Serum Levels of Pyridinium Crosslinks in Postmenopausal Women and in Paget's Disease of Bone

The purpose of this study was to measure pyridinium crosslinks in serum by high performance liquid chromatography (HPLC) and to correlate levels with urinary excretion in patients with different osteometabolic conditions. Blood and spot urine samples were collected between 9 and 11 A.M. in 92 early postmenopausal, untreated women (age 52.3 ± 2.6 years, months since menopause 20.4 ± 9.6), 17 patients with active Paget's disease (10 males, aged 65.1 ± 12.6) and 24 healthy premenopausal women (aged 28.4 ± 4.2). Urinary excretion of the total fraction (free + peptide bound) of pyridinolines (Pyr, Dpyr) was measured by HPLC. Before HPLC analysis, serum samples were submitted to a clean-up procedure by ultrafiltration. In 42 postmenopausal women, bone loss was calculated from two bone mass measurements (L2–L4, DXA), performed at study entry and after 12 months. Statistical analysis was performed by Student's t test for independent samples and linear regression analysis. In pagetic patients' serum levels of Pyr and Dpyr were more than threefold increased over the mean observed in healthy controls and were closely correlated with total alkaline phosphatase levels (Pyr: r = 0.73; Dpyr: r = 0.72, P < 0.0005). Compared with controls, postmenopausal women had significantly increased levels of both urinary and serum Pyr and Dpyr (P < 0.003). In pagetic patients and postmenopausal women, crosslinks serum levels were correlated with their urinary excretion with r values ranging from 0.46 to 0.84. In postmenopausal women, only serum Dpyr correlated with the rate of bone loss (r =−0.36, P= 0.02). The data suggest that serum levels of pyridinium cross-links are correlated with urinary excretion in patients with different osteometabolic conditions. The determination of serum levels prevents limitations related to urinary specimen collection and may be a more practical method for routine application, avoiding corrections for urinary creatinine which could be misleading. Received: 13 August 1996 / Accepted: 25 April 1997     

Effect of exercise training and detraining on bone mineral density in postmenopausal women with osteoporosis

We examined the effect of exercise training and detraining on bone mineral density (BMD) in postmenopausal women with osteoporosis. Thirty-five postmenopausal women with osteoporosis, aged 53–77 years, were randomly assigned to three groups: a control group (n = 20), a 2-year exercise training group (n = 8), and an 1-year exercise training plus 1-year detraining group (n = 7). Exercise training consisted of daily brisk walking and gymnastic training. Calcium lactate, 2.0 g, and 1α-hydroxyvitamin D₃, 1 μg were supplied daily to all subjects. No significant differences in initial lumbar BMD, measured by dual-energy X-ray absorptiometry (DXA) were found among the three groups. The mean percent change in BMD compared with the baseline was significantly higher at 1 and 2 years in the exercise training group and at 1 year in the detraining group than in the control group, and did not differ significantly at 2 years between the detraining and control groups. These findings indicate that our exercise training program led to a significant increase in lumbar BMD in postmenopausal women with osteoporosis compared with the control, but that the BMD reverted toward a level that was not significantly different from the control with detraining. Continued exercise training is needed to maintain the bone mass gained through exercise training. Received: May 6, 2000 / Accepted: October 6, 2000     

Effects of Tamoxifen and Toremifene on Urinary Excretion of Pyridinoline and Deoxypyridinoline and Bone Density in Postmenopausal Patients with Breast Cancer

Tamoxifen and toremifene are two mostly used antiestrogens in the treatment of breast cancer. To compare their effect on bone in postmenopausal breast cancer patients we measured the urinary output of two bone resorption markers, pyridinoline (Pyr) and deoxypyridinoline (Dpyr) as well as bone density (BMD) in 30 breast cancer patients using either tamoxifen (20 mg/day, n = 15) or toremifene (40 mg/day, n = 15) as adjuvant treatment of stage II breast cancer for 1 year. The urinary output of Pyr and Dpyr were assessed before and after 6 and 12 months of the antiestrogen regimen. Lumbar and femoral BMD were measured by dual energy X-ray absorptiometry (DXA) before and after 12 months of treatment. Both tamoxifen and toremifene were associated with significant decreases in Pyr (mean fall 19.6% and 12.6%, respectively) and Dpyr (mean fall 21.6% and 15.5%, respectively) at 6 months. After 12 months' treatment, Pyr decreased by 30.8% and Dpyr by 21.2% in women using tamoxifen and significantly less in women using toremifene (10.1% and 4.9%, respectively). BMD in the lumbar spine decreased by 1.8% in the toremifene group but increased by 0.4% in the tamoxifen group; in the proximal femur, BMD increased slightly during both tamoxifen and toremifene treatment in all sites measured. Individual changes in Pyr and Dpyr at 6 months showed no significant relation to the change in BMD at 12 months. We conclude that tamoxifen (20 mg/day) and toremifene (40 mg/day) reduce the bone resorption similarly, and this can be detected by falls in urinary output of Pyr and Dpyr at 6 months of treatment. Received: 1 October 1998 / Accepted: 23 April 1999     

