Early and Late Postmenopausal Bone Loss is Associated with BsmI Vitamin D Receptor Gene Polymorphism in Japanese Women

To determine whether vitamin D receptor (VDR) gene polymorphisms are associated with bone mineral density (BMD) and bone loss in the Japanese population, VDR BsmI RFLPs were analyzed in 191 postmenopausal Japanese women by comparing B allele and b allele DNA sequences, and a point mutation was confirmed. We examined VDR BsmI restriction fragment length polymorphism (RFLP) with an amplification refractory mutation system (ARMS) using this point of mutation. The frequency of VDR BsmI alleles in the Japanese population was significantly different from that in whites. The bb genotype was identified in 79.6%, of the subjects, the Bb genotype in 19.3%, and the BB genotype was in only 1.1%. We find no significant differences in lumbar spine baseline BMD between the bb genotype and the Bb genotype. In both early and late postmenopausal periods, serial measurements of vertebral BMD revealed that subjects with the Bb genotype lost BMD faster than those with the bb genotype (P= 0.001). We conclude that there is a significant relationship between RFLPs of BsmI VDR and the annual rates of bone loss during early and late postmenopausal periods in the Japanese population. Received: 14 May 1997 / Accepted: 9 July 1998     

Polymorphism of the Vitamin D Receptor Gene and Corticosteroid-Related Osteoporosis

Corticosteroid therapy (CST) is associated with reduced intestinal calcium absorption, bone loss and increased fracture risk. As polymorphisms of the vitamin D receptor (VDR) gene may be associated with bone mineral density (BMD) and intestinal calcium absorption, we asked whether patients with a given VDR genotype receiving CST may be at increased or decreased risk for corticosteroid-related bone loss and osteoporosis. We measured areal BMD (g/cm²) by dual-energy X-ray absorptiometry in 193 women (50 premenopausal, 143 postmenopausal) and 70 men with rheumatoid arthritis (n= 44), obstructive airway diseases (n= 128) and other corticosteroid-treated diseases (n= 91). All patients received a cumulative dose greater than 1.8 g per year or a minimum of 5 mg daily of prednisolone or equivalent for at least 1 year. VDR alleles were typed by polymerase chain reaction assay based on the polymorphic BsmI and TaqI restriction sites. BMD in patients was expressed as a Z-score (mean ± SEM) derived from age- and gender-matched controls. BMD was reduced in patients at the lumbar spine (bb, −0.52 ± 0.12; Bb, −0.47 ± 0.11; BB, −0.65 ± 0.18 SD; p<0.01), femoral neck (bb, −0.46 ± 0.10; Bb, −0.34 ± 0.10; BB, −0.54 ± 0.14 SD; p<0.01), Ward’s triangle (bb, −0.44 ± 0.10; Bb, −0.31 ± 0.10; BB, −0.45 ± 0.13 SD; p<0.01), and trochanter (bb, −0.50 ± 0.10; Bb, −0.30 ± 0.10; BB, −0.44 ± 0.14 SD; p<0.01). However, there was no significant difference in the deficit in BMD in any of the genotypes, either before or after adjusting for age, sex, body mass index, disease type, age at onset of disease, disease duration, cumulative steroid dosage, smoking status and dietary calcium intake. Similarly, there were no detectable differences between the BsmI genotypes and the rate of bone loss in 79 patients with repeated BMD measurements at an interval of 4–48 months. The data suggest that the VDR genotypes may not be a means of identifying patients at greater risk of corticosteroid-related bone loss. Received: 23 December 1997 / Accepted: 26 May 1998     

