Matrix Delivery Transdermal 17β-Estradiol for the Prevention of Bone Loss in Postmenopausal Women

A total of 277 early postmenopausal women were enrolled in this placebo-controlled 2-year study to examine the efficacy of a matrix transdermal 17β-estradiol system, at three different dosages (25, 50 and 75 mg/day) combined with sequential oral dydrogesterone 20 mg/day, in preventing bone loss. At 2 years, the difference from placebo in percentage change from baseline of L1–4 lumbar spine bone mineral density (BMD) (assessed by dual-energy X-ray absorptiometry) was 4.7%± 0.7% with estradiol 25 mg/day, 7.3%± 0.7% with estradiol 50 mg/day and 8.7%± 0.7% with estradiol 75 mg/day (all values mean ± SEM). There were also significant increases in femoral neck, trochanter and total hip BMD with all doses of estradiol compared with placebo. Additionally, most patients had a significant gain (increase greater than 2.08%) in lumbar spine bone mass compared with placebo. Patients who received estradiol also experienced clinically significant and dose-related decreases in total serum osteocalcin, serum bone alkaline phosphatase and urinary C-telopeptide, with all three markers of bone turnover returning to premenopausal levels. Estradiol was well tolerated during the 2-year treatment period. Transdermal estradiol is effective and well tolerated at dosages between 25–75 mg/day in the prevention of bone loss in postmenopausal women; 25 mg/day offers an effective option for those women who cannot tolerate higher doses. Received: 30 June 1998 / Accepted: 22 September 1998     

Identification of Early Postmenopausal Women with No Bone Response to HRT: Results of a Five-Year Clinical Trial

Hormone replacement therapy (HRT) prevents postmenopausal bone loss and fractures. However, the occurrence of women with no bone response to HRT has not been widely examined. We identified the densitometric nonresponders to long-term HRT and investigated some characteristics and biochemical variables as possible predictors of densitometric nonresponse in postmenopausal women. The study population was a subsample of the Kuopio Osteoporosis Study (n= 14.220). A total of 464 early postmenopausal women were randomized into four treatment groups: (1) HRT (sequential combination of 2 mg estradiol valerate and 1 mg cyproterone acetate); (2) vitamin D₃; (3) HRT + Vitamin D₃ combined; and (4) placebo. In this study, the data from HRT and placebo groups were analyzed. Lumbar (L2–4) and femoral neck bone mineral density (BMD) were determined by dual-energy X-ray absorptiometry (DXA) at baseline and after 5 years of treatment. A densitometric nonresponder was defined as a woman whose 5-year BMD change was similar to the mean BMD change (+ 95% CI) of the placebo group or worse. Altogether, 74 women in the HRT group and 104 women in the placebo group complied with the treatment. According to spinal BMD analysis, 11% of the women were classified as densitometric nonresponders; the corresponding proportion for femoral BMD analysis was 26%. Both smoking (p= 0.003) and low body weight (p= 0.028) were significant risk factors for densitometric nonresponse to HRT. After 6 months of treatment the densitometric nonresponders (hip) had a significantly higher mean serum follicle stimulating hormone (FSH) level (p= 0.038) and lower increases in serum estradiol levels (p= 0.006) than the densitometric responders. The mean changes in serum FSH and alkaline phosphatase levels were significantly lower among the densitometric nonresponders (spine) than responders (p= 0.043 and 0.017, respectively). In conclusion, this prospective study shows that especially current smokers and women with low body weight are at increased risk of poor bone response to HRT. Repeated serum FSH, estradiol and alkaline phosphatase measurements during the first months of long-term HRT may be helpful in identifying the women with no bone response to HRT. Received: 29 January 1999 / Accepted: 2 August 1999     

Prevention of Early Postmenopausal Bone Loss by Strontium Ranelate: The Randomized, Two-Year, Double-Masked, Dose-Ranging, Placebo-Controlled PREVOS Trial