Association of a G2014A Transition in Exon 8 of the Estrogen Receptor-α Gene with Postmenopausal Osteoporosis

We report the association of a newly identified synonymous G2014A single nucleotide polymorphism (SNP) which does not alter the amino acid sequence in exon 8 of the estrogen receptor-α (ERα) gene with osteoporosis in Thai postmenopausal women. Subjects consisted of 228 postmenopausal women aged more than 55 years divided into two groups – with vertebral or femoral osteoporosis (n= 106) or without osteoporosis (n= 122) – according to bone mineral density (BMD) criteria. The exon 8 G2014A SNP, which is 6 nucleotides upstream from the end of the stop codon, was identified by PCR-RFLP. Data are expressed as the mean and 95% CI. The allele frequency of the G2014A polymorphism was 26.4% in osteoporotic subjects and was significantly higher than that in non-osteoporotic women (15.2%) (p<0.05). By stepwise logistic regression analysis, it was found that the G2014A polymorphism was related to the presence of osteoporosis (odds ratio 2.7 per A allele, 95% CI 1.49–4.76) independently of body weight (odds ratio 0.93 per kg, 95% CI 0.89–0.96) and years since menopause (odds ratio 1.12 per year, 95% CI 1.08–1.19). In a multiple linear regression model, L2–L4 BMD of osteoporotic subjects was associated with body weight (p<0.05), endogenous estradiol levels (p<0.05) and the G2014A genotype (p<0.001), while it was related only to body weight (p<0.05) and estradiol levels in non-osteoporotic women (p<0.05). We conclude that a G2014A SNP in exon 8 of ERα is associated with the presence and severity of postmenopausal osteoporosis. Linkage disequilibrium between this polymorphism and the 3′-untranslated region of the ERα gene which may participate in the regulation of ERα gene expression remains to be determined. Received: 17 October 2000 / Accepted: 11 June 2001     

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.     

Changes in Levels of Biochemical Markers and Ultrasound Indices of Os Calcis Across the Menopausal Transition

The aim of this longitudinal study was to investigate the changes in the levels of biochemical markers and ultrasound indices of os calcis across the menopausal transition. One hundred and ten healthy women (age 35–59 years at the 1992 baseline) participated in this 4-year population-based longitudinal study. Serum intact osteocalcin (IOC), urinary pyridinoline (Pyr), urinary deoxypyridinoline (Dpyr) and ultrasound indices were measured at baseline and after 4 years. The percentage changes in biochemical markers (%DIOC, %DPyr and %DDpyr) and the percentage decreases in the ultrasound indices (%DSOS, %DBUA and %DStiffness) were calculated. The values of %DIOC and %DDpyr in the perimenopausal subgroup (−4 to−3 years since menopause) and the values of %DSOS and %DStiffness in the perimenopausal subgroup (−2 to 0 years since menopause) were significantly higher than those in other groups. Pyr was significantly correlated with %DSOS (r=−0.467, p<0.01) and %DStiffness (r = −0.330, p<0.05) and Dpyr was significantly correlated with %DSOS (r=−0.390, p<0.05), %DBUA (r=−0.353, p<0.05) and %DStiffness (r = −0.454, p<0.05), while %DIOC was significantly correlated with %DSOS (r=−0.278, p<0.05), %DBUA (r=−0.369, p<0.01) and %DStiffness (r = −0.383, p<0.01) in the peri- and postmenopausal groups. These results indicate that the increase in bone turnover occurs 4 years before menopause. However, the correlations between biochemical markers and ultrasound indices were too low to allow prediction of bone change in the individual patient. Received: 12 October 1999 / Accepted: 30 June 1999     

