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.     

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     

Effects of Postmenopausal Hormone Replacement Therapy With and Without Vitamin D3 on Circulating Levels of 25-Hydroxyvitamin D and 1,25-Dihydroxyvitamin D

The effects of postmenopausal hormone replacement therapy (HRT) and vitamin D₃ on vitamin D metabolites (25OHD and 1,25(OH)₂D) were studied in a population-based prospective 1-year study. The serum concentrations of intact parathyroid hormone (PTH), calcium, and phosphate were also studied. A total of 72 women were randomized into four treatment groups: HRT group (sequential combination of 2 mg estradiol valerate and 1 mg cyproterone acetate), Vit D₃ group (vitamin D₃ 300 IU/day + calcium lactate 500 mg/day), HRT + Vit D₃ group (both above) and placebo group (calcium lactate 500 mg/day). Serum samples were taken in March–April, when vitamin D formation from sunlight in Finland is minimal after the dark winter. Serum concentrations of 25OHD increased in the Vit D₃ group (33.5%, P < 0.001) and in the HRT + Vit D₃ group (38.2%, P < 0.001) but had not changed significantly in the HRT and placebo groups at the 1-year follow-up examination. Serum concentrations of calcitriol (1,25(OH)₂D) increased, however, only in the HRT group (23.7%, P < 0.05), and remained unchanged in other groups. Serum concentrations of PTH decreased by 23.2% (P < 0.05) in the placebo group, but did not change significantly in the other three groups. The concentrations of serum calcium increased in the nonhormone groups (P < 0.001), whereas serum phosphate concentrations decreased in the hormone groups (P < 0.05 and 0.001). Our results confirm the positive effect of 1 year of HRT on serum calcitriol. Vitamin D₃ supplementation increased 25OHD concentrations, but did not affect calcitriol concentrations even though the initial levels were low. Interestingly, the combination of HRT and vitamin D₃ did not increase serum calcitriol concentrations as much as HRT alone. Received: 14 June 1996 / Accepted: 17 June 1997     

Vitamin K1 Supplementation Retards Bone Loss in Postmenopausal Women Between 50 and 60 Years of Age

Although several observational studies have demonstrated an association between vitamin K status and bone mineral density (BMD) in postmenopausal women, no placebo-controlled intervention trials of the effect of vitamin K₁ supplementation on bone loss have been reported thus far. In the trial presented here we have investigated the potential complementary effect of vitamin K₁ (1 mg/day) and a mineral + vitamin D supplement (8 µg/day) on postmenopausal bone loss. The design of our study was a randomized, double-blind, placebo-controlled intervention study; 181 healthy postmenopausal women between 50 and 60 years old were recruited, 155 of whom completed the study. During the 3-year treatment period, participants received a daily supplement containing either placebo, or calcium, magnesium, zinc, and vitamin D (MD group), or the same formulation with additional vitamin K₁ (MDK group). The main outcome was the change in BMD of the femoral neck and lumbar spine after 3 years, as measured by DXA. The group receiving the supplement containing additional vitamin K₁ showed reduced bone loss of the femoral neck: after 3 years the difference between the MDK and the placebo group was 1.7% (95% Cl: 0.35–3.44) and that between the MDK and MD group was 1.3% (95% Cl: 0.10–3.41). No significant differences were observed among the three groups with respect to change of BMD at the site of the lumbar spine. If co-administered with minerals and vitamin D, vitamin K₁ may substantially contribute to reducing postmenopausal bone loss at the site of the femoral neck.     

Effects of cyclical etidronate therapy on bone loss in early postmenopausal women who are not undergoing hormonal replacement therapy

