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PubMed2004

Influence of LRP5 polymorphisms on normal variation in BMD.

UNLABELLED: Genetic studies based on cohorts with rare and extreme bone phenotypes have shown that the LRP5 gene is an important genetic modulator of BMD. Using family-based and case-control approaches, this study examines the role of the LRP5 gene in determining normal population variation of BMD and describes significant association and suggestive linkage between LRP5 gene polymorphisms and BMD in >900 individuals with a broad range of BMD. INTRODUCTION: Osteoporosis is a common, highly heritable condition determined by complex interactions of genetic and environmental etiologies. Genetic factors alone can account for 50-80% of the interindividual variation in BMD. Mutations in the LRP5 gene on chromosome 11q12-13 have been associated with rare syndromes characterized by extremely low or high BMD, but little is known about the contribution of this gene to the development of osteoporosis and determination of BMD in a normal population. MATERIALS AND METHODS: To examine the entire spectrum of low to high BMD, 152 osteoporotic probands, their families (597 individuals), and 160 women with elevated BMD (T score > 2.5) were recruited. BMD at the lumbar spine, femoral neck, and hip were measured in each subject using DXA. RESULTS: PAGE sequencing of the LRP5 gene revealed 10 single nucleotide polymorphisms (SNPs), 8 of which had allele frequencies of >5%, in exons 8, 9, 10, 15, and 18 and in introns 6, 7, and 21. Within families, a strong association was observed between an SNP at nucleotide C171346A in intron 21 and total hip BMD (p < 1 x 10(-5) in men only, p = 0.0019 in both men and women). This association was also observed in comparisons of osteoporotic probands and unrelated elevated BMD in women (p = 0.03), along with associations with markers in exons 8 (C135242T, p = 0.007) and 9 (C141759T, p = 0.02). Haplotypes composed of two to three of the SNPs G121513A, C135242T, G138351A, and C141759T were strongly associated with BMD when comparing osteoporotic probands and high BMD cases (p < 0.003). An SNP at nucleotide C165215T in exon 18 was linked to BMD at the lumbar spine, femoral neck, and total hip (parametric LOD scores = 2.8, 2.5, and 2.2 and nonparametric LOD scores = 0.3, 1.1, and 2.2, respectively) but was not genetically associated with BMD variation. CONCLUSION: These results show that common LRP5 polymorphisms contribute to the determination of BMD in the general population.

Adolescent↗
PubMed2006

Theoretical model for the interpretation of BMD scans in patients stopping strontium ranelate treatment.

UNLABELLED: Strontium ranelate is a new treatment for osteoporosis that results in large increases in BMD, much of which is an artefact caused by high bone strontium content. We used clinical trial data and a model of long-term strontium kinetics to estimate the effect of past strontium treatment on future BMD measurements. INTRODUCTION: The oral administration of strontium ranelate causes a clinically significant overestimation of BMD because of the high attenuation of X-rays by strontium atoms in bone. As more patients are treated with strontium ranelate, questions will arise about the correct interpretation of their future BMD measurements. We performed a theoretical study to calculate the long-term effect of strontium treatment on BMD and establish the duration of past treatment for which the remaining bone strontium content (BSC) has a negligible effect on BMD. MATERIALS AND METHODS: The BMD changes measured at the spine and hip during strontium ranelate treatment were interpolated from clinical trial data. The long-term retention of strontium in bone was estimated using the International Commission on Radiological Protection (ICRP) strontium retention function modified for use in postmenopausal women. Estimates of the strontium BMD artefact after treatment has stopped were performed on the assumption that the BSC effect accounts for 75% of the total measured BMD change at 3 years. RESULTS: If 75% of the BMD changes are explained by BSC, in the average patient, 3-year treatment leads to a spine BMD artefact of 11.2%, decreasing to 3.8% 10 years after stopping treatment. The BMD artefacts at the total hip and femoral neck sites are smaller by factors of 0.65 and 0.53, respectively. If pre- and post-therapy BMD measurements are available, these predictions can be tailored to the individual patient. On average, 6-month treatment is required for the spine BMD artefact to exceed 3%, the figure adopted as the maximum BMD change caused by bone strontium that has a negligible effect on scan interpretation. Ten years after stopping treatment, 28 months of treatment are required for the residual BMD artefact to still exceed the 3% threshold. CONCLUSIONS: Strontium ranelate treatment lasting for >6 months can affect BMD measurements for many years afterward.

Bone Density↗
PubMed2001

Changes in QUS and BMD measurements with antiresorptive therapy: a two-year longitudinal study.