Effect of combined administration of vitamin D3 and vitamin K2 on bone mineral density of the lumbar spine in postmenopausal women with osteoporosis

The effect of the combined administration of vitamin D₃ and vitamin K₂ on bone mineral density (BMD) of the lumbar spine was examined in postmenopausal women with osteoporosis. Ninety-two osteoporotic women who were more than 5 years after menopause, aged 55–81 years, were randomly divided into four administration groups: vitamin D₃ (1α hydroxyvitamin D₃, 0.75 μg/day) (D group; n = 29), vitamin K₂ (menatetrenone, 45 mg/day) (K group; n = 22), vitamin D₃ plus vitamin K₂ (DK group, n = 21), and calcium (calcium lactate, 2 g/day) (C group; n = 20). BMD of the lumbar spine (L2–L4) was measured by dual energy X-ray absorptiometry at 0, 1, and 2 years after the treatment started. There were no significant differences in age, body mass index, years since menopause, and initial BMD among the four groups. One-way analysis of variance (ANOVA) with repeated measurements showed a significant decrease in BMD in the C group (P < 0.001). Two-way ANOVA with repeated measurements showed a significant increase in BMD in the D and K groups compared with that in the C group (P < 0.05 and P < 0.001, respectively), and a significant increase in BMD in the DK group compared with that in the C, D, and K groups (P < 0.0001, P < 0.05 and P < 0.01, respectively). These findings indicate that combined administration of vitamin D₃ and vitamin K₂, compared with calcium administration, appears to be useful in increasing the BMD of the lumbar spine in postmenopausal women with osteoporosis. Received: January 13, 2000 / Accepted: June 5, 2000     

Early Postmenopausal Bone Loss is Prevented by Estrogen and Partially by 1α-OH-vitamin D3: Therapeutic Effects of Estrogen and/or 1α-OH-vitamin D3

A total of 79 Japanese women who were within 5 years of menopause were randomly assigned 1α-hydroxyvitamin D₃ [1α(OH)D₃] 1.0 μg/day, conjugated estrogens 0.625 mg/day, a combination of both, or control (no treatment). Lumbar spine and proximal femur bone mineral density (BMD) and biochemical indices were monitored over 2 years. In the 1α(OH)D₃-treated group, there was a nonsignificant decrease in lumbar spine BMD compared with controls, and no significant loss in the femoral neck compared with controls. In the estrogen-treated group, there was a nonsignificant increase in spine BMD (+2.17% in the first year and +1.71% in the second year), and no loss in femoral neck BMD. The combination of conjugated estrogens +1α(OH)D₃ was more effective in increasing BMD in the spine (+3.68% in the first year and +3.63% in the second year) and femur (+2.56% in the first year and +4.44% in the second year) BMD. There was a significant difference in lumbar spine BMD in both the first and second years between the combination-treated group and the 1α(OH)D₃-treated and control groups (P < 0.01). Serum osteocalcin (OC) significantly decreased in the combination-treated group (−23.8% in the first year) and the estrogen-treated group (−37.6% and −41.2% at 6 and 18 months, respectively), and serum alkaline phosphatase (Alp) decreased significantly in the first year in the combination-treated (−31.5%), estrogen-treated (−27.3%), and 1α(OH)D₃-treated (−7.9%) groups, whereas serum OC increased (+45.4% in the first year) in women without treatment. The results of this study indicate that early postmenopausal bone loss in the femoral neck is prevented by conjugated estrogens, 1α(OH)D₃, or both, whereas bone loss in the spine is not prevented by 1α(OH)D₃. Estrogen proves effective in preventing early postmenopausal bone loss by markedly inhibiting bone turnover. Moreover, a synergistic bone-sparing effect can be expected when estrogen is administered concomitantly with 1α(OH)D₃ rather than when used alone. Received: 28 April 1998 / Accepted: 23 December 1998     