This study was carried out to investigate the effectiveness and tolerability of cyclical etidronate therapy in the prevention of bone loss occurring in early postmenopausal women who are not undergoing hormone replacement therapy (HRT). A total of 109 Caucasian women aged 45–60 years were treated with etidronate 400 mg/day or placebo for 14 days followed by calcium supplementation 500 mg/day for 77 days. Ninety-one women completed the 2 years of the study. After 2 years, the estimated difference between the two groups as regards lumbar spine bone mineral density (BMD) was 2.53% (SEM 1.07%;p=0.01); BMD of the hip and wrist were not significantly different between treatment groups. A clear reduction in bone turnover was obtained as evidenced by a significant decrease in serum alkaline phosphatase level and in urinary N-telopeptide/creatinine ratio in the etidronate group; the difference between the two groups was –12%±3.2% for serum alkaline phosphatase level (p=0.019) and –22.9%+13.7% for the urinary N-telopeptide/creatinine ratio (p=0.047). There was no statistically significant difference between the two groups in terms of the serum osteocalcin levels and urinary hydroxyproline/creatinine and calcium/creatinine ratios. Etidronate was generally well tolerated and its adverse event profile was similar to that of placebo. The results of this study indicate that cyclic etidronate therapy can prevent trabecular bone loss, with no deleterious effect on cortical bone, in the first 5 years of menopause and that it has a very high safety margin.     

A Randomized Trial Comparing Hormone Replacement Therapy (HRT) and HRT Plus Calcitriol in the Treatment of Postmenopausal Osteoporosis with Vertebral Fractures: Benefit of the Combination on Total Body and Hip Density

We report a prospective, randomized, multicenter, open-label 2-year trial of 81 postmenopausal women aged 53-79 years with at least one minimal-trauma vertebral fracture (VF) and low (T-score below - 2) lumbar bone mineral density (BMD). Group HRT received piperazine estrone sulfate (PES) 0.625 – 1.25 mg/d ± medroxyprogesterone acetate (MPA) 2.5 – 5 mg/d; group HRT/D received HRT plus calcitriol 0.25 µg bd. All with a baseline dietary calcium (Ca) of <1 g/d received Ca carbonate 0.6 g nocte. Final data were on 66 – 70 patients. On HRT/D, significant (P < 0.001) BMD increases from baseline by DXA were at total body – head, trochanter, Wards, total hip, intertrochanter and femoral shaft (% group mean 4.2, 6.1, 9.3, 3.7, 3.3 and 3.3%, respectively). On HRT, at these 6 sites, significant s were restricted to the trochanter and Wards. Significant advantages of HRT/D over HRT were in BMD of total body (- head), total hip and trochanter (all P = 0.01). The differences in mean at these sites were 1.3, 2.6 and 3.9%. At the following, both groups improved significantly -lumbar spine (AP and lateral), forearm shaft and ultradistal tibia/fibula. The weightbearing, site — specific benefits of the combination associated with significant suppression of parathyroid hormone—suggest a beneficial effect on cortical bone. Suppression of bone turnover was significantly greater on HRT/D (serum osteocalcin P = 0.024 and urinary hydroxyproline/creatinine ratio P = 0.035). There was no significant difference in the number of patients who developed fresh VFs during the trial (HRT 8/36, 22%; HRT/D 4/34, 12% - intention to treat); likewise in the number who developed incident nonvertebral fractures. This is the first study comparing the 2 treatments in a fracture population. The results indicate a significant benefit of calcitriol combined with HRT on total body BMD and on BMD at the hip, the major site of osteoporotic fracture. Present address of K.J.: Department of Primary Health Care, Imperial College, London, UK     

Hip bone loss is attenuated with 1000 IU but not 400 IU daily vitamin D3: A 1‐year double‐blind RCT in postmenopausal women

Few year‐long vitamin D supplementation trials exist that match seasonal changes. The aim of this study was to determine whether daily oral vitamin D₃ at 400 IU or 1000 IU compared with placebo affects annual bone mineral density (BMD) change in postmenopausal women in a 1‐year double‐blind placebo controlled trial in Scotland. White women aged 60 to 70 years (n = 305) were randomized to one of two doses of vitamin D or placebo. All participants started simultaneously in January/February 2009, attending visits at bimonthly intervals with 265 (87%) women attending the final visit and an additional visit 1 month after treatment cessation. BMD (Lunar iDXA) and 1,25‐dihydroxyvitamin D[1,25(OH)₂D], N‐terminal propeptide of type 1 collagen [P1NP], C‐terminal telopeptide of type I collagen [CTX], and fibroblast growth factor‐23 [FGF23] were measured by immunoassay at the start and end of treatment. Circulating PTH, serum Ca, and total 25‐hydroxyvitamin D [25(OH)D] (latter by tandem mass spectrometry) were measured at each visit. Mean BMD loss at the hip was significantly less for the 1000 IU vitamin D group (0.05% ± 1.46%) compared with the 400 IU vitamin D or placebo groups (0.57% ± 1.33% and 0.60% ± 1.67%, respectively) (p < 0.05). Mean (± SD) baseline 25(OH)D was 33.8 ± 14.6 nmol/L; comparative 25(OH)D change for the placebo, 400 IU, and 1000 IU vitamin D groups was ?4.1 ± 11.5 nmol/L, +31.6 ± 19.8 nmol/L, and +42.6 ± 18.9 nmol/L, respectively. Treatment did not change markers of bone metabolism, except for a small reduction in PTH and an increase in serum calcium (latter with 1000 IU dose only). The discordance between the incremental increase in 25(OH)D between the 400 IU and 1000 IU vitamin D and effect on BMD suggests that 25(OH)D may not accurately reflect clinical outcome, nor how much vitamin D is being stored. © 2013 American Society for Bone and Mineral Research.     