There is lack of consensus on whether quantitative ultrasound (QUS) measurements can be used to monitor response to therapy. The aim of this 2-year longitudinal study was to assess whether calcaneal QUS measurement variables respond to antiresorptive therapy and whether these measurements display adequate long-term precision to be useful for monitoring purposes. The study population consisted of 195 postmenopausal women divided into three groups: Group 1: 39 women treated with antiresorptive therapy who commenced treatment at baseline; Group 2: 25 women treated with antiresorptive therapy who had been on treatment for at least 2 years at baseline; Group 3: 131 women who did not taken estrogen, bisphosphonates, or calcium during the 2-year study period. Subjects had baseline and 12 and 24 months follow-up BMD measurements at the lumbar spine (LS), femoral neck (FN), and total hip (THIP) and calcaneal QUS measurements of broadband ultrasound attenuation (BUA) and speed of sound (SOS). BUA and SOS were combined to provide an estimate of heel BMD (Est heel BMD). For women in Group 1, all BMD and QUS measurement variables increased significantly from baseline after 2 years of treatment. For women in Group 2, only THIP BMD and BUA increased significantly after 2 years and the changes were less than those observed in Group 1 women. The overall treatment effect for each measurement variable, defined as the difference in the mean absolute changes between Groups I and 3 after 2 years, was 0.08, 0.03, and 0.04 g/cm2 for LS, FN, and THIP BMD, and for BUA, SOS, and Est heel BMD it was 5.8 dB/MHz, 13.1 m/sec, and 0.05 g/cm2, respectively. When the overall treatment effect was expressed in T-score units, the effect was greatest for LS BMD (0.65 T-score units) and lowest for FN BMD (0.31 T-score units). QUS measurement variables yielded intermediate values of 0.43- 0.52 T-score units. The average least significant change (LSC) was 0.38 T-score units for BMD measurements, whereas the LSC for QUS measurements was three times greater at approximately 1.20 T-score units. Ninety-four percent of the women in Group 1 showed changes in LS BMD that exceeded the LSC after two years, while the percentage was lower for the other measurement variables ranging from approximately 6% for FN BMD, SOS and Est heel BMD to 50% for THIP BMD. A lower percentage of women in Groups 2 and 3 displayed changes that exceeded the LSC for both BMD and QUS measurement variables. Changes in all QUS variables were significantly correlated with changes in LS BMD, with correlation coefficients ranging from 0.26 to 0.40. In conclusion, calcaneal QUS measurement variables were found to show a highly significant response to antiresorptive therapy. However, the precision of QUS measurements was not good enough to allow QUS to be used for monitoring response to treatment. Future improvements in the precision of calcaneal QUS measurements are required to increase the utility of QUS for monitoring purposes.

Bone Density↗
PubMed2006

BMD and risk of hip and nonvertebral fractures in older men: a prospective study and comparison with older women.

UNLABELLED: In a prospective study of 5384 older men, hip BMD was a very strong predictor of hip fracture, much stronger than spine BMD. The relationship between hip BMD and hip fracture risk seemed to be stronger than observed in a large prospective study of women. Hip BMD is an excellent test for predicting fracture risk in men. INTRODUCTION: There have been few studies of the relationship between BMD and risk of fractures in men and none for the association between lumbar spine BMD and risk of hip and nonvertebral fractures. There is also controversy about whether the associations between BMD and risk of fracture are the same in men and women. MATERIALS AND METHODS: We measured proximal femur and lumbar spine BMD in 5384 men, 5384 men, >or= 65 years of age. We compared the results to the very similar cohort of 7871 women >or=65 of age. During 4.4 years of 99% complete follow-up, we validated 317 nonvertebral (59 hip) fractures in men and 1169 nonvertebral (208 hip) fractures in women. RESULTS: Total hip BMD was very strongly associated with risk hip fracture in men (3.2-fold increased risk per sex-specific SD decrease in BMD; 95% CI, 2.4-4.1). The association was stronger than observed in SOF (2.1; 95% CI, 1.8, 2.4; p < 0.001 for interaction). Among the men, lumbar spine BMD was weakly associated with risk of hip fracture (relative risk [RR] per sex-specific SD decrease in BMD: 1.5; 95% CI, 1.2, 2.0). The association between total hip BMD and risk of nonvertebral fractures was somewhat stronger for men (RR = 1.6; 95% CI, 1.5, 1.8) than found for women (p = 0.01 for interaction). The risk of nonvertebral fracture was substantially higher in women than in men for all T scores of hip BMD, regardless of whether sex-specific or female reference values were used. CONCLUSIONS: Hip BMD is strongly associated with risk of nonvertebral, and especially hip fracture, in older men. These associations are at least as strong as in women. As in women, lumbar spine BMD in men is only weakly associated with risk of hip fracture. Regardless of whether sex-specific or female reference values were used, T scores indicated different risks of fractures in men than in women.

Age Factors↗
PubMed2006

Change in lumbar spine BMD and vertebral fracture risk reduction in teriparatide-treated postmenopausal women with osteoporosis.