VDR Genotype and Response to Etidronate Therapy in Late Postmenopausal Women

Twenty-four late postmenopausal women with osteoporosis were studied. The patients were separated in three subgroups according to the BsmI polymorphism of the vitamin D receptor (VDR) gene: BB (n= 8), Bb (n = 10) and bb (n = 6). They did not differ in age (mean ages were 66.0 years, 65.9 years and 63.9 years, respectively), years after menopause (18.7 years, 18.1 years and 18.4 years) or body weight (64.9 kg, 65.3 kg and 63.8 kg), the variables known to be associated with bone mineral density (BMD). The results show that the response to antiresorptive bisphosphonate therapy in combination with calcium supplementation is modified by VDR genotype. The lumbar spine BMD increased significantly faster in the BB and Bb groups (7.3% and 7.0%, respectively) compared with the bb group (2.5%) during 1 year of cyclic etidronate therapy (400 mg/day) and calcium supplementation (1000 mg/day). The biochemical marker of bone resorption (urinary hydroxyproline excretion) as well as the bone formation marker (serum levels of osteocalcin) decreased during the treatment. With respect to VDR genotype, a significantly higher decrease in osteocalcin level was observed in bb as compared with BB subjects. We conclude that the VDR genotype is involved in an individual’s response to cyclic etidronate therapy with calcium supplementation. Received: 12 December 1998 / Accepted: 18 March 1999     

Association of Methylenetetrahydrofolate Reductase (MTHFR) Polymorphism with Bone Mineral Density in Postmenopausal Japanese Women

The pathogenesis of osteoporosis is controlled by genetic and environmental factors. Considering the high prevalence of osteoporosis in homocystinuria, abnormal homocysteine metabolism would contribute to the pathogenesis of osteoporosis. It is known that the polymorphism of methylenetetrahydrofolate reductase (MTHFR), the enzyme catalyzing the reduction of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, correlates with hyperhomocysteinemia. In this study, we examined the association of this polymorphism with bone mineral density (BMD). BMD was measured by dual-energy X-ray absorptiometry (DXA) in 307 postmenopausal women. MTHFR A/V polymorphism was analyzed using polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP). We compared BMD, clinical characteristics, and bone metabolic markers among MTHFR groups (AA, AV, VV). The groups did not differ in terms of baseline data. The values of lumbar spine BMD and total body BMD were as follows: lumbar spine: AA, 0.91 ± 0.18, AV, 0.88 ± 0.16, VV, 0.84 ± 0.14 g/cm²; total body: AA, 0.97 ± 0.11, AV, 0.96 ± 0.11, VV, 0.93 ± 0.09 g/cm². In the VV genotype, lumbar spine BMD values were significantly lower than those of the women with the AA genotype (P= 0.016) and total body BMD was significantly lower than those of the women with AA genotype (P= 0.03) and AV genotype (P= 0.04). This is the first report that suggests that the VV genotype of MTHFR is one of the genetic risk factors for low BMD. Received: 29 March 1999 / Accepted: 20 September 1999     

Lateral Spine Densitometry in Obese Women

The lateral (LAT) spine scan has been suggested as a more sensitive measure than posterior-anterior (PA) scanning for assessing age-related bone loss in normal-weight postmenopausal women. The measurement error of PA and LAT bone mineral density (BMD) using dual energy X-ray absorptiometry (DXA) has also been shown to rise with incremental increases in fat and from large variance in fat thickness, respectively. The purpose of this cross-sectional study was to determine specific affects of obesity on paired PA and LAT lumbar (L₂–L₄) BMD and Z score (BMD of patient versus age-matched reference database) correlation in 30 obese postmenopausal women (mean BMI ± SD = 33.3 ± 4.06). The mean PA and LAT BMD ± SD were 0.946 ± 0.123 and 0.749 ± 0.134, respectively. The mean PA and LAT Z scores were −0.17 ± 1.15 and 0.80 ± 1.7. The correlation between PA and LAT BMD was significantly lower (r = 0.55; P < 0.05) than previously reported, and PA and LAT Z score correlation was (r = 0.57; P= 0.0016). After adjusting for body mass index (BMI), percent body fat, fat mass, and truncal fat by DXA, waist:hip ratio (WHR) and visceral and subcutaneous abdominal fat by computerized axial tomography (CT), PA and LAT Z score correlation increased to r = 0.62; P= 0.0065. In our subjects, the mean LAT Z score was 4.6 times higher than the mean AP Z, contrary to previous observations in normal-weight postmenopausal women. Our findings may be due to increased soft tissue composition and fat inhomogeneity in the LAT scanning field resulting in increased X-ray attenuation in obesity. Received: 22 July 1997 / Accepted: 26 January 1998     