Early postmenopausal women (n = 160) were randomised to receive placebo or strontium ranelate (SR) 125 mg/day, 500 mg/day or 1 g/day for 2 years (40 participants per group). All participants received calcium 500 mg/day. The primary efficacy parameter was the percent variation in lumbar bone mineral density (BMD), measured using dual-energy X-ray absorptiometry. Secondary efficacy criteria included hip BMD and biochemical markers of bone turnover. At month 24, SR 1 g/day significantly increased lumbar BMD compared with placebo [mean (SD) +5.53% (5.12); p<0.001] for measured values and [mean (SD) +1.41% (5.33%); p<0.05] for values adjusted for bone strontium content. The annual increase for adjusted values was +0.66% compared with −0.5% with placebo, with an overall beneficial effect after 2 years of about 2.4% with SR 1 g/day relative to placebo. There were no other significant between-group differences in adjusted lumbar BMD. Femoral neck and total hip BMD were also significantly increased at month 24 with SR 1 g/day compared with placebo [mean (SD): +2.46% (4.78) and +3.21% (4.68), respectively; both p<0.001)]. SR 1 g/day significantly increased bone alkaline phosphatase at all time points (p<0.05) compared with baseline and between-group analysis showed a significant increase, compared with placebo, at month 18 (p = 0.048). No effect on markers of bone resorption was observed. SR was as well tolerated as placebo. The minimum does at which SR is effective in preventing bone loss in early postmenopausal non-osteoporotic women is therefore 1 g/day. Received: 7 February 2002 / Accepted: 2 July 2002     

Prevention of Bone Loss by Clodronate in Early Postmenopausal Women with Vertebral Osteopenia: A Dose-Finding Study

This double-masked, placebo-controlled study was undertaken to determine the efficacy and safety of oral clodronate in the prevention of bone loss in early postmenopausal women with vertebral osteopenia. Altogether 610 women with a mean age of 53 years were recruited for the study. They were 1–5 years postmenopausal and their lumbar spine bone mineral density (BMD) was at least 1 standard deviation below the mean of premenopausal women (T-score ≤−1). The subjects were randomized into five study groups to receive either placebo, clodronate 65 mg, 400 mg or 800 mg daily, or intermittent clodronate in 3 month cycles with 400 mg daily for 15 days followed with no treatment for 75 days for 3 years. One hundred and eighty-seven of 509 women who completed the primary study continued in the extension study of 2 years in which previous placebo users were switched to clodronate 800 mg daily, while previous users of 400 mg or 800 mg of clodronate used either placebo or 800 mg of clodronate daily. In the primary study clodronate was administered in the evening, and in the extension 1 h before breakfast on an empty stomach. In the primary study mean changes in lumbar spine BMD were −3.4% in the placebo group and +0.4% in 800 mg clodronate group [difference between groups at 3 years 3.8% (95% CI 2.7% to 4.9%, p<0.0001)], and in the trochanter area BMD −1.1% in the placebo group, and + 0.4% in the 800 mg clodronate group [difference between groups at 3 years 1.5% (95% CI 0.05% to 2.9%)]. During the extension study mean changes in lumbar spine BMD were +1.5% in the clodronate group and −0.2 % in the placebo group [difference between groups 1.7% (CI 0.4% to 3.0%, p = 0.010)] and in trochanter BMD were +2.5% in the clodronate group and no change in the placebo group [difference between groups 2.1% (CI 0.3% to 3.9%, p = 0.007)]. No statistically significant differences between the placebo and 800 mg clodronate groups were found in the femoral neck BMD. In the primary study the urinary excretion of type I collagen aminoterminal telopeptide (NTX) decreased by 44% (p<0.0001 compared with placebo) and that of deoxypyridinoline by 18% (p<0.0001) in the clodronate 800 mg group. In the extension study urinary NTX decreased by 51% (p<0.0001) in those who were switched to 800 mg of clodronate and increased by 67% (p<0.0001) in those who stopped using that dose. There was no difference in the frequency of gastrointestinal complaints between clodronate- and placebo-treated patients in the primary study, but they were more common among women who received clodronate in the extension phase. Clodronate in daily doses of 400–800 mg caused a slight elevation of aminotransferase levels, usually within the reference range. In bone biopsies no defect in mineralization was found. In conclusion, clodronate in a daily dose of 800 mg prevents early postmenopausal bone loss at the sites of the skeleton in which cancellous bone predominates. It effectively reduces bone resorption and bone turnover rate. Antifracture efficacy of clodronate remains to be established by prospective, placebo-controlled trials. Received: 4 March 2002 / Accepted: 9 July 2002     