UNLABELLED: Increases in lumbar spine BMD account for 30-41% of the vertebral fracture risk reduction with teriparatide treatment. The remaining fracture risk reduction is caused by improvements in non-BMD determinants of bone strength. INTRODUCTION: Changes in BMD account for a small percentage of the fracture risk reduction seen in patients treated with antiresorptive drugs. The relationship between changes in lumbar spine BMD and vertebral fracture risk reduction with teriparatide treatment has not been assessed. MATERIALS AND METHODS: The relationship between spine BMD and the risk of new vertebral fractures after teriparatide treatment was assessed using data from the Fracture Prevention Trial. Postmenopausal women with osteoporosis (n = 1637) were randomized to placebo or teriparatide 20 or 40 microg/day for a median of 19 months. Spine BMD was assessed at baseline and 18 months. Vertebrae whose fracture status changed during the trial were removed from the calculation of BMD. Baseline and endpoint lateral spine radiographs were assessed using a visual semiquantitative technique. RESULTS: Both the baseline and change in spine BMD were contributors to vertebral fracture risk. The mean spine BMD increase in teriparatide-treated patients was 0.09 g/cm(2) across tertiles of baseline spine BMD. Compared with placebo, teriparatide significantly reduced the risk of new vertebral fracture for all endpoint BMD values. Teriparatide-mediated increases in spine BMD accounted for 30% (in the low baseline spine BMD tertile) to 41% (in the high baseline spine BMD tertile) of the reduction in vertebral fracture risk. CONCLUSIONS: Increases in BMD account for approximately one third of the vertebral fracture risk reduction seen with teriparatide. The majority of the risk reduction, however, results from improvements in non-BMD determinants of bone strength.

Aged↗
PubMed2007

Genetic and environmental determinants of volumetric and areal BMD in multi-generational families of African ancestry: the Tobago Family Health Study.

UNLABELLED: BMD is higher and fracture risk is lower among individuals of African versus European descent, but little is known about the genetic architecture of BMD in the former group. Heritabilities of areal and volumetric BMD were moderate in our large families of African descent but differed for trabecular and cortical BMD. INTRODUCTION: Populations of African ancestry have lower osteoporotic fracture risk and higher BMD than other ethnic groups. However, there is a paucity of information regarding the genetic and environmental influences on bone health among populations of African heritage. MATERIALS AND METHODS: We dissected the genetic architecture of areal BMD measured by DXA at the proximal femur, lumbar spine, and whole body and volumetric BMD measured by pQCT at the distal and proximal radius and tibia in 283 women and 188 men > or =18 years of age (mean, 43 years) from eight multigenerational Afro-Caribbean families (mean family size > 50). Using quantitative genetic methods, we estimated the residual heritability and the effects of anthropometric, demographic, lifestyle, and medical variables on areal and volumetric BMD. RESULTS: Compared with U.S. non-Hispanic blacks and whites, areal BMD at the femoral neck was highest in the Afro-Caribbean men and women at all ages. Trabecular volumetric BMD decreased linearly with increasing age, whereas cortical volumetric BMD did not decrease until age 40-49, especially in women. Anthropometric, lifestyle, and medical factors accounted for 12-32% of the variation in areal and volumetric BMD, and residual heritabilities (range, 0.23-0.52) were similar to those reported in other ethnic groups. Heritability of cortical BMD was substantially lower than that of areal or trabecular volumetric BMD, although the measured covariates accounted for a similar proportion of the total phenotypic variation. CONCLUSIONS: Our study is the first comprehensive genetic epidemiologic analysis of volumetric BMD measured by QCT and the first analysis of these traits in extended families of African descent. Genes account for as much or more of the total variation in areal and volumetric BMD than do environmental factors, but these effects seem to differ for trabecular and cortical bone.

Adolescent↗
PubMed2004

Randomized trial of effect of alendronate continuation versus discontinuation in women with low BMD: results from the Fracture Intervention Trial long-term extension.

UNLABELLED: To determine the effects of continuation versus discontinuation of alendronate on BMD and markers of bone turnover, we conducted an extension trial in which 1099 older women who received alendronate in the FIT were re-randomized to alendronate or placebo. Compared with women who stopped alendronate, those continuing alendronate for 3 years maintained a higher BMD and greater reduction of bone turnover, showing benefit of continued treatment. However, among women who discontinued alendronate and took placebo in the extension, BMD remained higher, and reduction in bone turnover was greater than values at FIT baseline, showing persistence of alendronate's effects on bone. INTRODUCTION: Prior trials including the Fracture Intervention Trial (FIT) have found that therapy with alendronate increases BMD and decreases fracture risk for up to 4 years in postmenopausal women with low BMD. However, it is uncertain whether further therapy with alendronate results in preservation or further gains in BMD and if skeletal effects of alendronate continue after treatment is stopped. MATERIALS AND METHODS: We conducted a follow-up placebo-controlled extension trial to FIT (FIT long-term extension [FLEX]) in which 1099 women 60-86 years of age who were assigned to alendronate in FIT with an average duration of use of 5 years were re-randomized for an additional 5 years to alendronate or placebo. The results of a preplanned interim analysis at 3 years are reported herein. Participants were re-randomized to alendronate 10 mg/day (30%), alendronate 5 mg/day (30%), or placebo (40%). All participants were encouraged to take a calcium (500 mg/day) and vitamin D (250 IU/day) supplement. The primary outcome was change in total hip BMD. Secondary endpoints included change in lumbar spine BMD and change in markers of bone turnover (bone-specific alkaline phosphatase and urinary type I collagen cross-linked N-telopeptide). RESULTS: Among the women who had prior alendronate therapy in FIT, further therapy with alendronate (5 and 10 mg groups combined) for 3 years compared with placebo maintained BMD at the hip (2.0% difference; 95% CI, 1.6-2.5%) and further increased BMD at the spine (2.5% difference; 95% CI, 1.9-3. 1%). Markers of bone turnover increased among women discontinuing alendronate, whereas they remained stable in women continuing alendronate. Cumulative increases in BMD at the hip and spine and reductions in bone turnover from 8.6 years earlier at FIT baseline were greater for women continuing alendronate compared with those discontinuing alendronate. However, among women discontinuing alendronate and taking placebo in the extension, BMD remained higher and reduction in bone turnover was greater than values at FIT baseline. CONCLUSIONS: Compared with women who stopped alendronate after an average of 5 years, those continuing alendronate maintained a higher BMD and greater reduction of bone turnover, showing benefit of continued alendronate treatment on BMD and bone turnover. On discontinuation of alendronate therapy, rates of change in BMD at the hip and spine resumed at the background rate, but discontinuation did not result in either accelerated bone loss or a marked increase in bone turnover, showing persistence of alendronate's effects on bone. Data on the effect of continuation versus discontinuation on fracture risk are needed before making definitive recommendations regarding the optimal length of alendronate treatment.