Vitamin D and Estrogen Receptor Polymorphisms and Bone Mineral Changes in Postpartum Women

BsmI restriction fragment length polymorphism (RFLP) of the vitamin D receptor (VDR) gene and PvuII RFLPs of the estrogen receptor (ER) gene and their relation to changes in areal bone mineral density (BMD) were examined in 43 healthy postpartum Finnish women aged 31.3 (SD 4.7) years. BMD was measured by dual energy X-ray absorptiometry at lumbar spine, right femoral neck, and dominant distal radius immediately after delivery, 1 month after resumption of menses, and 1 year thereafter. The RFLPs were represented as Bb (BsmI) and Pp (PvuII), the capital letters denoting the absence of and the small letters the presence of the restriction sites. The frequency of VDR alleles was as follows: bb (20.9%), Bb (60.5%), and BB (18.6%), and that of ER alleles was pp (39.5%), Pp (51.2%), and PP (9.3%). Altogether, BMD decreased significantly during postpartum amenorrhea at all sites [the mean bone loss ranging from −1.2 (SD 3.6)% at the distal radius to −3.7 (2.9)% at the femoral neck], and increased after resumption of menses [the 1-year follow-up BMD values ranging from −1.0 (2.4)% at the femoral neck to +3.3 (4.0)% at the lumbar spine as compared with baseline]. No obvious genotype-related differences were found between these changes. These results suggest that the BsmI and PvuII polymorphisms may not have substantial influence on BMD changes postpartum. Received: 20 November 1998 / Accepted: 30 September 1999     

Correlation Between Vitamin D Receptor Genotypes and Bone Mineral Density in Japanese Patients with Osteoporosis

In order to better understand the pathogenesis of osteoporosis, we investigated the correlation between the vitamin D receptor (VDR) genotypes defined by BsmI restriction enzyme, as well as other related factors, and the bone mineral density (BMD) at the lumbar spine in 90 Japanese patients with osteoporosis. The same study was performed in 36 patients with osteoarthrosis of the hip joint and 92 healthy volunteers. The majority of the VDR genotypes were bb, and a few of the population showed either the BB or Bb genotype in all three groups. There was no statistical difference in the frequencies of these VDR genotypes in the three groups. The mean age-matched value of BMD (Z scores) at the lumbar spine in patients with osteoporosis was significantly lower than that in patients with osteoarthrosis or healthy volunteers. The mean Z scores of the healthy volunteers with bb genotype were significantly higher than those with BB genotype, whereas those of the osteoporosis patients with BB genotype were significantly higher than those with Bb genotype. There was no significant difference in the mean Z scores between bb and Bb genotypes in patients with osteoporosis and healthy volunteers. No significant difference was seen in the mean Z scores in patients with osteoarthrosis regardless of genotype. On the other hand, body weight significantly correlated with BMD in patients with osteoporosis by simple- and multiple-regression analysis. These results indicate that the BMD at the lumbar spine in Japanese patients with osteoporosis is affected by body weight, and might be affected partially by the VDR genotypes defined by BsmI. Received: 22 September 1995 / Accepted: 24 September 1996     

Androgen-Receptor Blockade Does Not Impair Bone Mineral Density in Adolescent Females