Characteristics of Long-Term Femoral Neck Bone Loss in Postmenopausal Women: A 25-Year Follow-Up

The aim of this study was to monitor long-term changes in bone mineral density (BMD) after menopause and factors affecting BMD. The study population consisted of a random sample of 3222 women from the Kuopio Osteoporosis Risk Factor and Prevention (OSTPRE) study, of which 62.1% were postmenopausal at the beginning of the study. This group of women underwent dual-energy X-ray absorptiometry (DXA) measurements at the femoral neck every 5 years from baseline (in 1989) up to 25-year follow-up. They also responded to risk-factor questionnaires at 5-year intervals. During the 25-year follow-up, the baseline cohort decreased to 686 women. The women were divided into quartiles based on their baseline BMD. Self-reported hormone replacement therapy (HRT) and corticosteroid use were divided into ever users and never users. Morbidity was assessed as the total number of self-reported diseases and BMD-affecting diseases. The mean 25-year BMD change was found to be −10.1%, p < 0.001. Higher baseline BMD was associated with higher bone loss rate; the reduction in the highest quartile BMD was 11.1% and in the lowest quartile 7.4% (p = 0.0031). Lower baseline body mass index (BMI) and a greater increase in BMI were found to protect against postmenopausal bone loss (p < 0.001). The lowest bone loss quartile included 15.2% more HRT users than the highest bone loss quartile (p = 0.004). The number of diseases/bone-affecting diseases, use of vitamin D/calcium supplementation, use of corticosteroids, smoking or alcohol use had no statistical significance for annual bone loss rate. This study presents hitherto the longest (25-year) BMD follow-up in postmenopausal women. The linear femoral neck bone loss of 10% was less than previously assumed. A 5-year BMD change appeared to predict long-term bone loss in postmenopausal women. © 2021 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).     

Effects of raloxifene,hormone replacement therapy,and placebo on bone turnover in postmenopausal women

Raloxifene, a nonsteroidal selective estrogen receptor modulator (SERM), increases bone mineral density (BMD), decreases biochemical markers of bone turnover, and prevents incident vertebral fractures in postmenopausal women, while sparing the breast and endometrium from the undesirable stimulation caused by estrogen. How the long-term beneficial effects of raloxifene on bone turnover, as assessed by bone histomorphometry, compare with hormone replacement therapy (HRT) and placebo are not known. We studied 66 healthy postmenopausal women (age 55 to 75 years, mean 63 years) who were randomized to either raloxifene 150 mg/day, HRT (Premarin 0.625 mg/day, and Provera 2.5 mg/day), or placebo for 1 year. All women received 1–1.5 g of calcium/day. Following double tetracycline labeling, transiliac bone biopsies were obtained at baseline and 1 year and analyzed for changes in histologic indexes of bone remodeling on the cancellous surface as well as at the endocortical subdivision of the endosteal envelope, the location of the greatest fraction of postmenopausal bone loss. BMD and biochemical markers of bone turnover were also determined at baseline and 1 year. Four paired biopsies were obtained in the HRT group, six in the raloxifene group, and five in the placebo group. The frequency of remodeling events on cancellous bone and rate of bone formation in both cancellous and endocortical bone increased in the placebo group, while these measurements decreased in both drug treatment groups. Using analysis of mean percentage changes, when compared with the placebo group, these changes were significantly different for both raloxifene and HRT treatment groups (p<0.02). In all subjects, the bone was lamellar with discrete tetracycline labels and there was no evidence of marrow fibrosis or abnormal bone cells. BMD increased from baseline at the lumbar spine (p<0.05 in the HRT group) and in the total body (p<0.05 for both raloxifene and HRT). Compared with that of the raloxifene group, the increase in BMD was greater in the HRT group at the lumbar spine but not in the total body. Serum bone alkaline phosphatase, serum osteocalcin, and urine C-terminal cross-linking telopeptide of type I collagen significantly decreased (p<0.05) in both active treatment groups, changes significantly different from those seen with placebo. Overall, these results support the hypothesis that raloxifene preserves bone mass by reducing the elevated bone turnover found in postmenopausal women receiving placebo, by mechanisms similar to those operative in postmenopausal women receiving HRT.     