Aged↗
PubMed2005

Establishment of BMD reference curves at different skeletal sites in women, using a Cartesian coordinate numeration system.

The BMD reference curve is the reference value used for diagnosing osteoporosis and assessing bone mass changes. Its accuracy would affect the correctness of T-score and Z-score values and thus the reliability of diagnostic results. In this paper, we report the use of a new method, a Cartesian coordinate numeration system, to establish BMD reference curves at different skeletal sites in women. In a reference population of 3,919 women ranging in age from 5-85 years, we used the dual X-ray absorptiometry (DXA) bone densitometer to measure BMD at the posteroanterior spine (PA; vertebrae L1-L4), followed by a paired PA/lateral spine scan of the vertebral bodies of L2-L4, expressed in g/cm2 and g/cm3, and of the hip and forearm. We chose the cubic regression model to best fit BMD curves that varied with age at different skeletal sites. We then referred the BMD of the fitting curves established by the method of the coordinate numeration system as reference curves, compared them to BMD reference curves derived from the fitting curve equation or age cross-section, and calculated the deflection degrees of the BMD reference curves acquired from the fitting curve equation. At the PA spine, lateral spine (expressed in g/cm3), femoral neck, Ward's triangle and radius + ulna ultradistal, the reference curves calculated from the equation were significantly lower than those confirmed by the method of the coordinate numeration system; whereas, at the lateral spine (expressed in g/cm2), total hip, and radius + ulna 1/3 sites, the reference curves derived from the equation were markedly higher than those acquired from the coordinate numeration system. The differences in the two kinds of reference curves calculated by these two different methods gradually increased along with the increment in ages of the women. At the peak value of the reference curves, the BMD calculated from the equation deflected from 2.02% to -10.0% from the BMD acquired from the coordinate numeration system at different skeletal sites, and from 21.5% to -121.8% until the age of 85 years. The highest positive deflection of 65.2% existed at the lateral spine (expressed in g/cm2) and the lowest positive deflection of 21.5% at the total hip. The maximum negative deflection of -121.8% was at the radius + ulna ultradistal, and the minimum negative deflection of -32.6% at the PA spine. The BMD curve acquired from age cross-section was highly positive compared with the one derived from the coordinate numeration system (r=0.955-0.985 p=0.000) with no significant difference between them. Various analysts used such a method to obtain the coefficient of variance (CV) in BMD precision on each curve that was from 0.05-0.19%. Our study shows that the Cartesian coordinate numeration system is an accurate, precise and reliable method and can serve to reveal the serious drawbacks of using the fitting curve equation to calculate BMD. The BMD reference curves established by this coordinate numeration system maintained the authenticity of the fitting curve, whereas, using the fitting curve equation to obtain BMD reference curves at different skeletal sites led to distortion, and resulted in false increases or decreases in T-score and Z-score values.

Absorptiometry, Photon↗
PubMed2006

Geographic and other determinants of BMD change in European men and women at the hip and spine. a population-based study from the Network in Europe for Male Osteoporosis (NEMO).