Estrogen Metabolism Modulates Bone Density in Men

Estrogen is a critical hormone for bone homeostasis in men, but no information is available on the role of estrogen metabolism among men. The aim of this study was to evaluate the effect of estrogen hydroxylation on male bone mineral density (BMD). Participants consisted of 61 healthy Caucasian males (mean age 66.6 ± 1.0 years). Urinary estrogen metabolites were measured by enzyme-linked immunosorbent assay, serum estradiol by ultrasensitive radioimmunoassay, sex hormone binding globulin by radioimmunoassay, and BMD of the lumbar spine and the proximal femur by dual-energy X-ray absorptiometry. Active estrogen metabolites, 16α-hydroxyestrone (16αOHE₁) and estriol (E₃), positively correlated with adjusted BMD in all regions of the proximal femur (all P < 0.05) but not at the lumbar spine, and those in the highest tertile of urinary 16αOHE₁ had the highest BMD. Free estradiol index (FEI) also positively correlated with BMD of the total hip, femoral neck, and intertrochanter (all P < 0.05), while there was no correlation between BMD with inactive metabolites (2−hydroxyestrone and 2-methoxyestrone) and serum testosterone. Multiple regression analysis showed 16αOHE₁, FEI, and body mass index are important independent predictors of BMD in all regions of the proximal femur. Estrogen metabolism may modulate BMD in men. Increased urinary 16αOHE₁ and E₃ levels are associated with high BMD at the proximal femur, and 16αOHE₁ appears to be a major determinant of BMD among the metabolites evaluated.     

The Less Potent Estrogenic Effect of Tamoxifen on Bone in Ovariectomized Rats With Established Osteopenia

The longitudinal effects of tamoxifen (TAM) treatment on bone metabolism, spinal bone mineral density (BMD), and bone mineral content (BMC) were compared with those of estrogen in ovariectomized (OVX) rats with established osteopenia. The 6-month-old rats were divided into Sham (n = 8) and OVX (n = 24) groups. First, the OVX rats were allowed to lose bone for 6 weeks. Six weeks after ovariectomy they were divided into three groups: (1) OVX rats treated with solvent vehicle (OVX+Vehicle), (2) OVX rats injected with TAM subcutaneously six times a week at a dosage of 1.0 mg/kg body weight (OVX+TAM), (3) OVX rats injected with 17-β estradiol subcutaneously six times a week at a dosage of 0.1 mg/kg body weight (OVX+ET). The longitudinal effects of TAM and estrogen on bone were studied by dual energy X-ray absorptiometry (DXA) and biochemical markers including urinary pyridinoline (Pyr) and deoxypyridinoline (Dpyr). Ovariectomy resulted in a significant increase in urinary Pyr, Dpyr, and a significant decrease in spine BMD and BMC. TAM treatment completely inhibited the further bone loss in OVX rats with established osteopenia, however, estrogen increased spine BMD and BMC significantly compared with OVX+Vehicle, OVX+TAM, and baseline of treatment. Both TAM and estrogen treatment decreased urinary Pyr and Dpyr significantly in OVX rats. Our findings indicate that TAM acts as an estrogen agonist with respect to effects on spine BMD, BMC, and bone resorption in OVX rats with established osteopenia, but fails to restore spine BMD and BMC to the extent observed with estrogen in this study.     

The effect of cyclooxygenase-2 inhibitors on bone mineral density: results from the Canadian Multicentre Osteoporosis Study

Introduction The use of cyclooxygenase-2 (COX-2) inhibitors has been demonstrated to not only impair load-induced bone formation but also prevent menopause-associated bone loss. We hypothesized that COX-2 inhibitor use would be associated with increased bone mineral density (BMD) in postmenopausal women not using estrogen therapy and, conversely, with decreased BMD in men.Methods The Canadian Multicentre Osteoporosis Study is a longitudinal, randomly selected, population-based community cohort. We present data from men (n=2,004) and postmenopausal women age 65 and older (n=2,776) who underwent a BMD measurement and structured interview in the 5th year of the study. The outcome measure was percent difference in BMD (g/cm²).Results Daily COX-2 inhibitor use was reported by 394 subjects. In men, daily use of COX-2 inhibitors was associated with a lower BMD at all hip sites, with a percent difference of −3.1% [95% confidence interval (CI), −6.0, −0.3] between users and nonusers at total hip. In postmenopausal women not using estrogen replacement therapy, daily COX-2 inhibitor use was associated with higher BMD at most sites [percent difference at total hip: +3.0% (95% CI, 0.3, 5.8)]. These effects appeared to be dose-dependent.Conclusion COX-2 inhibitor use was associated with a lower BMD in men and, on the other hand, with a higher BMD in postmenopausal women not using estrogen replacement therapy. Men who have used COX-2 inhibitors may wish to seek BMD measurement to assess their fracture risk. However, COX-2 inhibitors may have utility in postmenopausal women if bone-selective analogs can be developed.     