The effect of peripheral androgen hypersensitivity on bone mineral density (BMD) was investigated in a group of adolescent women with idiopathic hirsutism (n= 17; mean age 17.0 ± 1.7 years). The effect of long-term androgen-receptor blockade with flutamide (500 mg daily in two divided doses for 12 months) on BMD was assessed too. BMD was measured at lumbar spine (L2–L4) by a dual energy X-ray densitometer. Before flutamide treatment, patient BMD (1.14 ± 0.07 g/cm²) was not significantly different from that of the control group (1.16 ± 0.12 g/cm², n= 22), and was normal for age and sex (BMD 0.14 ± 0.69 SDS, P= NS vs. 0). After 12 months of treatment, absolute BMD in patients increased (1.18 ± 0.08 g/cm², P < 0.002), but SDS BMD did not change (0.21 ± 0.72, P= NS vs. baseline). Flutamide treatment determined a clinical, marked improvement of androgen hypersensitivity (Ferriman–Gallwey score: before 22.0 ± 6.2; 6 months: 13.2 ± 6.4, P < 0.003; 12 months; 7.6 ± 4.1, P < 0.001; acne score: before 3.8 ± 0.8; 3 months 0.8 ± 0.5, P < 0.001; later disappeared). The serum levels of 3α-androstenediol-glucoronide decreased (before: 8.6 ± 1.1 μg/liter; 12 months: 7.2 ± 1.0 μg/liter, P < 0.02), whereas the other endocrinological parameters did not change. No relationship was found between BMD and clinical or biochemical parameters of hyperandrogenism. We concluded that in adolescent women, peripheral hyperandrogenism is not associated with abnormal BMD; long-term treatment with flutamide, which blocks the androgen receptor, does not alter their BMD. Received: 19 February 96 / Accepted: 31 December 96     

Vitamin D Receptor Alleles and Bone's Response to Physical Activity

The objective of this prospective controlled study was to determine whether the osteogenic response of bone to mechanical loading is dependent on the vitamin D receptor (VDR) polymorphism. Thirty-five healthy premenopausal women took part in a progressive, high-impact exercise three times a week for a period of 18 months and 45 women served as nonexercising controls. The trainees were divided into three groups: bb (n = 12, 34%); Bb (n = 16, 46%); BB (n = 7, 20%) according to polymorphism at the gene encoding the VDR (BB representing subjects without the restriction enzyme BsmI sites on the two VDR gene alleles). Bone mineral content (BMC) and areal bone mineral density (BMD) were measured at the lumber spine, proximal femur, knee, calcaneus, and dominant distal radius before the beginning of the exercise regimen and at 12 and 18 months of training using dual-energy x-ray absorptiometry (DXA). As an indicator of the total osteogenic effect of the training, ΣBMC was derived by summing up the BMC values of the loaded sites (i.e., the lower limb sites and the lumbar spine). The mean ΣBMC increased 2.0% in the bb group, 3.0% in the Bb group, and 2.8% in the BB group (P= 0.184 for the intergroup difference), but only 0.8% in the controls (exercisers versus controls, P < 0.001). Individuals with the BB genotype of the VDR gene, subjects with whom the BMC can be lower than normal and whose bones can be less responsive to pharmacological therapies than bones of the other individuals, seem to have as good osteogenic response to mechanical loading as subjects with other VDR genotypes. Thus, irrespective of the VDR genotype, physical activity seems to be beneficial for bones of premenopausal women. Received: 14 May 1997 / Accepted: 14 November 1997     

Bone Mineral Density of the Skull in Premenopausal Women

Dual-energy X-ray absorptiometry (DXA) of the head has received little attention. We used DXA to measure bone mineral density (BMD) of the entire skull including the mandible (BMD_Head) and BMD of the cranial vault (BMD_Vault) in 91 normal young women. We also measured BMD of the total body (BMD_{Total body}), proximal femur (``total femur'), and lumbar vertebrae (L1–L4). BMD (g/cm²; mean ± SE) was 1.032 ± 0.011 for L1–L4, 0.995 ± 0.011 for total femur, and 2.283 ± 0.028 for BMD_Vault (cranial vault) and the mean body weight of all subjects was 59.8 kg. Correlation between BMD_Vault and BMD_Head was 0.991 and this was not different from 1.0 (P= 0.473). The average difference between BMD_Vault and BMD_Head was −0.004 g/cm² suggesting that these two measurements of bone mass of the skull were similar. To determine the correlation between the different variables after accounting for external sources of variation, partial correlation derived from multiple regression was determined. Correlations between BMD at the various locations and with BMD_{Total body} were moderate to strong. Although small in magnitude, the partial correlations of body weight with BMD_{Total body}, total femur, and L1–L4 were significantly different from zero (P < 0.02). The results show that BMD_Vault, total femur, and L1–L4 were of equal value in predicting BMD_{Total body} and further, BMD_Vault was not influenced by body weight. Including body weight in multiple regression in addition to total femur or L1–L4 removed the extraneous variation due to body weight, and predictions of BMD_{Total body} were as reliable as when BMD_Vault was based on goodness of fit tests (P= 0.314). The technique used to measure BMD of the cranial vault is a relatively new variation of DXA technology. The precision was as good as other measurements of bone mass of the entire skull (including the mandible). Because the cranial vault is less sensitive to mechanical influences, it may be a region where response to therapy could be evaluated. The cranial vault may be a useful area to study certain heritable diseases that affect the skeleton, skeletal artifact, or evaluation of oral bone loss. Received: 22 December 1995 / Accepted: 24 September 1996     