INTRODUCTION: While the determinants of BMD change have been studied in women, there have been few longitudinal studies in men. As part of the Network in Europe for Male Osteoporosis (NEMO) study, data were analysed from 1337 men and 1722 women aged 50-86y (mean=67 years) from 13 centres across Europe to assess determinants of BMD change and between-gender contrasts. METHODS: BMD was measured at the femoral neck, trochanter and/or L2-L4 spine on 2 occasions 0.8-8 years apart (mean=3.5 years) using DXA densitometers manufactured by Hologic (n=6), Lunar (n=5) and Norland (n=2). Each was cross-calibrated using the European Spine Phantom and annual rates of BMD change (g/cm(2)/year) were calculated from the standardised paired BMD values. The EPOS risk factor questionnaire was administered at baseline. RESULTS: In multivariate linear regression models, there were large between centre differences in the mean rates of BMD change in all 3 sites for both genders (P<0.0001) with the standard deviation of the between centre heterogeneity in the adjusted means being 0.005 g/cm(2)/year at the femoral neck. The overall adjusted mean annual rates of BMD change in g/cm(2)/year (95% CI) pooled across centres by random effects meta-analysis in men were: femoral neck -0.005 (-0.009, -0.001); trochanter -0.003 (-0.006, -0.001); and spine 0.000 (-0.004, 0.004). In women the respective estimates were: -0.007 (-0.009, -0.005); -0.004 (-0.006, -0.003); and -0.005 (-0.008, -0.001). The I(2) statistic for heterogeneity was between 81% and 94%, indicating strong evidence of between centre heterogeneity. Higher baseline BMD value was associated with subsequent greater decline in BMD (P<0.001). Preserved BMD was associated with higher baseline body weight in all 3 sites in men (P<0.012) but not in women. Weight gain preserved BMD (P<0.039) in all 3 sites for both genders, except the male spine. Increasing age was associated with faster BMD decline at the trochanter in both genders (P<0.026) and with a slower rate of decline at the female spine (P=0.002). Effects of lifestyle, physical activity, medications, and reproductive factors were not consistent across sites or between genders. CONCLUSION: These results show major geographic variations in rates of BMD change in men and women over 50 years of age across diverse European populations and demonstrate that body weight and weight gain are key determinants of BMD change in men.

Absorptiometry, Photon↗
PubMed2003

Relationship between changes in biochemical markers of bone turnover and BMD to predict vertebral fracture risk.

UNLABELLED: The change in BMD is a poor predictor of vertebral fracture risk after raloxifene treatment. One-year percent change in bone turnover and BMD was used to predict vertebral fracture risk. The percent change in osteocalcin was determined to be a better predictor of vertebral fracture risk than BMD. INTRODUCTION: The association between baseline BMD and fracture risk is well understood. However, the relationship between changes in BMD and fracture risk is not well defined. It has previously been demonstrated that BMD change was a poor predictor of vertebral fracture risk in raloxifene-treated women, whereas bone turnover markers were significantly associated with fracture risk. In the current analysis, we explore the prediction of vertebral fracture risk using changes in both BMD and bone turnover. MATERIALS AND METHODS: The Multiple Outcomes of Raloxifene Evaluation (MORE) trial was a randomized, placebo-controlled trial of 7705 women with osteoporosis treated with raloxifene 60 or 120 mg/day for 3 years. Markers of bone turnover were measured in one-third of the study population (n = 2503), and the present analyses include these women. Logistic regression models were constructed using one-year percent changes in BMD and bone turnover and relevant baseline demographics to predict the risk of vertebral fracture with pooled raloxifene therapy at 3 years. All covariates were standardized before modeling to facilitate direct comparisons between changes in BMD and bone turnover. RESULTS AND CONCLUSION: Prevalent vertebral fracture status (p < 0.0001), baseline lumbar spine BMD (p < 0.0001), and number of years postmenopausal (p = 0.0005) were independent predictors of fracture risk in raloxifene-treated patients. Therapy-by-change in femoral neck BMD (p = 0.02) and therapy-by-change in osteocalcin (OC; p = 0.01) were also significant for all treatment groups, indicating that changes in BMD and OC have different effects on fracture risk for the placebo and pooled raloxifene groups. The final model included significant baseline variables and change in OC (p = 0.01), whereas change in femoral neck BMD was not significant. After adjustment of each significant baseline variable, the percent change in OC was better able to predict the reduction in vertebral fracture risk than the percent change in femoral neck BMD in patients treated with raloxifene.

Aged↗
PubMed2005

Reduced training is associated with increased loss of BMD.