A Prospective Study of Bone Loss in Menopausal Australian-Born Women

Two hundred and twenty-four women (74 pre-, 90 peri-, 60 post-menopausal), aged 46–59 years, from a population-based cohort participated in a longitudinal study of bone mineral density (BMD). BMD was measured by dual-energy X-ray absorptiometry (DXA) at the lumbar spine and femoral neck and the time between bone scans was on average 25 (range 14–41) months. The aim of the study was to assess changes in BMD in relation to changes in normal menopausal status. During the study period women who were between 3 and 12 months past their last menstrual period (n= 22, late perimenopausal) at the time of the second bone scan had a mean (SE) annual change in BMD of 70.9% (0.4%) at the lumbar spine and 70.7% (0.6%) at the femoral neck (both p50.05 compared with women who remained premenopausal). In the women who became postmenopausal (n= 42) the mean annual changes in BMD were 72.5% (0.2%) at the lumbar spine and 71.7% (0.2%) at the femoral neck (both p50.0005), and in the women who remained postmenopausal (n= 60) they were 70.7% (0.2%) per year and 70.5% (0.3%) per year respectively (both p50.05), compared with women who remained premenopausal. In the 1–3 years after the final menstrual period (FMP) there was greater bone loss from the lumbar spine than the femoral neck (p50.05). In women who were menstruating at the time of the second bone scan and whose FMP could be dated prospectively (n= 35), higher baseline oestradiol levels were associated with less lumbar spine bone loss (p50.005). In the women who remained postmenopausal there was an association between baseline body mass index (BMI) and percentage change per year in femoral neck BMD (p50.05), such that women with higher BMI had less bone loss. In conclusion, during the time of transition from peri- to post-menopause, women had accelerated BMD loss at both the hip and spine. Received: 23 June 1997 / Accepted: 5 November 1997     

The Prevention of Osteoporosis Using Sequential Low-Dose Hormone Replacement Therapy with Estradiol-17β and Dydrogesterone

Low-dose hormone replacement therapy (HRT) in postmenopausal women may produce fewer side-effects but its efficacy in the prevention of bone loss and osteoporosis is not established. To address this we compared the effect of 1 mg estradiol-17β with a 2 mg dose, in combination with cyclical dydrogesterone, in the prevention of postmenopausal bone loss. We conducted a multicenter double-masked prospective randomized, placebo-controlled study in 595 apparently healthy postmenopausal women randomized to either placebo, or continuous oral estradiol-17β 1 mg or 2 mg with sequential dydrogesterone for 2 years. The primary endpoint was the percentage change from baseline in bone mineral density (BMD) in the lumbar spine (LS) and femoral neck (FN) of actively treated groups compared with placebo. Women taking either 1 mg or 2 mg estradiol-17β showed a significant increase in BMD of the LS (mean ± SD, 5.2 ± 3.8% and 6.7 ± 4.0% respectively, both p <0.001) whilst BMD in the placebo group decreased (–1.9 ± 4.0%). Increases were also observed in FN BMD in both treated groups (2.7 ± 4.2% and 2.5 ± 5.2% respectively, both p <0.001) in contrast to the placebo group (–1.8 ± 4.8%). The oldest women showed the greatest treatment response. One milligram estradiol-17β in combination with dydrogesterone is effective in conserving LS and proximal femur bone mass, both of which are clinically important sites of osteoporotic fracture, and is as effective as 2 mg in preventing FN bone. The lower dose of estradiol-17β is a particularly suitable treatment for osteoporosis management in older women since it should minimize side-effects and improve the acceptability of HRT. Received: 19 June 2000 / Accepted: 26 October 2000     

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     

Age-Related Bone Mineral Density, Accumulated Bone Loss Rate and Prevalence of Osteoporosis at Multiple Skeletal Sites in Chinese Women