Vitamin D Receptor Genotypes and Intestinal Calcium Absorption in Postmenopausal Women

Several studies have shown that bone mass and bone turnover are genetically determined. This genetic component is thought to be mediated in part by polymorphisms at the vitamin D receptor (VDR) locus, even though the underlying molecular mechanisms are still unknown. To evaluate a possible site of differential action of the VDR gene alleles we examined their correlation with intestinal calcium absorption in 120 Caucasian postmenopausal women (aged 61 ± 0.6 years). VDR gene polymorphisms for Apa I, Bsm I, and Taq I restriction endonucleases were assessed by Southern blotting analysis. The most common genotypes observed in our population were AaBbTt (37%), AABBtt (20%), aabbTT (15%), AabbTT (15%), and AABbTt (9%). Although there was some evidence of 13% higher lumbar BMD values in aabbTT genotype with respect to AABBtt genotype, this difference of approximately 0.1 g/cm² did not reach statistical significance, possibly because of the limited number of observations. On the contrary, no relationship was found between genotypes and femoral neck BMD values. Intestinal calcium absorption was significantly lower in BB and tt genotypes than, in bb and TT genotypes, respectively, and in AABBtt genotype than in either aabbTT or AaBbTt genotypes (P= 0.0015 ANOVA). No significant differences in intact PTH, alkaline phosphatase, 25OHD₃, and 1,25(OH)₂D₃ were found among subjects with different VDR genotypes. These results are consistent with a possible role of VDR alleles on intestinal calcium absorption.     

Effect of High Impact Activity on Bone Mass and Size in Adolescent Females: A Comparative Study Between Two Different Types of Sports

The purpose of this cross-sectional study was to investigate the influence of two different types of weight-bearing activity, muscle strength, and body composition on bone mineral density (BMD), bone mineral content (BMC), and bone area in three different groups of late adolescent girls. The first group consisted of 10 females participating in competitive rope-skipping (age 17.8 ± 0.8 years) training for 6.7 ± 3.1 hours/week; the second group consisted of 15 soccer players (age 17.4 ± 0.8 years) training for 6.1 ± 2.0 hours/week; and the third group consisted of 25 controls (age 17.6 ± 0.8 years) with physical activity of 0.9 ± 1.1 hours/week. The groups were matched for age, height, and weight. BMD (g/cm²), BMC (g), and bone area (cm²) of the total body, lumbar spine, hip, total femur, distal femur, diaphyses of femur and tibia, proximal tibia, and humerus were measured using dual-energy X-ray absorptiometry (DXA). Bone density was also assessed in the radial forearm site of the dominant limb in the rope skippers and in 10 matched controls. The rope skippers had 22% higher BMD at the ultradistal site (P < 0.01). Both high-activity groups had significantly higher BMD (P < 0.05) at most loaded sites compared with the control group. When adjusting for differences in lean mass and starting age of sport-specific training between the activity groups, the rope-skipping group had a higher BMD of the total body, lumbar spine, and right humerus compared with the soccer group. They also had a significantly higher bone area of the total body, total femur, and the proximal femur than both other groups, and a significantly higher bone area of the tibia diaphysis, compared with the soccer group. In a multivariate analysis among all subjects (n = 50), all BMD sites, except the femur diaphysis, distal femur, and proximal tibia, were significantly related to type of physical activity (β= 0.25–0.43, P < 0.05). The bone area values at different sites were strongly related to muscle strength and parameters related to body size [height, weight, lean mass, fat mass, and body mass index (BMI)]. In conclusion, it appears that in late adolescent women, weight-bearing activities are an important determinant for bone density, and high impact activities such as jumping also seem to be associated with a modification of the bone geometry (hence, the bone width) at the loaded sites. Received: 28 June 1999 / Accepted: 22 March 2000     