Differences in Bone Resorption after Menopause in Japanese Women with Normal or Low Bone Mineral Density: Quantitation of Urinary Cross-Linked N-Telopeptides

The objective of this study was to examine the value of NTx, a urinary cross-linked N-telopeptides of type I collagen, as a marker of bone resorption. We assessed changes in pre- and postmenopausal bone resorption by evaluating the correlation of NTx with L2–4 bone mineral density (BMD) in a total of 1100 Japanese women, aged 19–80 years [272 premenopausal (45.2 ± 6.2 years) and 828 postmenopausal (59.5 ± 6.2 years)]. Postmenopausal women were divided into three groups based on the range of BMD (normal, osteopenic, and osteoporotic). Within each group, subjects were further segregated according to years since menopause (YSM). NTx values were then evaluated for each group. Our results showed that BMD was significantly decreased (P < 0.05) and NTx was significantly increased (P < 0.01) after menopause in age-matched analysis. Consistent with a previous report, NTx was inversely correlated with BMD for the entire cohort of study subjects (r =−0.299), although NTx correlated better with premenopausal than postmenopausal BMD (r =−0.240 versus r =−0.086). This may have been due to the fact that elevated values of NTx were exhibited over the entire range of BMD present in the postmenopausal women, suggesting that NTx might respond faster to the estrogen withdrawal than BMD. In all postmenopausal women, regardless of the range of BMD, the increase in NTx reached a peak within 5 YSM. After 11 YSM, however, NTx remained elevated in the osteoporotic group but it decreased in the osteopenic group, and showed no significant change in the group of postmenopausal women with normal BMD. These findings suggest that bone resorption is dramatically increased within 5 years after menopause but remains increased only in osteoporotic women. Received: 29 April 1997 / Accepted: 12 August 1997     

Does Vitamin D Strengthen the Increase in Femoral Neck BMD in Osteoporotic Women Treated with Estrogen?

The long-term effects on bone of estrogen therapy (HRT) combined with vitamin D₃ supplementation were evaluated and compared with the effects of HRT without vitamin D₃ supplementation in a 4-year prospective, partly randomized study among 60 osteoporotic women (mean age 55.4 years; range 49.7–59.4 years). The women studied were a subgroup of the population-based Kuopio Osteoporosis Risk Factor and Prevention Study (OSTPRE) (n = 13100). The bone mineral densities (BMD) of the lumbar spine and femoral neck were determined by dual-energy X-ray absorptiometry (DXA) in 3236 perimenopausal women. Those 106 women with baseline BMD more than 2 SDs less than the mean value in this population, either at the lumbar spine (BMD < 0.826 g/cm²) and/or femoral neck (BMD < 0.684 g/cm²), were offered treatment for osteoporosis. After exclusions, 60 women were included in the analyses. Group allocation was: HRT (estradiol valerate (2 mg) plus cyproterone acetate, 1 mg, sequentially: Climen^R) (n = 21); HRT + Vit D: Climen + vitamin D₃ (cholecalciferol, 300 IU/day, no intake during June–August) (n = 23); controls: 16 women who refused all treatment served as a non-randomized control group. In the HRT group, the highly significant increase in lumbar BMD was 5.4%, 5.3%, 4.7% and 4.0% after 1, 2, 3 and 4 years of treatment, respectively, all compared with the baseline values and with the control group. The increase in femoral neck BMD was statistically insignificant (1.4%, 2.2%, 1.9% and 2.1%, respectively; p > 0.05). In the HRT + Vit D group, the lumbar BMD increased by 3.7%, 4.9%, 4.9% and 4.9% (p < 0.001), whereas the 5.8% increase in femoral neck BMD reached significance at 4 years (p < 0.01) when compared with the control group as well as with the baseline values. However, there were no statistically significant differences in lumbar or femoral BMD changes between the two HRT groups. In conclusion, estrogen can substantially increase lumbar bone mass in patients with postmenopausal osteoporosis. In addition, the combination of HRT and vitamin D₃ may increase femoral neck BMD in osteoporotic women more than estrogen alone.     

