Evidence that Treatment with Risedronate in Women with Postmenopausal Osteoporosis Affects Bone Mineralization and Bone Volume

Risedronate is used in osteoporosis treatment. Postmenopausal women enrolled in the Vertebral Efficacy with Risedronate Therapy trial received either risedronate (5 mg/day) or placebo for 3 years. Subjects received calcium and vitamin D supplementation if deficient at baseline. Lumbar spine bone mineral density (BMD) was measured at baseline and at 3 years. Quantitative back-scattered electron imaging (qBEI) was performed on paired iliac crest biopsies (risedronate, n = 18; placebo, n = 13) before and after treatment, and the mineral volume fraction in the trabecular bone was calculated. Combining dual-energy X-ray absorptiometric values with the mineral volume fraction for the same patients allowed us to calculate the relative change in trabecular bone volume with treatment. This showed that the effect on BMD was likely to be due partly to changes in matrix mineralization and partly due to changes in bone volume. After treatment, trabecular bone volume in the lumbar spine tended to increase in the risedronate group (+2.4%, nonsignificant) but there was a significant decrease (−3.7%, P < 0.05) in the placebo group. Calcium supplementation with adequate levels of vitamin D led to an ∼3.3% increase in mineral content in the bone material independently of risedronate treatment. This increase was larger in patients with lower matrix mineralization at baseline and likely resulted from correction of calcium/vitamin D deficiency as well as from reduced bone remodeling. Combining BMD and bone mineralization density distribution data show that in postmenopausal osteoporosis 3-year treatment with risedronate preserves or may increase trabecular bone volume, unlike placebo. This analysis also allows, for the first time, separation of the contributions of bone volume and matrix mineralization to the increase in BMD.     

Risedronate Rapidly Reduces the Risk for Nonvertebral Fractures in Women with Postmenopausal Osteoporosis

Prevention of nonvertebral fractures, which account for a substantial proportion of osteoporotic fractures, is an important goal of osteoporosis treatment. Risedronate, a pyridinyl bisphosphonate, significantly reduces clinical vertebral fracture incidence within 6 months. To determine the effect of risedronate on osteoporosis-related nonvertebral fractures, data from four large, randomized, double-blind, placebo-controlled, Phase III studies were pooled and analyzed. The population analyzed consisted of postmenopausal women, with and without vertebral fractures, who had low bone mineral density (lumbar spine T-score <–2.5). Patients received placebo (N = 608) or risedronate 5 mg daily (N = 564) for 1 to 3 years. At baseline, 58% had at least one prevalent vertebral fracture, and the mean lumbar spine T-score was –3.4. Among placebo-treated patients, the presence of prevalent vertebral fractures did not increase the risk of incident nonvertebral fractures overall, although fractures of the humerus and hip and pelvis were more common in patients who had prevalent vertebral fractures than in those who did not. Risedronate 5 mg significantly reduced the incidence of nonvertebral fractures within 6 months compared with control. After 1 year, nonvertebral fracture incidence was reduced by 74% compared with control (P = 0.001), and after 3 years, the incidence was reduced by 59% (P = 0.002). The results indicate that risedronate significantly reduces the incidence of osteoporosis-related nonvertebral fractures within 6 months.     

Five Years of Treatment with Risedronate and its Effects on Bone Safety in Women with Postmenopausal Osteoporosis

We have recently reported that risedronate preserves normal bone formation and decreases bone remodeling in women with postmenopausal osteoporosis after 3 years of treatment. We report now the results of a 2-year extension study. The primary objective of this study was to determine the effect of 5 years of risedronate treatment (5 mg daily) on bone quality and bone remodeling based on paired transiliac bone biopsies. There were additional measurements that included bone turnover markers and bone mineral density (BMD). Histologic evaluation of biopsy sections (placebo, n = 21; risedronate, n = 27) yielded no pathologic findings after 5 years in either treatment group. Histomorphometric assessment of paired biopsy specimens after 5 years (placebo, n =12; risedronate, n = 13) found no statistically significant differences between treatment groups in structural or resorption parameters. There was a significant reduction in osteoid (–27%) and mineralizing surfaces (–49%) from baseline values in the risedronate group that were also significantly different from placebo at 5 years. Similarly, activation frequency decreased significantly (–77%) in the risedronate group, although it was not significantly different from placebo at 5 years (0.09 vs. 0.21, respectively). Double tetracycline labels were identified in all biopsy specimens indicating continuous bone turnover. After 5 years of risedronate treatment, serum bone-specific alkaline phosphatase (bone ALP) and N-telopeptide (NTX) decreased significantly from baseline by 33.3% and 47.5%, respectively. In the placebo group, bone ALP decreased by 3.9% (P = NS), whereas NTX decreased by 27.0% (P < 0.005). Lumbar spine BMD increased significantly in the risedronate group (9.2%), whereas no significant change was seen in the placebo group (–0.26%). Risedronate was overall well tolerated; during the 2-year study extension nonvertebral fractures occurred in 7 patients in placebo and 2 patients in risedronate groups. The findings from this study are consistent with the antiremodeling effect of risedronate and support long-term bone safety and antifracture efficacy of risedronate treatment.This work was supported by grants from Procter & Gamble Pharmaceuticals, Inc., Mason, Ohio, and Aventis Pharmaceuticals, Bridgewater, New Jersey.     