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

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

Long-Term Effects of Continuous Combined HRT on Bone Turnover and Lipid Metabolism in Postmenopausal Women

This study was undertaken to investigate the effect of 10 years of hormone replacement therapy (HRT) on bone turnover and lipid metabolism in postmenopausal women. The single-centre trial was initiated as a 1-year, double-masked, randomized, parallel-group study of continuous combined HRT with 2 mg 17b-estradiol and 1 mg norethisterone acetate administered once daily with or without 1 mg estriol. Following preliminary results which showed no difference between the addition and omission of estriol, patients continued on an open-label extension phase of continuous combined HRT without estriol for a further 9 years. Of the 52 women who entered the original double-masked study, 32 entered the open-label extension phase. The 10-year analysis was based on 27 patients. Major increases in bone mineral density (BMD) of the lumbar spine were seen during the first 3 years of treatment, remaining statistically significant compared with baseline at all visits throughout the 10-year follow-up (p40.025). Statistical modelling confirmed that there were no decreases in BMD after these initial increases. BMD remained 5.5% higher than baseline values after 10 years of continuous combined HRT. Mean total cholesterol levels were significantly reduced after 10 years of therapy (p= 0.012), with no significant changes in serum triglyceride and low-density lipoprotein (LDL)-cholesterol levels from baseline values at this time. High-density lipoprotein (HDL)-cholesterol levels, however, were reduced by 15.4% (p50.001). In conclusion, 10 years of continuous combined HRT resulted in a significant and sustained increase in BMD. This treatment regimen therefore appears to be well suited for the long-term prevention of osteoporosis in postmenopausal women. Received: 1 July 1997 / Accepted: 15 December 1997     

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     

Skeletal Effects of Vitamin D Supplementation in Postmenopausal Black Women

Black women have lower serum 25-hydroxyvitamin D (25[OH]D) levels and higher parathyroid hormone (PTH) levels than white peers but lower bone turnover, suggesting skeletal resistance to PTH. Our objective was to determine if vitamin D supplementation (1,000?IU/day) would prevent bone loss and whether vitamin D receptor (VDR) polymorphisms modify the response. We performed a 2-year randomized, controlled, double-blind study of 1,000?IU vitamin D₃ vs. placebo in postmenopausal black women with serum 25(OH)D levels <20?ng/mL (n?=?103). Measurements of 25(OH)D, PTH, and bone turnover were evaluated at baseline and 3, 6, 12, 18, and 24?months. DNA was extracted from peripheral blood leukocytes, and genotyping was conducted using standard techniques. Spine and hip bone mineral density (BMD) was measured at baseline and every 6?months. Serum 25(OH)D increased 11?ng/mL with vitamin D supplementation (p?<?0.001), with no change in the placebo group. Vitamin D supplementation produced a significant decline in PTH at 3?months only, with no differences in bone turnover between placebo and vitamin D at any time point. Two-year changes in BMD were not significantly different between placebo- and vitamin D-treated black women at any skeletal site. Despite similar elevations in 25(OH)D, femoral neck BMD was only responsive to vitamin D supplementation in FF subjects (n?=?47), not Ff/ff subjects (n?=?31). Vitamin D supplementation does not appear to influence bone loss in black women. However, in the FF polymorphism of the VDR gene group, vitamin D supplementation may retard the higher rate of bone loss.     