UNLABELLED: This 8-year controlled, follow-up study in 66 Swedish soccer women evaluated the effect of training and reduced training on BMD. The players who retired during the follow-up lost BMD in the femoral neck, whereas the controls did not. INTRODUCTION: Physical activity during adolescence increases BMD, but whether the benefits are retained with reduced activity is controversial. MATERIALS AND METHODS: At baseline, DXA evaluated BMD in 48 active female soccer players with a mean age of 18.2 +/- 4.4 (SD) years, in 18 former female soccer players with a mean age of 43.2 +/- 6.2 years and retired for a mean of 9.4 +/- 5.3 years, and in 64 age- and sex-matched controls. The soccer women were remeasured after a mean of 8.0 +/- 0.3 years, when 35 of the players active at baseline had been retired for a mean of 5.3 +/- 1.6 years. RESULTS AND CONCLUSIONS: The players still active at follow-up had a higher BMD at baseline than the matched controls in the femoral neck (FN; 1.13 +/- 0.19 versus 1.00 +/- 0.13 g/cm2; p = 0.02). The yearly gain in BMD during follow-up was higher in the active players than in the controls in the leg (0.015 +/- 0.006 versus 0.007 +/- 0.012 g/cm2, p = 0.04). The soccer players who retired during follow-up had a higher BMD at baseline than the matched controls in the FN (1.13 +/- 0.13 versus 1.04 +/- 0.13 g/cm2; p = 0.005). The players that retired during follow-up lost BMD, whereas the controls gained BMD during the study period in the FN (-0.007 +/- 0.01 versus 0.003 +/- 0.02 g/cm2 yearly; p = 0.01). The soccer players already retired at baseline had higher BMD at study start than the matched controls in the leg (1.26 +/- 0.09 versus 1.18 +/- 0.10 g/cm2; p = 0.01). The former players who were retired at study start lost BMD, whereas the controls gained BMD during the study period in the trochanter (-0.006 +/- 0.01 versus 0.004 +/- 0.014 g/cm2 yearly; p = 0.01). This study shows that, in girls, intense exercise after puberty is associated with higher accrual of BMD, and decreased physical activity in both the short-term and long-term perspective is associated with higher BMD loss than in controls.

Absorptiometry, Photon↗
PubMed2005

Predictive value of BMD for hip and other fractures.

UNLABELLED: The relationship between BMD and fracture risk was estimated in a meta-analysis of data from 12 cohort studies of approximately 39,000 men and women. Low hip BMD was an important predictor of fracture risk. The prediction of hip fracture with hip BMD also depended on age and z score. INTRODUCTION: The aim of this study was to quantify the relationship between BMD and fracture risk and examine the effect of age, sex, time since measurement, and initial BMD value. MATERIALS AND METHODS: We studied 9891 men and 29,082 women from 12 cohorts comprising EVOS/EPOS, EPIDOS, OFELY, CaMos, Rochester, Sheffield, Rotterdam, Kuopio, DOES, Hiroshima, and 2 cohorts from Gothenburg. Cohorts were followed for up to 16.3 years and a total of 168,366 person-years. The effect of BMD on fracture risk was examined using a Poisson model in each cohort and each sex separately. Results of the different studies were then merged using weighted coefficients. RESULTS: BMD measurement at the femoral neck with DXA was a strong predictor of hip fractures both in men and women with a similar predictive ability. At the age of 65 years, risk ratio increased by 2.94 (95% CI = 2.02-4.27) in men and by 2.88 (95% CI = 2.31-3.59) in women for each SD decrease in BMD. However, the effect was dependent on age, with a significantly higher gradient of risk at age 50 years than at age 80 years. Although the gradient of hip fracture risk decreased with age, the absolute risk still rose markedly with age. For any fracture and for any osteoporotic fracture, the gradient of risk was lower than for hip fractures. At the age of 65 years, the risk of osteoporotic fractures increased in men by 1.41 per SD decrease in BMD (95% CI = 1.33-1.51) and in women by 1.38 per SD (95% CI = 1.28-1.48). In contrast with hip fracture risk, the gradient of risk increased with age. For the prediction of any osteoporotic fracture (and any fracture), there was a higher gradient of risk the lower the BMD. At a z score of -4 SD, the risk gradient was 2.10 per SD (95% CI = 1.63-2.71) and at a z score of -1 SD, the risk was 1.73 per SD (95% CI = 1.59-1.89) in men and women combined. A similar but less pronounced and nonsignificant effect was observed for hip fractures. Data for ultrasound and peripheral measurements were available from three cohorts. The predictive ability of these devices was somewhat less than that of DXA measurements at the femoral neck by age, sex, and BMD value. CONCLUSIONS: We conclude that BMD is a risk factor for fracture of substantial importance and is similar in both sexes. Its validation on an international basis permits its use in case finding strategies. Its use should, however, take account of the variations in predictive value with age and BMD.

Absorptiometry, Photon↗
PubMed2005

Polymorphisms of the CLCN7 gene are associated with BMD in women.