We investigated the age-related bone mineral density (BMD), accumulated bone loss rate (ABLR) and the prevalence of osteoporosis at different skeletal sites in Chinese women. BMD was measured at the anteroposterior (AP) spine, supine lateral spine (areal BMD at the midarea [mLat] and the whole region [Lat], volumetric BMD at the middle region [MVD] and total region [TVD]), hip (femoral neck [FN], trochanter [Troc] and Ward’s triangle [Ward’s]) and forearm (radius + ulna ultradistal [RUUD], 1/3 region [RU1/3] and total region [RUT]) using a dual-energy X-ray absorptiometry (DXA) fan-beam bone densitometer (Hologic QDR 4500A) in 2702 females aged from 5 to 96 years old. Data were analyzed by eight different regression models. We found that the cubic regression model was the best for describing age-related changes in BMD. The coefficients of determination (R ²) of the fitting curve were 0.398 to 0.612 (p= 0.000). The data were then analyzed by 5-year age groups. This showed that the earliest peak BMD was at the age of 20–24 years at Troc and Ward’s, and the latest at the age of 40–44 years at RU1/3 and RUT of the distal forearm. Compared with BMD, the ABLRs were highest at Ward’s (−66.2%) and the lowest at RU1/3 of the distal forearm (−31.3%) in subjects over 80 years old. The prevalence of osteoporosis at at least one site in these women was 0.5 ± 0.4% in those 30–39, 4.6 ± 4.4% in those 40–49, 23.9 ± 13.3% in those 50–59, 56.3 ± 20.3% in those 60–69, 71.8 ± 16.7% in those 70–79 and 83.2 ± 12.1% those over 80 years of age, respectively. The prevalence of osteoporosis in these women was 8.6–11.1% at the age of 40–49 and 36.5–40.6% at the age of 50–59 at the lateral spine regions (mLat, Lat, MVD and TVD), and 0.5–3.7% at the age of 40–49 and and 3.9–21.7% at the age of 50–59 years at the other skeletal sites (AP, FN, Troc, Ward’s, RUUD, RU1/3 and RUT). Significant differences were found in the prevalence of osteoporosis between the lateral spine regions and other skeletal sites (p<0.001) at the age of 40–59 years. In summary, we demonstrated significant age-related differences in peak BMD, ABLR and osteoporosis prevalence among various skeletal sites. Our data suggest that the supine lateral spine is the most sensitive site for the diagnosis of osteoporosis, especially in the early menopausal period, although the prevalence of osteoporosis varied with age and with different sites measured. Received: 20 November 2001 / Accepted: 13 February 2002     

Comparison of Bone and Total Alkaline Phosphatase and Bone Mineral Density in Postmenopausal Osteoporotic Women Treated with Alendronate

Alendronate therapy in osteoporotic women decreases bone turnover and increases bone mineral density (BMD). Optimal patient management should include verification that each patient is responding to therapy. Markers of bone turnover and BMD have both been proposed for this purpose. We have investigated changes resulting from alendronate therapy with an enzyme immunoassay for bone alkaline phosphatase (BAP) and compared it with total alkaline phosphatase (TAP) and BMD of the lumbar spine, hip, and total body. Subjects were drawn from a multicenter randomized, placebo-controlled trial of alendronate in postmenopausal women with osteoporosis. BAP and TAP levels were measured at baseline and following 3, 6 and 12 months of therapy with either placebo (n= 180) or alendronate 10 mg/day (n= 134). All subjects also received 500 mg/day supplemental calcium. BMD was measured at baseline and following 3, 6, 12, 18, 24 and 36 months of therapy. To compare BAP, TAP and BMD at each site for identifying women that experienced a skeletal effect of alendronate, we calculated least significant change (LSC) values from the long-term intraindividual variability in each placebo-treated woman. Median levels of BAP decreased by 34%, 44% and 43% at 3, 6 and 12 months, respectively, in alendronate-treated women (p<0.0001 compared with baseline and with placebo). These changes were significantly greater (p<0.0001) than changes observed for TAP. Following 6 months of alendronate therapy, 90% of the women had experienced a decrease in BAP exceeding the LSC compared with only 71% for TAP. The greatest number of women similarly identified with BMD at any site (i.e. a gain in BMD exceeding the LSC) was 81% for spinal BMD at 36 months. All other sites were less than 70% at 36 months. Short-term changes in BAP and TAP were modestly associated with subsequent changes in BMD at all sites (Spearman’s rho −0.22 to −0.52, p<0.05). Compared with TAP and BMD, BAP testing rapidly and sensitively identified skeletal effects of alendronate thus enabling appropriate drug monitoring of osteoporotic women. Though BAP and TAP changes were modestly predictive of BMD changes, the value of the bone marker tests is their ability to detect rapidly a skeletal effect of therapy. Received: 19 May 2000 / Accepted: 31 October 2000     

Anabolic Effect of Long-term Estrogen Replacement on Bone Collagen in Elderly Postmenopausal Women with Osteoporosis