Randomized Controlled Trial of the Effects of Calcium With or Without Vitamin D on Bone Structure and Bone‐Related Chemistry in Elderly Women With Vitamin D Insufficiency

There are few data on the relative effects of calcium supplementation with or without extra vitamin D on BMD in patients selected for low vitamin D status. The aim of this study is to evaluate the relative importance of vitamin D and calcium treatment on BMD and bone‐related chemistry in elderly women with vitamin D insufficiency. Three hundred two elderly women (age, 77.2 ± 4.6 yr) with serum 25(OH)D concentrations <60 nM participated in a 1‐yr randomized, double‐blind, placebo‐controlled trial. All subjects received 1000 mg calcium citrate per day with either 1000 IU ergocalciferol (vitamin D₂) or identical placebo (control). The effects of time and time treatment interactions were evaluated by repeated‐measures ANOVA. At baseline, calcium intake was 1100 mg/d, and 25(OH)D was 44.3 ± 12.9 nM; this increased in the vitamin D group by 34% but not the control group after 1 year (59.8 ± 13.8 versus 45.0 ± 13.3 nM, p < 0.001). Total hip and total body BMD increased significantly, and procollagen type I intact N‐terminal propeptide (PINP) decreased during the study with no difference between the treatment groups (hip BMD change: vitamin D, +0.5%; control, +0.2%; total body BMD change: vitamin D, +0.4%; control, +0.4%; PINP change: vitamin D, ?3.9%; placebo, ?2.8%). Although the fasting plasma and urine calcium increased in both groups equally, there was no detectable change in serum PTH. The increase in 25(OH)D achieved with vitamin D supplementation had no extra effect on active fractional intestinal calcium absorption, which fell equally in both groups (vitamin D, ?17.4%; control, ?14.8%). In patients with a baseline calcium intake of 1100 mg/d and vitamin D insufficiency, vitamin D₂ 1000 IU for 1 year has no extra beneficial effect on bone structure, bone formation markers, or intestinal calcium absorption over an additional 1000 mg of calcium. Vitamin D supplementation adds no extra short‐term skeletal benefit to calcium citrate supplementation even in women with vitamin D insufficiency.     

BsmI vitamin D receptor genotypes influence the efficacy of antiresorptive treatments in postmenopausal osteoporotic women. A 1-year multicenter, randomized and controlled trial

Vitamin D receptor (VDR) gene polymorphisms could be considered one of the factors influencing the efficacy of the anti-osteoporotic treatments. In this multicenter, prospective, randomized and controlled trial we evaluated whether BsmI vitamin D receptor (VDR) genotypes influence the efficacy of antiresorptive treatment regimes (administered alone or in combination) in postmenopausal osteoporotic women. Using restriction endonuclease, we identified the BsmI VDR polymorphism in 1,100 postmenopausal women with osteoporosis. The women were randomized, taking account of genotype, into five treatment groups: (1) alendronate (Aln, 10 mg/day) plus raloxifene (Rlx, 60 mg/day); (2) Aln plus hormone replacement therapy (HRT, 0.625 mg/day conjugated equine estrogens plus 2.5 mg/day medroxyprogesterone acetate); (3) Aln alone; (4) HRT alone; and (5) Rlx alone. Lumbar-spine bone mineral density (BMD) and bone turnover markers were measured at study entry and after 1 year of treatment. Using the general linear model (GLM) repeated-measures procedure, the means of BMD and bone turnover markers significantly differed from baseline after a period of treatment. In particular, the mean change from baseline for BMD was –0.034 (95% confidence interval [CI]: –0.037 to –0.031, P <0.001); for serum osteocalcin (OC) it was 1.369 (95% CI: 1.289 to 1.448, P <0.001); and for urinary deoxypyridinoline (DPD) it was 1.322 (95% CI: 1.242 to 1.401, P <0.001), indicating a considerable variation before and after treatment of these indicators. In all three cases these effects appeared significantly influenced by treatments, genotypes, and the treatments*genotypes interaction term (P <0.001 each, except for the BMD and genotype effect with P =0.02), and not by the investigational centers involved in the study. In conclusion, in postmenopausal osteoporotic women, BsmI VDR genotypes influence the efficacy of antiresorptive drugs particularly when used in combination.     