UNLABELLED: Here we show that a common polymorphism causing a valine to methionine amino acid substitution at codon 418 (V418M) in the CLCN7 gene is associated with femoral neck BMD in women. Our study adds to accumulating evidence that shows that common allelic variants in monogenic bone disease genes often contribute to BMD regulation in normal subjects. INTRODUCTION: The CLCN7 gene is a strong candidate for regulation of BMD, because mutations in CLCN7 cause some forms of osteopetrosis, a disease characterized by impaired osteoclast function and increased BMD. In this study, we sought to determine whether common allelic variation within CLCN7 was associated with BMD in the normal population. MATERIALS AND METHODS: We conducted mutation screening of the exons and intron-exon boundaries in CLCN7 by DNA sequencing in 50 normal subjects. We conducted an association study between common polymorphisms in CLCN7 and haplotypes defined by these polymorphisms and BMD values at the lumbar spine and femoral neck in a population-based cohort study of 1077 Scottish women 45-55 years of age. RESULTS: We identified 24 polymorphisms, but most were rare and only 4 had allele frequencies of >5%. These were a conservative single nucleotide polymorphism (SNP) in exon 1 (rs3751884), a 50-bp tandem repeat polymorphism within intron 8, and two SNPs within exon 15 (rs12926089 and rs12926669), of which one (rs12926669) predicts an amino acid change from valine to methionine at codon 418 (V418M). The exon 15 SNPs were in strong linkage disequilibrium and were both associated with femoral neck BMD (p = 0.001-0.003). None of the other polymorphisms were associated with BMD, and long-range haplotypes showed a much weaker association with BMD than the exon 15 SNPs. The V418M polymorphism was an independent predictor of femoral neck BMD on multiple regression analysis accounting for 1% of the variance in BMD at this site. CONCLUSIONS: Our study indicates that the V418M polymorphism of CLCN7 contributes to the genetic regulation of femoral neck BMD in women and adds to accumulating evidence that indicates that subtle polymorphic variation in genes that cause monogenic bone diseases also contribute to regulation of BMD in normal subjects.

Adult↗
PubMed2006

QCT versus DXA in 320 survivors of childhood cancer: association of BMD with fracture history.

PURPOSE: To assess agreement on diagnosis of diminished bone mineral density (BMD) and correlation between BMD values obtained by dual-energy X-ray absorptiometry (DXA) and quantitative computed tomography (QCT) in childhood cancer survivors. PATIENTS AND METHODS: We retrospectively reviewed lumbar spine QCT and DXA studies for BMD in patients who underwent both imaging studies within a 24-hr period. We determined correlation between BMD values and agreement on diagnosis of diminished BMD obtained by both modalities. Diminished BMD was defined as two or more SDs below mean for age- and gender-matched reference values. We evaluated the relationship of BMD values determined by each modality to self-reported fracture history in the 160 (50%) patients with available reports. RESULTS: Of 320 patients, 56% (178) were male; 87% (277) were white. Median age was 16.4 (range, 5.1-36.0) years. Median BMD Z-score was -1.43 (range, -5.96 to 3.20) by QCT and -1.30 (range, -5.50 to 2.80) by DXA. Correlation between QCT- and DXA-determined BMD values was significant but low, and agreement on diminished BMD was fair (kappa = 0.32). There was no association between BMD measured by either QCT or DXA and self-reported traumatic fracture history. Male gender was associated with doubling the traumatic fracture risk (P = 0.0499). CONCLUSIONS: Quantitative computed tomography and DXA may give discrepant results when used to assess bone health in childhood cancer survivors, especially in those of non-white race. This inconsistency in indicators of BMD deficiency may complicate clinical decision-making. Consecutive use of a single modality is recommended to provide reliable longitudinal information.

Absorptiometry, Photon↗
PubMed2003

Hip section modulus, a measure of bending resistance, is more strongly related to reported physical activity than BMD.

We hypothesized that measures of physical activity would have a closer relationship with section modulus (SM), an indicator of bending resistance, than with bone mineral density (BMD) because physical activity might expand the bony envelope, which tends to reduce BMD for a constant bone mineral content. Four hundred twenty-three men and 436 women (mean age 72 years, SD =3) were recruited from a prospective population-based cohort study to a study of hip bone loss. Hip BMD was measured on two occasions 2-5 years apart (mean 2.7, DXA-Hologic 1,000 W). Hip structural analysis (HSA) software was used to calculate SM and BMD from the DXA scans on three narrow regions: the narrow neck (NN), intertrochanter (IT) and shaft (S). A physical activity and lifestyle questionnaire was administered at baseline. Multivariate repeated measures analysis of variance was used to model the associations between personal attributes (weight, height, age), physical activity and lifestyle variables with SM, cross-sectional area (CSA), sub-periosteal diameter (PD) and BMD. Men and women were analysed together after tests for interactions with gender, which were found not to be significant. In all regions female gender was associated with having lower values of all outcomes, and body weight was positively associated with all outcomes, i.e., SM, CSA, PD and BMD ( P<0.0001). Sub-periosteal diameter was positively associated with reported lifetime physical activity (IT and S, P<0.0001). There was a significant decline of BMD with age at the NN and S regions ( P<0.026), and the PD increased with age (NN and S, P<0.019). Previous fracture history was associated with having lower values of BMD, SM and CSA (except for S; P<0.022). Both section modulus and CSA were positively associated with heavy physical activity after age 50 years in all regions ( P<0.019), whereas NN BMD was the only BMD associate of heavy physical activity after 50 ( P=0.036). Time spent per week on recreational activities classified as no impact activity was positively associated with BMD, CSA and SM (multivariate P<0.016). In conclusion, proximal femur diameter is associated positively with reported life-long physical activity. If this is mediated through a loading related effect on sub-periosteal expansion, BMD would be an unsatisfactory outcome measure in physical activity studies since it is inversely related to projected bone area. SM in contrast was associated with several measures of recent physical activity and relates more directly to the bending experienced by the proximal femur in response to a given load. These data are consistent with an effect of mechanical loading to regulate bone strength through an anabolic effect maximal in the subperiosteal cortex, where the highest loading-related strains are experienced.