Estrogen has been shown to stimulate osteoblasts in cell culture and increase bone formation in animal models. Such an anabolic effect of estrogen replacement therapy (ERT) would be beneficial to postmenopausal women with osteoporosis. Hence, we assessed the total collagen content and collagen crosslink maturity in iliac crest bone biopsy from 18 such women before and after 6 years of higher-dose ERT. These results were compared with the serum estradiol level and bone mineral density (BMD). Total collagen content of both cortical and cancellous bone increased, showing a median (95% CI) percent change of 6.7 (0.3–14.2) and 25.6 (13.5–33.8), respectively. Increase in collagen synthesis was supported by a rise in intermediate crosslinks in both cortical and cancellous bone, and mature crosslinks in cortical bone only. At the same time, BMD showed a substantial rise both at the lumbar spine and proximal femur with a median (95% CI) percent change of 28.6 (19.8–37.3) and 14.5 (8.4–20.7), respectively. Serum estradiol and BMD results correlated with cortical bone collagen levels. Our results suggest that long-term higher-dose ERT has a therapeutic role due to its anabolic effect on bone in postmenopausal women with osteoporosis. Received: 3 May 2000 / Accepted: 14 December 2000     

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     

Skeletal Benefits of Two Years of Alendronate Treatment Are Similar for Early Postmenopausal Asian and Caucasian Women

Alendronate has been shown to increase bone density among early postmenopausal women. Osteoporosis is common among both Asian and Caucasian women, but most clinical trials have consisted primarily of Caucasian women, and it does not appear that the effectiveness of antiresorptive agents such as alendronate has been compared between the two races. In this study we compared the response of bone density and biochemical markers to alendronate among 136 Asian and 126 Caucasian women who participated in the Early Postmenopausal Interventional Cohort (EPIC) at the Hawaii center. Approximately 40 women of each race were randomly assigned to placebo or to 2.5 mg/day or 5 mg/day alendronate. Bone mineral density (BMD) was measured at the spine, total hip and total body at baseline, 12 months and 24 months; biochemical markers of bone turnover were measured at 6-month intervals. Responses were greater for the 5 mg dose than 2.5 mg, and were similar in the two races. For example, mean (SE) changes in spine BMD at 24 months for Caucasians and Asians, respectively, were –1.9% (0.5%) and –1.9% (0.4%) for the placebo group, 2.0% (0.5%) and 3.4% (0.5%) at 2.5 mg/day and 4.2% (0.5%) for both races at 5 mg/day. Corresponding changes in urinary N-telopeptide collagen crosslinks were –33.6% (5.6%) and –27.8% (5.8%) for placebo, –51.4% (4.0%) and –62.1 (4.3%) at 2.5 mg/day and –70.8% (2.4%) and –73.5% (3.1%) at 5 mg/day. We conclude that (1) the rate of bone loss in untreated Asian and Caucasian postmenopausal women is similar, with the possible exception of the hip; (2) 5 mg alendronate daily provides greater skeletal benefits than 2.5 mg/day in both Asian and Caucasian early postmenopausal women; and (3) the response at 5 mg/day is similar in the two races. Received: 15 July 1998 / Accepted: 30 September 1998     

Fractal Analysis of Trabecular Bone Texture on Calcaneus Radiographs: Effects of Age, Time Since Menopause and Hormone Replacement Therapy

An analysis of trabecular bone texture based on fractal mathematics, when applied to trabecular bone images on plain radiographs, can be considered as a reflection of trabecular bone microarchitecture. It has been shown to be able to distinguish postmenopausal osteoporosis cases from controls. This cross-sectional study was carried out to investigate the influence of age, time since menopause and hormone replacement therapy (HRT) on the fractal dimension of trabecular bone texture at the calcaneus in a sample of 537 healthy women. Fractal analysis of texture was performed on calcaneus radiographs and the result expressed as the Hmean parameter (H = 2–fractal dimension). Total hip, femoral neck and lumbar spine bone mineral density (BMD) was measured by dual-energy X-ray absorptiometry. There was a statistically significant Hmean parameter decrease with age (p<0.0001) but the degree of correlation was low (r=–0.2) compared with the correlation between age and BMD (r=–0.36 to –0.61 according to the BMD site). We found a weak but statistically significant correlation between time since menopause and Hmean (r=–0.14, p= 0.03) in the 241 postmenopausal women included in the study. Hmean was significantly lower in a group of postmenopausal women without HRT (n= 110) compared with a group of age-matched postmenopausal women with HRT (n = 110): respectively 0.683 ± 0.043 and 0.695 ± 0.038 (p= 0.03). In conclusion, this study suggests that there is a menopause- and age-related decrease in the Hmean parameter and that HRT interferes with the results of the fractal analysis of trabecular bone texture on calcaneus radiographs. Received: 2 March 2001 / Accepted: 2 October 2001     

Do Men and Women Fracture Bones at Similar Bone Densities?