Women with climacteric symptoms: A target group for prevention of rapid bone loss and osteoporosis

The relations of vasomotor symptoms to the rate of bone loss and to the response of forearm bone mineral density (BMD) to hormone replacement therapy (HRT) were analyzed in a 2-year non-randomized study. Forty peri/postmenopausal women who were given HRT for climacteric symptoms were compared with untreated control women, individually matched for age and length of time since the last menstrual period. The women who received HRT gained, on average, about 2% in BMD, while the control women lost about 6% (mean group difference 8%; 95% confidence interval (CI) 5.7–10.2). Adjustment for potential confounders did not change the results. Sweating frequency was inversely correlated with serum estradiol levels (p=0.05). Among untreated women the rate of bone loss was higher in those who had frequent sweating initially than in those with less frequent sweating (9% vs. 4%, mean difference 4.3%; 95% CI 0.7–7.8,p=0.023). Among women who received HRT, those who had the highest frequency of sweating initially, compared with those with a lower frequency, showed a greater gain in bone density (mean difference 4%; 95% CI 1.2–6.8,p=0.007). In multivariate analysis adjusting for covariates, sweating frequency remained an independent determinant of change in bone density in women both with and without HRT. When sweating frequency and serum estradiol levels were compared in a multivariate analysis, only sweating frequency showed an independent association with rate of bone loss. The findings indicate that women with severe climacteric symptoms may have an excessive rate of bone loss and should therefore be considered as a special target group for prevention of osteoporosis. This group of women may be those who will have substantial benefit from HRT both immediately, through relief of climacteric symptoms, and in the long-term with regard to bone loss and fracture risk.     

Effects of 1-year treatment with ipriflavone on bone in postmenopausal women with low bone mass

Ipriflavone (IP) (7-isopropoxyisoflavone), a synthetic isoflavone derivative, is active in both inhibiting bone resorption and enhancing osteoblast function. This property suggested its clinical use in the treatment of involutional osteoporosis, and in the prevention of postmenopausal bone mass loss. Forty postmenopausal women with low bone mineral content were enrolled and randomly treated for 12 months with IP 600 mg/day or placebo (PL), according to a double-blind, parallel group design. All patients wee also given an oral calcium supplementation (1 g/day). Bone mineral density (BMD) was measured at the spine (L₂–L₄) by dual-energy X-ray absorptiometry. Bone metabolism markers (serum calcium, phosphate, osteocalcin, and alkaline phosphatase, and urinary calcium, phosphate, and hydroxyproline) were assessed at the same times. After 12 months, a reduction of BMD was evidenced in the PL-treated group, at both the spine (–2.2%, P<0.01 vs baseline) and the forearm (–1.2%). In the IP-treated group, an increase of BMD was obtained (+1.2%, P<0.01 vs placebo, at the spine; +3%, not significant, at the forearm). Bone markers were in the normal range for postmenopausal women; no statistically significant modificantions were observed during the treatment period. Three patients were withdrawn from the treatment in the IP-treated group, and two in the PL-treated group for gastrointestinal disturbances. In the other women, the tolerance of the drug was good and the complicance with the oral treatment was excellent.     

Treatment for patients with postmenopausal osteoporosis who have been placed on HRT and show a decrease in bone mineral density: effects of concomitant administration of vitamin K(2)

 We have been using hormone replacement therapy (HRT) as the treatment of choice for menopausal symptoms and osteoporosis. Estrogen increases bone mineral density (BMD) for 2 or 3 years, and only maintains BMD thereafter. In the present study, we investigated whether BMD improved with HRT in combination with vitamin K₂. Ninety-four patients with postmenopausal osteoporosis were studied. All patients were placed on HRT for more than 1 year. Ten patients whose BMD had increased up to a plateau and showed a decreasing trend thereafter while they were receiving HRT were placed on HRT in combination with vitamin K₂. The long-term BMD (L₂-L₄) profiles of those receiving HRT alone, and the effects of HRT in combination with vitamin K₂ on the BMD profiles were examined. The rate of change in BMD (mean ± SE) of all patients who underwent HRT alone was 2.9 ± 1.2% 1 year after the initiation of HRT, 4.6 ± 1.2% 2 years later, and 5.4 ± 1.2% 3 years later. The BMD in these patients, which reached a peak increase after 3 years, no longer increased from the following year. When vitamin K₂ was administered concomitantly to 10 patients for 12 months because of the decrease in BMD, their BMD (mean ± SE) increased significantly, from 0.734 ± 0.021 g/cm² to 0.783 ± 0.026 g/cm² (P < 0.03; paired-t test). We conclude that HRT in combination with vitamin K₂ significantly improved BMD that was on the decrease after HRT alone. Therefore, as a supplementary drug for postmenopausal osteoporosis, vitamin K₂ is a good therapeutic option for patients who are placed on HRT. Received: August 29, 2001 / Accepted: January 18, 2002     