Absorptiometry, Photon↗
PubMed2004

Differential effects of teriparatide on BMD after treatment with raloxifene or alendronate.

UNLABELLED: We investigated the effects of 18 months of treatment with teriparatide in patients previously treated with long-term antiresorptive therapy using bone turnover markers and bone densitometry. Previous raloxifene treatment allowed for teriparatide-induced early bone marker and BMD increases comparable with previously published results for treatment-näive patients. Conversely, previous alendronate treatment reduced the bone marker and BMD response. INTRODUCTION: Teriparatide [rhPTH(1-34)] has been shown to increase BMD and reduce the risk of fracture in postmenopausal women with osteoporosis. Our objective was to investigate the skeletal effects of 18 months of treatment with teriparatide in women whose osteoporosis was previously treated with either alendronate or raloxifene. MATERIALS AND METHODS: Daily subcutaneous injections of 20 microg teriparatide were administered for 18 months to 59 postmenopausal women, 60-87 years of age, with BMD T-scores </= -2.0 who had previously received either alendronate (ALN) or raloxifene (RLX) therapy for 18-36 months. All patients received daily calcium (1000 mg) and vitamin D (400 IU) supplementation. The primary study outcome was change in lumbar spine BMD measured by DXA. Secondary outcomes included changes in bone turnover markers, total hip BMD, and safety. RESULTS: Median baseline bone turnover marker levels in prior ALN patients were about one-half those of prior RLX patients. During teriparatide treatment, bone markers in prior ALN patients increased later and peaked at about one-third lower levels compared with prior RLX patients. During the first 6 months, there were statistically significant (p < 0.05) group differences in BMD change at the hip (prior ALN -1.8% versus prior RLX +0.5%) and at the spine (prior ALN +0.5% versus prior RLX +5.2%). The positive slopes in hip and lumbar spine BMD were similar in both groups between 6 and 18 months. After 18 months, mean lumbar spine BMD increased 10.2% in prior RLX compared with 4.1% in prior ALN (p < 0.05) patients. Furthermore, at 18 months, mean total hip BMD had significantly increased (1.8%, p < 0.05) in prior RLX patients but was not different from baseline in prior ALN patients. CONCLUSIONS: Teriparatide treatment stimulates bone turnover in patients pretreated with both RLX and ALN. Prior treatment with RLX allows for the expected teriparatide-induced BMD increases comparable with those previously reported for treatment-näive patients. In contrast, prior treatment with ALN prevents increases in BMD, particularly in the first 6 months.

Aged↗
PubMed2005

Early changes in biochemical markers of bone formation predict BMD response to teriparatide in postmenopausal women with osteoporosis.

UNLABELLED: The relationship between early changes in biochemical markers of bone turnover and the subsequent BMD response to daily teriparatide therapy in women with postmenopausal osteoporosis was studied. Changes in five biochemical markers, obtained from a subset of women enrolled in the Fracture Prevention Trial, were examined. Early increases in the PICP and the PINP were the best predictors of BMD response to teriparatide in this analysis. INTRODUCTION: Early reductions in biochemical markers of bone turnover with antiresorptive therapy negatively correlate with subsequent increases in BMD. We undertook this analysis to determine if early changes in biochemical markers with teriparatide therapy predict subsequent increases in BMD. MATERIALS AND METHODS: In the Fracture Prevention Trial, 1637 postmenopausal women with osteoporosis were randomized to receive daily, self-administered, subcutaneous injections of placebo, teriparatide 20 microg/day, or teriparatide 40 microg/day. Serum concentrations of two bone formation markers (bone-specific alkaline phosphatase [bone ALP] and the carboxy-terminal extension peptide of procollagen type 1 [PICP]) and urinary concentrations of two bone resorption markers (free deoxypyridinoline [DPD] and N-terminal telopeptide [NTX]) were assessed in a trial population subset (n = 520) at baseline and at 1, 3, 6, and 12 months. We also assessed serum concentrations of another bone formation marker, the amino-terminal extension peptide of procollagen type 1 (PINP), in a subset of 771 women at baseline and 3 months. Lumbar spine (LS) BMD was measured by DXA at baseline and 18 months. Femoral neck BMD was measured at baseline and 12 months. RESULTS AND CONCLUSION: Baseline bone turnover status correlated positively and significantly with BMD response. The highest correlations occurred for the LS BMD response to teriparatide 20 microg/day. Among all studied biochemical markers, increases in PICP at 1 month and PINP at 3 months correlated best with increases in LS BMD at 18 months (0.65 and 0.61, respectively; p < 0.05). The relationships between these two biochemical markers and the LS BMD response were stronger than the corresponding relationships for the femoral neck BMD response. Using receiver operator curve analysis, we determined that the increases in PICP at 1 month and PINP at 3 months were the most sensitive and accurate predictors of the LS BMD response.

Adult↗