but decreased in the placebo group (–1.9±3.9%,p<0.05). There were significant differences over 2 years between the groups at all anatomical sites (lumbar spine, femoral neck and trochanteric region, allp<0.001; Ward's triangle,p<0.01). However, there were no significant differences between groups A and B, suggesting that the two treatment regimens were equally effective in conserving BMD. There were, however, marked differences in tolerability between the two treatment regimens: 13 women (34%) in group A withdrew from the study because of side-effects, but only 5 women (12%) in group B, which was comparable with placebo. These data demonstrate that intermittent oral pamidronate will prevent bone loss from the lumbar spine and proximal femur of postmenopausal women, and that the more frequent but lower dose regimen is well tolerated.