When the World Health Organization (WHO) guidelines for the definition of osteoporosis in postmenopausal women were identified similar proposals were not developed for men as there was insufficient evidence about the relationship between bone density and fracture in men. We have therefore examined the relationship between bone density and vertebral fracture in men and women attending for assessment of possible osteoporosis. Two hundred and sixty-four women (age 64 [SD 10] years) and 37 men (age 55 [10] years) were studied. Bone density was measured in the lumbar spine and femoral neck by dual-energy X-ray absorptiometry and expressed both as bone mineral density (BMD; g/cm²) and as T-scores. In both sexes there was a sigmoid relationship between the cumulative frequency of vertebral fracture and bone density at both sites. There was a linear relationship between the log odds of fracture and bone mass for both sexes and both sites (r= 0.97–0.99; p<0.0001). The slope of these lines was significantly steeper for men than women. The BMD at which there was 50% risk of fracture was higher in men than women (0.908 vs 0.844 g/cm²). The difference between the slopes was similar when the bone mass was expressed as a T-score. However, the T-score associated with 50% prevalence of fracture was similar in the two sexes (F: −2.77 vs M: −2.60). We conclude that although there is a different relationship between bone density and fracture in the two sexes the current WHO definition of osteoporosis in postmenopausal women can be appropriately applied to men. Received: 24 February 1999 / Accepted: 12 July 1999     

Quantitative Ultrasound and Symptomatic Vertebral Fracture Risk in Chinese Women

Quantitative ultrasound (QUS) is emerging as a simple, inexpensive and noninvasive method for assessing bone quality and assessing fracture risk. We assessed the usefulness of a contact calcaneal ultrasonometer by studying normal premenopausal women (group I, n= 53), normal postmenopausal women (group II, n= 198), and osteoporotic women without (group III, n= 141) and with vertebral fractures (group IV, n= 53). The osteoporotic subjects had a T-score of the spine or hip neck bone mineral density (BMD) <−2.5 based on the local Chinese peak young mean values. When compared with postmenopausal controls, mean broadband ultrasound attenuation (BUA), speed of sound (SOS), and quantitative ultrasound index (QUI) were 26%, 2.1% and 25% lower in women with vertebral fractures (p all <0.005). The correlation coefficients between QUS parameters and BMD of the spine and hip ranged between 0.4 and 0.5. The ability of the QUS to discriminate between patients groups was determined based on the mean value of normal premenopausal women in group I. The mean T-score for women with fractures was −2.87 ± 1.02 for BUA, −2.54 ± 0.79 for SOS, −3.17 ± 0.70 for QUI, −2.65 ± 0.86 for L2–4 BMD and −2.53 ± 0.66 for hip neck BMD. After adjustment for age and body mass index, the odds ratio of vertebral fracture was 1.71 (95% CI 1.2–2.6) for each 1 SD reduction in BUA, 2.72 (1.3–5.3) for SOS, 2.58 (1.4–4.6) for QUI, 2.33 (1.6–3.3) for L2–4 BMD, 2.09 (1.37–3.20) for femoral neck BMD and 1.88 (1.34–2.92) for total hip BMD. The association between the QUS parameters and vertebral fracture risk persisted even adjustment for BMD. The area under the receiver operating characteristic curve for BUA for vertebral fracture was 0.92, for SOS, QUI, L2–4 BMD and femoral neck BMD was 0.95, and for total hip was 0.91. Received: 7 January 1999 / Accepted: 18 May 1999     

Performance of COLIA1 Polymorphism and Bone Turnover Markers to Identify Postmenopausal Women with Prevalent Vertebral Fractures