Bone health in urban midlife Malaysian women: risk factors and prevention

The aim of this study was to identify risk factors associated with osteoporosis in urban midlife Malaysian women and to assess the effectiveness of lifestyle intervention in bone loss prevention with hormone replacement therapy (HRT) as a positive control. A total of 514 disease-free, uterus-intact, non-HRT-using women aged 45 years and older were recruited into the study. After initial bone mineral density (BMD) assessments, they were randomized into three groups: GI (control), G2 (lifestyle intervention), and G3 (lifestyle intervention with HRT). The study group was composed of 67.5% Chinese, 27.8% Malay, and 4.2% Indians with a mean age of 51.07±5.28 years. Two-fifths were postmenopausal, and the prevalence of osteoporosis was 24.1%, seen predominantly at the hip. Postmenopausal women had significantly lower mean BMD and a higher incidence of osteoporosis compared with the premenopausal women, 42.1% vs. 11.1% (p<0.0005). A lower incidence of osteoporosis was found in women who took calcium supplementation regularly as opposed to those who do not, 18.7% vs. 29.3% (p=0.036). Age and a greater postmenopausal duration showed a significant negative association with BMD, whereas higher family income, weight, body mass index, and waist and hip circumference were positively correlated. After 18–20 months, the effect of intervention was assessed based on BMD values of 279 women at baseline and after intervention. Lifestyle intervention alone was effective in premenopausal women, preventing over 90% of spinal bone loss compared with the controls, who lost 11.6% (0.046 g/cm²) bone mass with similar losses of hip bone, 2.0% (0.026 g/cm²) vs. 1.5% (0.020 g/cm²). Premenopausal women on HRT also showed a substantial decrease in spine and hip BMD, 18.6% (0.081 g/cm²) and 9.0% (0.122 g/cm²), respectively. The lifestyle intervention program retarded postmenopausal bone loss by 21% and 37% compared with controls, who lost 9.6% (0.141 g/cm²) and 6.0% (0.138 g/cm²) bone mass at the spine and hip. In comparison, lifestyle intervention with HRT increased postmenopausal BMD by 12.7% (0.216 g/cm²) at the spine and 1.9% (0.042 g/cm²) at the hip. The changes in hip BMD were influenced by current age, ethnicity, and income, while intervention had the strongest effect on spine BMD changes. In conclusion, lifestyle intervention prevented spinal bone loss in premenopausal women and retarded postmenopausal spine and hip bone loss compared with controls. The benefits of physical activity on spine and hip BMD highlight its potential as a safe and cost-effective alternative to HRT, which is not advocated because of its potential adverse effects.     

Effect of the menopause and hormone replacement therapy on the carboxy-terminal pyridinoline cross-linked telopeptide of type I collagen

We investigated the effect of the menopause and postmenopausal hormone replacement therapy (HRT) on the serum concentration of carboxy-terminal pyridinoline cross-linked telopeptide of type I collagen (ICTP), a potential new biochemical marker of bone resorption. A group of 44 healthy postmenopausal women, aged 45–54 years, had about 19% higher serum ICTP than did a group of 42 healthy premenopausal women aged 35–50 years (3.6±0.8 µg/l v 3.0±0.7 µg/l (mean ±SD);p<0.01), although there was a large overlap in the values. The 44 postmenopausal women also participated in a longitudinal clinical study, in which 20 received HRT and 24 received a placebo. Compared with the placebo group, those who received HRT had a significant (p<0.05) decrease in ICTP of about 12% at the end of 1 year of treatment, but again there was considerable overlap in the values. The menopause-and HRT-induced changes in ICTP were less than those seen in serum osteocalcin, serum total alkaline phosphatase, and fasting urinary excretion of hydroxyproline, calcium, pyridinoline and deoxypyridinoline. We conclude that the menopause increases and HRT decreases ICTP, although these changes are less pronounced than those seen in other biochemical markers of bone turnover.