Seven Years of Treatment with Risedronate in Women with Postmenopausal Osteoporosis

The effects of 7 years of risedronate treatment were evaluated in a second 2-year extension of a 3-year vertebral fracture study in women with osteoporosis. For the first 5 years of the study, women received risedronate 5 mg/day or placebo according to the original randomization, with maintenance of blinding. All the women who entered into the 6–7 years extension study received risedronate 5 mg/day. Endpoints included vertebral and nonvertebral fracture assessments, changes in biochemical markers of bone turnover, and bone mineral density (BMD) measurements. A total of 164 women (placebo/risedronate group, 81; risedronate group, 83) entered the 6–7 years extension study and 136 (83%) completed the study. Annualized incidence of new vertebral fractures during the 6–7 years was similar between the 2 treatment groups (3.8%). The incidence of vertebral fractures did not change in the 7-year risedronate group during the 6–7 years as compared to 4–5 years, while a significant reduction was observed in the placebo group that switched to risedronate treatment during years 6–7. The incidence of nonvertebral fractures was 7.4% and 6.0% in the placebo/risedronate and risedronate groups, respectively, during years 6–7. Urinary N-telopeptide decreased from baseline by 54% and 63% at 3 months and 7 years, respectively, in the risedronate group. The increases in BMD from baseline after 5 years of risedronate treatment were maintained or increased further during years 6–7; lumbar spine BMD after 5 and 7 years of risedronate treatment increased from baseline by 8.8% and 11.5%, respectively, for this extension study population. Risedronate was well tolerated and the occurrence of upper gastrointestinal adverse events was low. After 7 years of continuous risedronate treatment there were significant increases in BMD and decreases in bone turnover to within premenopausal levels and there was no indication of any loss of anti-fracture efficacy.     

Short-Term Risedronate Treatment in Postmenopausal Women: Effects on Biochemical Markers of Bone Turnover

The development of new biochemical markers has made it possible to assess the effects of therapeutic agents on bone turnover more rapidly and precisely. In this early phase II study, we analyzed the effects of short-term, high-dose treatment with risedronate, a potent pyridinyl bisphosphonate, on markers of bone resorption and formation. Resorption markers included urinary free deoxypyridinoline (D-Pyr) crosslinks, N-terminal telopeptide (NTx) and C-terminal telopeptide (CTx) type I collagen crosslinks. Bone formation markers included osteocalcin (OC), bone-specific alkaline phosphatase (BSAP) and the C-terminal peptide of type I procollagen (PICP). All three resorption markers showed rapid, significant (p<0.05) decreases from baseline following daily administration of 30 mg risedronate for 2 weeks. The mean decreases at 2 weeks were 28% for D-Pyr, 61% for NTx and 73% for CTx, respectively. Over the next 10 weeks after treatment, D-Pyr approached baseline while NTx and CTx remained well below baseline values. The markers of bone formation showed little change during therapy but decreased significantly at 4–10 weeks after therapy – an expected outcome of bisphosphonate therapy. Moreover, there was a significant correlation between the early effects on bone resorption markers and the delayed effects on formation markers. This study demonstrates that the approved dose of risedonate (30 mg/day) for Paget”s disease is effective at decreasing bone turnover after 2 weeks of treatment, as observed by the sensitive response of bone turnover markers. Received: 18 August 1999 / Accepted: 18 January 2000     

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.     

Soluble RANKL Induces High Bone Turnover and Decreases Bone Volume,Density, and Strength in Mice

Receptor activator for nuclear factor-kappa B ligand (RANKL) is an essential mediator of osteoclastogenesis. We hypothesized that administration of soluble RANKL to mice would result in high turnover and deleterious effects on both cortical and trabecular bone. For 10 days, 10-week-old C57BL/6J female mice (n = 12/group) were given twice-daily subcutaneous injections of human recombinant RANKL (0.4 or 2 mg/kg/day) or inert vehicle (VEH). Bone turnover was greatly accelerated by RANKL, as evidenced by the 49-84% greater levels of serum TRAP-5b (bone resorption marker) and 300-400% greater levels of serum alkaline phosphatase (bone formation marker). RANKL resulted in significantly greater endocortical bone erosion surface (79-83%) and periosteal bone formation rate (64-87%) vs. VEH. Microcomputed tomographic (microCT) analysis of the proximal tibia indicated a reduction in trabecular volume fraction (-84%) for both doses of RANKL. Cortical bone geometry and strength were also negatively influenced by RANKL. MicroCT analysis of the femoral diaphysis indicated significantly lower cortical bone volume (-10% to -13%) and greater cortical porosity (8-9%) relative to VEH. Biomechanical testing of the femur diaphysis revealed significantly lower maximum bending load (-19% to -25%) vs. VEH. Bone strength remained correlated with bone mass, independent of RANKL stimulation of bone turnover. These findings are consistent with the hypothesis that soluble RANKL could be an important etiologic factor in pathologic bone loss. RANKL also has potential utility as a model for studying the consequences of high bone turnover on bone quality and strength in animals.     