Some studies have suggested that bone turnover markers (BTM) and collagen type I alpha 1 gene (COLIA1) may be useful in the prediction of rates of future bone loss, and may therefore provide information about fracture risk. Our study aimed to examine the association of the COLIA1 genotype with the risk of vertebral fracture and to investigate the predictive value of this genetic factor in comparison with bone mineral density (BMD) and BTM, in ambulatory postmenopausal Spanish women. We determined the COLIA1 polymorphism by polymerase chain reaction, BMD by dual-energy X-ray absorptiometry and BTM in 43 postmenopausal women with prevalent vertebral fracture and a control group of 101 postmenopausal women without fracture. There was a significant overrepresentation of the ‘T’ allele in fractured women (p= 0.029). BTM exhibited no differences between women with or without fractures or COLIA1 genotype groups. After adjusting for all other variables, the osteoporosis densitometric criteria variable was the most strongly associated with fracture (OR = 5 [1.8–13.3]) followed by COLIA1 (OR = 2.1 [1–4.3] per copy of the ‘T’ allele). Our study shows that COLIA1 is associated with prevalent vertebral fracture independently of bone mass, and the performance of this genetic factor to assess prevalent vertebral fracture is better than bone turnover markers. Received: 29 June 2001 / Accepted: 11 December 2001     

Determinants of Bone Loss in a Rural Japanese Community: The Taiji Study

The objective of this study was to assess the rate of bone loss and characterize its determinants, among the inhabitants of Taiji, a rural Japanese community. A cohort of 2261 inhabitants aged 40–79 years was established using resident registration in 1992. Fifty men and 50 women in each of four age strata between 40 and 79 years were randomly selected and completed a self-administered risk factor questionnaire. Baseline bone density of lumbar spine and proximal femur was measured by dual-energy X-ray absorptiometry in 1993. BMD was measured again on the same participants in 1996. The rates of change of lumbar spine BMD in men in their 40s, 50s, 60s and 70s were 0.20%, 0.34%, 0.43% and 0.28% respectively. Rates in women were –0.35%, –1.02%, –0.10% and –0.20% respectively. At the femoral neck, rates of change in BMD among men in their 40s, 50s, 60s and 70s were 0.09%, –0.07%, 0.34% and 0.31% respectively. Femoral neck rates of change among women were –0.55%, 0.02%, 0.49% and –0.25% respectively. The rate of change of lumbar spine BMD was –0.24% in premenopausal women with regular periods, –1.99% in premenopausal women with irregular periods and –0.33% in postmenopausal women. Anthropometric measurements at baseline were also related significantly to change in bone density. Baseline weight and height were statistically significant predictors of bone loss rate.These data provide estimates of the rate of bone loss among Japanese men and women aged 40– 79 years. They suggest that body build and menstrual function in women are important determinants of bone loss. Received: 20 November 1997 / Revised: 1 April 1998     

Short-Term Increases in Bone Turnover Markers Predict Parathyroid Hormone-Induced Spinal Bone Mineral Density Gains in Postmenopausal Women with Glucocorticoid-Induced Osteoporosis

The purpose of this study was to test the ability of early changes in markers of bone turnover to predict subsequent changes in bone mineral density (BMD) induced by parathyroid hormone fragment, PTH (1–34), in postmenopausal osteoporotic women treated with estrogen and glucocorticoids. Forty-nine postmenopausal women with chronic, inflammatory diseases and BMD T-scores ≤–2.5 at the lumbar spine or femoral neck who were concurrently treated with estrogen ≥ 1 year and prednisone 5–20 mg/day for ≥ 1 year participated. Subjects were randomized to treatment with human PTH (1–34) 400 IU/day or to a control group for 1 year and followed for an additional year. Serum and urine were collected at baseline and 1, 3, 6, 9, 12, 18 and 24 months for measurement of bone alkaline phosphatase (BAP), osteocalcin (OC) and deoxypyridinoline (DPD). We constructed an Uncoupling Index (UI) from all three markers (UI = [Z _BAP+Z _OC]/2 –Z _DPD, where the Z-score for each marker in each subject was calculated from the mean and standard deviation of the study population at baseline). BMD of the lumbar spine and hip was measured at baseline and every 6 months thereafter by dual-energy X-ray absorptiometry (DXA) and annually by quantitative computed tomography (QCT; spine only). BMD of the spine, but not hip (total, femoral neck or trochanter), and levels of all three markers increased significantly as a result of PTH treatment (p<0.01 compared with controls). The resorption response lagged behind that of formation as evidenced by a significant increase (p<0.05) in the UI for the first 9 months of treatment. The UI values and changes from baseline to 1, 3 and 6 months in BAP, OC and DPD were correlated with the 12- and 24-month changes in spine BMD measured both with QCT and with DXA (Spearman’s rank coefficients ≤0.76; p<0.05). Most PTH-treated subjects could be identified as biochemical responders by least significant change analysis. Following 1 month of therapy, BAP and OC identified 65% and 81% as responders, respectively. The responder rates were 79%, 79% and 75% for BAP, OC and DPD, respectively by 6 months. Responders exhibited a high level of diagnostic accuracy for predicting a gain in BMD (areas under the receiver operating characteristic curves exceeding 0.79 for QCT and 0.70 for DXA), but not the magnitude of the gain. These data suggest that serial bone marker measurements may be useful in identifying skeletal responders to an anabolic therapy, such as PTH, in estrogen-replete postmenopausal women with glucocorticoid-induced osteoporosis. Received: 27 July 1999 / Accepted: 2 November 1999     