Treatment of Postmenopausal Women with Osteoporosis or Low Bone Density with Raloxifene

Raloxifene, a selective estrogen receptor modulator (SERM), has been shown to improved bone mineral density (BMD) and serum lipid profiles in healthy postmenopausal women. The objective of this study was to examine the effects of raloxifene on BMD, biochemical markers of bone metabolism and serum lipids in postmenopausal women with low bone density or osteoporosis. This Phase II, multicenter, 24-month, double-masked study assessed the efficacy and safety of raloxifene in 129 postmenopausal women (mean age ± SD: 60.2 ± 6.7 years) with osteoporosis or low bone density (baseline mean lumbar spine BMD T-score: −2.8). Women were randomly assigned to one of three treatment groups: placebo, 60 mg/day raloxifene-HCl (RLX 60) or 150 mg/day raloxifene-HCl (RLX 150) and concomitantly received 1000 mg/day calcium and 300 U/day vitamin D₃. At 24 months, BMD was significantly increased in the lumbar spine (+3.2%), femoral neck (+2.1%), trochanter (+2.7%) and total hip (+1.6%) in the RLX 60 group compared with the placebo group (p<0.05). The RLX 150 group had increases in BMD similar to those observed with RLX 60. A greater percentage of raloxifene-treated patients, compared with those receiving placebo, had increased BMD (p<0.05). Serum bone-specific alkaline phosphatase activity, serum osteocalcin, and urinary type I collagen:creatinine ratio were significantly decreased in the RLX-treated groups, compared with the placebo group (p<0.01). RLX 60 treatment significantly decreased serum levels of triglycerides, and total- and LDL-cholesterol levels (p<0.01). The rates of patient discontinuation and adverse events were not significantly different among groups. In this study, raloxifene increased bone density, decreased bone turnover, and improved the serum lipid profile with minimal adverse events, and may be a safe and effective treatment for postmenopausal women with osteoporosis or low bone density. Received: 26 December 1998 / Accepted: 31 March 1999     

Baseline BMD and Bone Loss at Distal Radius Measured by Peripheral Quantitative Computed Tomography in Peri- and Postmenopausal Hong Kong Chinese Women

The current study was designed to investigate the rate of bone loss in distal radius and its association with baseline volumetric bone mineral density (BMD) and years since menopause (YSM) in peri- and postmenopausal women using precise and multislice peripheral quantitative computed tomography (pQCT; Densiscan 2000). Two hundred and five healthy Hong Kong Chinese perimenopausal (n = 26) and postmenopausal (n = 179) women within 10 years of the onset of menopause were recruited. Anthropometric parameters and menstrual status were also measured. The linear regression model derived from the baseline volumetric BMD revealed a significant and slightly better correlation with YSM than age, with a YSM-related annual decline of 2.56%, 1.82% and 0.65% in trabecular BMD (tBMD), integral BMD (iBMD) and cortical BMD (cBMD), respectively. Follow-up measurements after a time interval of 12 months showed that the rate of bone loss was higher than the annual decline in BMD calculated from the baseline BMD, with decreases of 2.89%, 2.16% 0.91% in tBMD, iBMD and cBMD, respectively. Baseline BMD was associated with age or YSM (r ranges from −0.283 to −0.502; p<0.001 in all cases), but no relationship was found between annual rate of bone loss and age or YSM. The rate of bone loss did not correlate with baseline volumetric BMD values or YSM after dividing the subjects into fast bone losers (with annual tBMD loss ≥3%), normal bone losers (with annual tBMD loss ≥ 1% but <3%) or slow bone losers (with annual tBMD loss <1%). The rate of bone loss was greater in both trabecular and cortical bone of postmenopausal women within the first 3 menopausal years but was only significant in the iBMD as compared with perimenopausal and postmenopausal women over 7 years after onset of menopause. The percentage distribution of slow and fast bone losers was not found to be associated with YSM. As a total of only 4 fracture cases were documented, the study could not provide conclusive information on whether perimenopausal and early postmenopausal baseline volumetric BMD or rate of bone loss determines the development of osteoporosis or fracture occurrence. Received: 12 November 2001 / Accepted: 18 July 2002     

Effects of alfacalcidol alone or in combination with elcatonin on incidence of osteoporotic vertebral fractures in postmenopausal women with spondylosis