Does the vitamin D receptor genotype predict bone mineral loss in haemodialysed patients?

Background. It has been suggested that the vitamin D receptor (VDR) gene BsmI-polymorphism is a genetic determinant of bone metabolism. Design. To test this hypothesis, the relationship between VDR genotypes, bone mineral density (baseline and after 18 months) and parameters of calcium metabolism and bone turnover were investigated prospectively in 88 haemodialysed patients not receiving active vitamin D metabolites. Methods. Whole body, lumbar spine and femoral neck bone mineral density (BMD) were assessed by dual energy X-ray absorptiometry (DEXA). In addition calcium, phosphorus, 25(OH)D3, 1,25(OH)2D3, osteocalcin serum concentrations, alkaline phosphatase activity and intact, 1,84 PTH levels were measured. Results. VDR genotype BB, Bb and bb were found in 27, 49 and 24% of patients. Initial BMD (g/cm²) of whole body, lumbar spine and femoral neck did not differ between genotypes (whole body: BB 1.055 ± 0.120, Bb 1.082 ± 0.102, bb 1.128 ± 0.120; lumbar spine: BB 1.075 ± 0.199, Bb 1.079 ± 0.185, bb 1.099 ± 0.170; femoral neck: BB 0.808 ± 0.160, Bb 0.862 ± 0.127, bb 0.842 ± 0.125; mean ± SD), but the decrease of whole body and femoral neck BMD during 18 months was significantly (P < 0.02) different between the genotype groups (whole body: BB -0.048 ± 0.028, Bb -0.031 ± 0.029, bb -0.024 ± 0.023; femoral neck BB -0.044 ± 0.069, Bb -0.032 ± 0.081, bb -0.012 ± 0.029 g/cm²). Conclusions. This preliminary study suggests faster mineral loss in BB genotype of VDR in haemodialysed patients.     

Circulating β2 Microglobulin in Relation to Bone Metabolism: Implications for Bone Loss with Aging

The aim of this cross-sectional study was to evaluate the relationships between circulating β₂ microglobulin (β₂ m) and bone mineral density (BMD), parameters of bone remodeling, vitamin D metabolites, parathyroid hormone (PTH), estradiol levels, and age in a group of 165 clinically healthy or osteoporotic, but otherwise normal untreated women. In this group of women, systemic β₂ m correlated with BMD (g/cm²) levels for total hip and Ward's triangle (r =−0.298, P < 0.0001; and r =−0.299, P < 0.0001, respectively), but only at the borderline level with BMD at the spine (r =−0.145, P= 0.0604). Serum β₂ microglobulin markedly correlated with age (r = 0.512, P= 0.0001). β₂ m levels correlated with indices of bone remodeling, as well as with serum creatinine and estradiol levels. However, after stratification of all analyses by age, body mass index, and serum 25OHD₃, 1,25(OH)₂D₃, PTH, or estradiol levels (using standard multiple regression and stepwise forward regression models), only 25OHD₃ was found to be an independent predictor of BMD at the hip, including Ward's triangle, as estradiol of BMD at the spine. On the other hand, β₂ m was not associated with BMD at any of the measured regions. Also, no association was found between serum PTH and BMD values. Therefore, systemic β₂ m seems to be an indicator of bone remodeling in the course of natural skeletal aging rather than a variable independently predicting bone loss. Received: 21 July 1998 / Accepted: 10 June 1999     