Bone Mineral Density of the Lebanese Reference Population

We determined the bone mineral density (BMD) of normal Lebanese subjects and compared results with US/European reference data. The investigation was conducted at one center, and included 858 women and 165 men aged 20–79 years. Spine, femoral and radial BMD measurements were made using dual-energy X-ray absorptiometry. Age-related changes in BMD were similar in form to those of US/European reference data. However, BMD values of Lebanese were generally lower than US/European values. Spine BMD of Lebanese women was about 8% lower than US/European values between ages 20 and 59 years, and 5–6% lower for ages 60–79 years. Femoral neck BMD values for Lebanese women were 8% lower in the young adult years (age 20–39 years), but only 2–3% lower in the postmenopausal years, compared with US/European women. There were smaller postmenopausal decreases in femoral and radial BMD in Lebanese women compared with US/European women, which led to a convergence of BMD after age 70 years. The BMD of Lebanese men was 5–8% lower than US/European values throughout the age range (20–79 years). The effect of weight on BMD ranged from 0.2% to 0.4% per kilogram. Height was not significantly associated with BMD when both height and weight were entered in multiple regression analyses. The prevalence of osteoporosis appeared to be overestimated if the US/European reference data, rather than Lebanese reference data, were used to calculate T-scores. Received: 25 February 1999 / Accepted: 9 March 2000     

Linkage and Association for Bone Mineral Density and Heel Ultrasound Measurements with a Simple Tandem Repeat Polymorphism near the Osteocalcin Gene in Female Dizygotic Twins

In this confirmatory candidate gene study, we investigated possible linkage and association for bone density, heel ultrasound and bone turnover with the osteocalcin gene using the nearby (50–180kb) microsatellite marker D1S3737. Non-identical twin sisters aged 18–75 years at first interview were recruited for the study from the St Thomas’ UK Adult Twin Registry with 1366 women being genotyped for marker D1S3737. Linkage, allelic association and joint linkage and association tests were carried out using quantitative transmission disequilibrium tests (QTDT), along with post-hoc multivariate tests of linkage and association. Phenotypes tested were bone mineral density (BMD) at the spine, left forearm and left total hip; quantitative ultrasound measurements of the heel including velocity of ultrasound (VOS) and broadband ultrasound attenuation (BUA); and bone turnover markers, urine deoxypyridinoline (DPD), serum osteocalcin, bone specific and total alkaline phosphatase (ALP). BMD and ultrasound variables showed evidence of pleiotropic linkage (p= 0.05) and association (p= 0.02) with the marker in postmenopausal women. Bone markers showed little or no evidence of linkage and association for any age group. Evidence for pleiotropic linkage appeared to be strongest for BUA and spine BMD in postmenopausal women. The univariate test statistic for BUA was χ² ₁=12.8 (p= 0.0003), equivalent to a LOD score of 2.8. DPD showed borderline evidence of linkage to the marker for women of all ages. Multivariate model-fitting showed allele 10 to be negatively associated with BMD, VOS and BUA via a common pathway, suggesting the putative functional polymorphism affects both bone content and structure through shared underlying metabolic pathways. It is likely that the alleles are in linkage disequilibrium with functional polymorphism(s) in or nearby the osteocalcin gene, which may contribute to the onset of osteoporosis. Received: 24 January 2002 / Accepted: 25 April 2002