Osteoporosis and spondylosis often occur simultaneously. However, there are no previous reports about the effects of osteoporosis medication on incidence of vertebral fractures in people with spondylosis. In this study, we conducted a retrospective investigation of the effects of alfacalcidol alone or in combination with elcatonin on incidence of osteoporotic vertebral fractures in women with spondylosis. The present subjects were 101 postmenopausal women with osteoporosis aged >60 years, divided into three groups: D group (n = 45), treated for >5 years with alfacalcidol; D+ECT group (n = 26), treated for >5 years with alfacalcidol plus elcatonin; control group (n = 30), who received no medications for >5 years. Over the 5-year treatment period, bone mineral density (BMD) of the lumbar spine and proximal femur did not significantly change in the D and D+ECT groups, but they significantly decreased in the control group (P < 0.05). The number of incident vertebral fractures per patient was significantly higher in the control group (2.9) than in the D group (1.2) and D+ECT group (1.5) (P < 0.01). There was no significant difference in BMD or incident vertebral fractures between the D and D+ECT groups. In all three groups, the number of incident vertebral fractures positively correlated with the number of prevalent vertebral fractures (0.303 ≤ r ≤ 0.434), and negatively correlated with baseline BMD (−0.703 ≤ r ≤ −0.326) and the osteophyte score representing the degree of spondylosis (−0.769 ≤ r ≤ −0.365). Further multiple regression analysis revealed that the medication (D or D+ECT, P < 0.001) and the osteophyte score (P < 0.001) were the most significant contributors for the number of incident vertebral fractures. In conclusion, elcatonin had no additive effects on BMD or prevention of vertebral fractures in postmenopausal women receiving alfacalcidol. Presence of spondylosis (indicated by a high osteophyte score) appears to have an effect on prevention of vertebral fractures.     

Hand Ultrasound for Osteoporosis Screening in Postmenopausal Women

There is a need for low-cost screening methods to detect low bone mass (osteopenia or osteoporosis) in postmenopausal women. The utility of quantitative ultrasonography (QUS) of the hand was assessed for osteoporosis screening using the WHO criteria. Bone mineral density (BMD) was measured in 206 postmenopausal Mexican-American women at the total hip and lumbar spine by dual-energy X-ray absorptiometry (DXA). The amplitude-dependent speed of sound (AD-SoS) was measured in the phalanges by QUS. Subjects identified by DXA as having osteopenia or osteoporosis had significantly lower AD-SoS values in comparison with normals. Estrogen users had significantly higher spine and hip BMD and AD-SoS values compared with non-estrogen users. The areas under the receiver operating characteristic (ROC) curves (AUC) for AD-SoS to screen for osteoporosis (T-score ≤−2.5) at the spine or hip were 0.73 for all subjects, 0.74 for estrogen users and 0.68 for non-estrogen users. The AUC for non-estrogen users to screen for osteopenia (T-score −1 to −2.5) was 0.77. Performance comparisons of AD-SoS with SCORE (a risk factor questionnaire) and body weight showed AUC values of 0.73, 0.69 and 0.65, respectively. QUS was the superior screening test when considering both the AUC and the shape of the ROC curves. For non-estrogen users, the group at higher risk for osteoporosis, QUS correctly identified 31% as normal, and 62% as having low bone mass and needing DXA referral; and the remaining 7% were false negatives. These data suggest phalangeal QUS can be effectively used for screening osteoporosis in postmenopausal women. Received: 2 April 1998 / Accepted: 27 July 1999     

Comparison of effects of estriol on bone mineral density of vertebrae between elderly and postmenopausal women

To compare the efficacy of estriol (E₃) for postmenopausal and senile osteoporosis, we administered orally 1 g/day calcium lactate alone (control groups) or with 2 mg/day estriol (E₃ groups) to 20 postmenopausal women aged 50–65 years and 29 elderly women aged 70–84 years, and determined their bone mineral density (BMD) of the lumbar vertebrae AP scan by dual-energy X-ray absorptiometory. Of 41 subjects who completed 10 months of treatment, 8 postmenopausal women and 12 elderly women in the E₃ groups showed a significant (P < .05) increase in BMD, 5.59% ± 4.79% and 3.83% ± 7.90% of the respective basal values, while 10 postmenopausal women and 11 elderly women in the control groups showed a decrease in BMD, −4.02% ± 7.00% and −3.26% ± 4.60% of the respective basal values, after 10 months. On the other hand, genital bleeding as a side effect of E₃ occurred in 6 elderly subjects at this dose. Moreover, decrease in serum level of corrected calcium was seen only in the elderly women receiving E₃. Although a lower dosage of E₃ may be recommended for elderly subjects, these observations suggest, first, that hormone replacement therapy with E₃ has efficacy for involutional osteoporosis, and, second, that the bones in elderly women also maintain responsiveness to E₃. Received: May 19, 1997 / Accepted: July 7, 1997     