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     

Bone Mineral Density and Bone Turnover in Patients with Knee Osteoarthritis Compared with Generalized Osteoarthritis

The aim of this study was to investigate bone mineral density (BMD) and bone turnover in patients with primary knee osteoarthritis (KOA) and to compare them with generalized OA (GOA) and nonGOA patients. A total of 88 postmenopausal primary KOA patients were studied. OA was graded by using knee radiographs. BMD of the lumber spine, femur, and radius, and biochemical markers of bone turnover, pyridinoline (Pyr), deoxypyridinoline (Dpyr), CTx, and osteocalcin were compared among each grade. BMD was also compared with 88 normal controls who were age and weight-matched. In 88 KOA patients, 56 were divided into 28 GOA and 28 non-GOA groups by grading hand radiographs. BMD and biochemical markers were compared between GOA and non-GOA. KOA patients had higher BMD at several skeletal sites compared with age- and weight-matched normals. A significant difference of BMD between each grade was observed between grades 0–1 and 3 (0.774 ± 0.143 versus 0.940 ± 0.185 g/cm², P < 0.001), grades 2 and 3 (0.781 ± 0.125 versus 0.940 ± 0.185 g/cm², P < 0.01) in the spine, and between grades 0–1 and 3 (0.505 ± 0.100 versus 0.564 ± 0.127 g/cm², P < 0.05) in the trochanter. A significant difference of biochemical bone markers was observed between grades 0–1 and 3 (P < 0.05) and between grades 2 and 3 (P < 0.05) in Pyr and grades 0–1 and 3 (P < 0.05) and between grades 1 and 4 (P < 0.05) in Dpyr, but not in osteocalcin and CTx. GOA patients had higher BMD of the spine (0.902 ± 0.175 versus 0.747 ± 0.138 g/cm², P < 0.01), trochanter (0.535 ± 0.107 versus 0.480 ± 0.107 g/cm², P < 0.05), and one-third of the radius (0.526 ± 0.068 versus 0.472 ± 0.089 g/cm², P < 0.05) and had significantly higher biochemical markers in Pyr and Dpyr than non-GOA patients. It is concluded that KOA patients had higher BMD at several skeletal sites. Biochemical bone markers were influenced by some degree of cartilage damage in OA patients. This tendency was stronger in GOA patients than in non-GOA patients. Received: 12 February 1999 / Accepted: 2 November 1999     

Bone Mineral Content and Density in Professional Tennis Players

Total and regional bone mineral content (BMC) as well as lean and fat mass were measured in nine male professional tennis players (TPs) and 17 nonactive subjects; dual-energy X-ray absorptiometry (DXA) was used for measuring. The mean (±SD) age, body mass, and height were 26 ± 6 and 24 ± 3 years, 77 ± 10 and 74 ± 9 kg, and 180 ± 6 and 178 ± 6 cm for the TP and the control group (CG), respectively. The whole body composition for BMC, lean mass, and fat of the TP was similar to that observed in the CG. The tissue composition of the arms and legs was determined from the regional analysis of the whole-body DXA scan. The arm region included the hand, forearm, and arm, and was separated from the trunk by an inclined line crossing the scapulo-humeral joint. In the TP, the arm tissue mass (BMC + fat + lean mass) was about 20% greater in the dominant compared with the contralateral arm because of a greater lean (3772 ± 500 versus 3148 ± 380 g, P < 0.001) and BMC (229.0 ± 43.5 versus 188.2 ± 31.9 g, P < 0.001). In contrast, no significant differences were observed either in BMC or BMD between arms in the CG. Total mass, lean mass, and BMC were greater in the dominant arm of the TP than in the CG (all P < 0.05). In the TP, BMD was similar in both legs whereas in the CG, BMD was greater in the right leg. Lumbar spine (L2–L4) BMD, adjusted for body mass and height, was 15% greater in the TP than in the CG (P < 0.05). Femoral neck BMDs (femoral neck, Ward's triangle, greater trochanter, and intertrochanteric regions) adjusted for body mass and height were 10–15% greater in the TP (all P < 0.05). Ward's triangle BMD was correlated with the maximal leg extension isometric strength (r = 0.77, P < 0.05) even when adjusted for body mass (r = 0.76, P < 0.05) and height (r = 0.77, P < 0.05). In summary, the participation in tennis is associated with increased BMD in the lumbar spine and femoral neck. These results may have implications for devising exercise strategies in young and middle-aged persons to prevent involutional osteoporosis later in life. Received: 29 April 1997 / Accepted: 14 November 1997     