CD38 is associated with premenopausal and postmenopausal bone mineral density and postmenopausal bone loss

One goal of osteoporosis research is to identify the genes and environmental factors that contribute to low bone mineral density (BMD) and fracture. Linkage analyses have identified quantitative trait loci (QTLs), however, the genes contributing to low BMD are largely unknown. We examined the potential association of an intronic polymorphism in CD38 with BMD and postmenopausal bone loss. CD38 resides in 4p15, where a QTL for BMD has been described. CD38−/− mice display an osteoporotic phenotype at 3 months, with normalization of BMD by 5 months. The CD38 polymorphism was identified by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis in 457 postmenopausal and 173 premenopausal Caucasian women whose spine and hip BMD was measured by dual energy X-ray absorptiometry (DXA). Influence of the CD38 polymorphism on bone loss was analyzed in 273 postmenopausal women over a follow-up of 2.94 ± 1.50 years. The CD38-PvuII polymorphism was significantly associated with premenopausal and postmenopausal (P = 0.001) lumbar spine BMD. Women homozygous for the G allele had >14% lower spinal BMD than women with GC/CC genotypes. An allele dose effect was observed at the spine in premenopausal (P = 0.002) and postmenopausal (P < 0.001) cohorts. The CD38-PvuII polymorphism was significantly associated with femoral neck BMD in pre- and postmenopausal women (P = 0.002 and P = 0.011, respectively). However, significance was lost following adjustment of hip BMD for covariates in the postmenopausal cohort (P = 0.081). The CD38-PvuII polymorphism was weakly associated with bone loss at the spine (P = 0.024), in postmenopausal women not taking hormone replacement therapy. We suggest that the CD38-PvuII polymorphism may influence the attainment and maintenance of peak BMD and postmenopausal bone loss.     

Comparison of vitamin D metabolism in early healthy and late osteoporotic postmenopausal women

Summary We studied 20 healthy premenopausal women aged 36.5±4.0 years (mean±1 SD), 123 healthy postmenopausal women aged 50.0±2.4 years, and 103 postmenopausal women aged 65.1±5.6 years with symptomatic osteoporosis (forearm and spinal fracture). Serum levels of vitamin D metabolites [25(OH)D, 24,25(OH)₂D₃, and 1,25(OH)₂D] were compared with (1) bone mass in the forearm (single photon absorptiometry) and in the spine (dual photon absorptiometry); (2) biochemical indices of bone formation (serum alkaline phosphatase, plasma bone Gla protien), and bone resorption (fasting urinary hydroxyproline); and (3) other biochemical estimates of calcium metabolism (serum calcium, serum phosphate, 24-hour urinary calcium, intestinal absorption of calcium). The present study revealed no difference in any of the vitamin D metabolites between the premenopausal women, the healthy postmenopausal women and the osteoporotic women as a group. The concentrations of 1,25(OH)₂D and 25(OH)D were significantly lower in patients with spinal fracture than in those with forearm fracture. In the early postmenopausal women, serum 1,25(OH)₂D was related to forearm bone mass (r=−0.20;P<0.05), intestinal calcium absorption (r=0.18;P<0.05), and 24-hour urinary calcium (r=0.21;P<0.05); serum 25(OH)D was related to spinal bone mass (r=0.23;P<0.01). In the osteoporotic women, serum vitamin D metabolites were not related to bone mass, but 1,25(OH)₂D was related to bone Gla protein (r=0.33;P<0.001), serum phosphate (r=−0.27;P<0.01), and 24-hour urinary calcium (r=0.43;P<0.001). The present study demonstrates that in a population that is apparently not deficient in vitamin D, a disturbance of the vitamin D metabolism is not likely to play a pathogenetic role in early postmenopausal bone loss. Patients with spinal fractures have low levels of vitamin D metabolites, which may aggravate their osteoporosis.