Biochemical Markers as Predictors of Bone Mineral Density Changes After GnRH Agonist Treatment

To evaluate bone biochemical markers as predictors of the efficacy of a hormone replacement therapy (HRT), we studied the bone changes induced by the cessation and return of ovarian function in 28 patients treated for 6 months with a GnRH agonist. This model reproduced the effects observed in postmenopausal women with high bone turnover treated with HRT. At the end of the treatment, Z scores were 1.8 ± 0.3 for Crosslaps (CTx) and deoxypyridinoline (D-Pyr), and 1.1 ± 0.2 for bone alkaline phosphatase (B-ALP) and osteocalcin (OC). This indicated an imbalance in bone remodeling with a high bone resorption. Bone mineral density (BMD) fell by 4.2 ± 2.5%. The changes in BMD between the 6th and 12th months were 0.34 ± 2.24 and −1.73 ± 3.25% at the lumbar spine and the femoral neck, respectively. Biochemical markers except urinary calcium and hydroxyproline measured at 6 months were positively correlated with the BMD changes at the lumbar spine. After the resumption of menstruation, 13 of 28 women displayed positive spine BMD changes between the 6th and 12th months; in this group, bone biochemical markers measured at 6 months were significantly higher (P= 0.02). Stepwise regression analysis showed that the association of B-ALP and D-Pyr measured at 6 months explained 40% of BMD variance and the association of B-ALP, PTH, and estradiol 56%. We conclude that measuring individual biochemical bone markers can help to predict the bone effect of an increase in the circulating estradiol in women with ovarian deficiency. Received: 16 January 1997 / Accepted: 17 June 1997     

Net Fluxes Over Working Thigh of Hormones,Growth Factors and Biomarkers of Bone Metabolism During Short Lasting Dynamic Exercise

The purpose of this study was to evaluate the responses of hormones, growth factors, and biomarkers involved in bone and muscle metabolism during exercise and in recovery. One leg knee-extension exercise and concomitant sampling from the artery and vein were performed. In 12 healthy individuals (6 men and 6 women; age 21–36 years) blood was drawn from the femoral artery and vein at rest, after 10 minutes warm-up, after 15 minutes work at 61% of peak one leg VO₂, and after 5 minutes work at peak one leg VO₂, as well as 5, 30, and 60 minutes in recovery. Blood flow in the femoral vein was measured using the thermodilution technique. Arteriovenous differences were measured over working thigh for growth hormone (GH), insulin-like growth factor I (IGF-I), insulin-like growth factor binding protein 3 (IGF BP3), parathyroid hormone (PTH) and bone biomarkers, i.e., the carboxyterminal propeptide of type I procollagen (PICP), the carboxyterminal cross-linked telopeptide of type I collagen (ICTP), osteocalcin, and bone-specific alkaline phosphatase (b-ALP). There was an uptake of GH (3.1 ± 1.2 mU · min⁻¹, P < 0.001; mean ± SE) over thigh during exercise and a release of IGF-I at the end of exercise (60 ± 36 μg · min⁻¹; P < 0.01). PICP was also released after the maximal exercise (23 ± 12 μg · min⁻¹; P < 0.01) as well as ICTP (0.5 ± 0.3 μg · min⁻¹; P < 0.05) and b-ALP (0.2 ± 0.1 μkat · min⁻¹; P < 0.05). Osteocalcin, IGF BP3, and PTH revealed no clearcut pattern. In the present study, exercise induces endocrine changes which point to anabolic effects on muscle and bone tissue. Received: 12 February 1996 / Accepted: 6 June 1996