Randomized Trial of the Effects of Risedronate on Vertebral Fractures in Women with Established Postmenopausal Osteoporosis

The purpose of this randomized, double-masked, placebo-controlled study was to determine the efficacy and safety of risedronate in the prevention of vertebral fractures in postmenopausal women with established osteoporosis. The study was conducted at 80 study centers in Europe and Australia. Postmenopausal women (n= 1226) with two or more prevalent vertebral fractures received risedronate 2.5 or 5 mg/day or placebo; all subjects also received elemental calcium 1000 mg/day, and up to 500 IU/day vitamin D if baseline levels were low. The study duration was 3 years; however, the 2.5 mg group was discontinued by protocol amendment after 2 years. Lateral spinal radiographs were taken annually for assessment of vertebral fractures, and bone mineral density was measured by dual-energy X-ray absorptiometry at 6-month intervals. Risedronate 5 mg reduced the risk of new vertebral fractures by 49% over 3 years compared with control (p<0.001). A significant reduction of 61% was seen within the first year (p= 0.001). The fracture reduction with risedronate 2.5 mg was similar to that in the 5 mg group over 2 years. The risk of nonvertebral fractures was reduced by 33% compared with control over 3 years (p= 0.06). Risedronate significantly increased bone mineral density at the spine and hip within 6 months. The adverse-event profile of risedronate, including gastrointestinal adverse events, was similar to that of control. Risedronate 5 mg provides effective and well-tolerated therapy for severe postmenopausal osteoporosis, reducing the incidence of vertebral fractures and improving bone density in women with established disease. Received: 29 September 1999 / Accepted: 10 November 1999     

Risedronate Reduces the Risk of First Vertebral Fracture in Osteoporotic Women

Risedronate treatment reduces the risk of vertebral fracture in women with existing vertebral fractures, but its efficacy in prevention of the first vertebral fracture in women with osteoporosis but without vertebral fractures has not been determined. We examined the risk of first vertebral fracture in postmenopausal women who were enrolled in four placebo-controlled clinical trials of risedronate and who had low lumbar spine bone mineral density (BMD) (mean T-score =–3.3) and no vertebral fractures at baseline. Subjects received risedronate 5 mg (n= 328) or placebo (n= 312) daily for up to 3 years; all subjects were given calcium (1000 mg daily), as well as vitamin D supplementation (up to 500 IU daily) if baseline serum 25-hydroxyvitamin D levels were low. The incidence of first vertebral fracture was 9.4% in the women treated with placebo and 2.6% in those treated with risedronate 5 mg (risk reduction of 75%, 95% confidence interval 37% to 90%; P= 0.002). The number of patients who would need to be treated to prevent one new vertebral fracture is 15. When subjects were stratified by age, similar significant reductions were observed in patients with a mean age of 64 years (risk reduction of 70%, 95% CI 8% to 90%; P= 0.030) and in those with a mean age of 76 years (risk reduction of 80%, 95% CI 7% to 96%; P= 0.024). Risedronate treatment therefore significantly reduces the risk of first vertebral fracture in postmenopausal women with osteoporosis, with a similar magnitude of effect early and late after the menopause. Received: 12 September 2001 / Accepted: 11 December 2001     

Analysis of Trabecular Bone Structure with Multidetector Spiral Computed Tomography in a Simulated Soft-Tissue Environment

We investigated the influence of soft tissue (ST) on image quality by high-resolution multidetector computed tomography (MDCT) scans and assessed the effect of surrounding ST on the quantification of trabecular bone structure. Eight bone cores obtained from human proximal femoral heads discarded during hip replacement surgery were scanned with micro-computed tomography (μCT) as well as with MDCT both without (w/o) and with (w) simulated surrounding ST, where a phantom imitated a human torso. Signal-to-noise ratio (SNR) and contrast-to-noise ratio (CNR) were measured in all scans. Apparent trabecular bone structure parameters were calculated and compared to similar parameters obtained in coregistered sections of the μCT scans. Residual errors were calculated as root-mean-square (RMS) errors relative to the μCT measurements. Compared to μCT results, trabecular structure parameters were overestimated by MDCT both w and w/o ST. SNR and CNR were significantly higher in the scans w/o ST. Significant correlations between μCT and MDCT results were found for bone fraction (r = 0.90 w/o ST, r = 0.84 w ST), trabecular number, and separation. RMS ranged from 10% to 15% for MDCT w/o ST and from 10% to 17% for MDCT w ST. Only bone fraction showed significantly different RMS and correlations for scans w/o vs. w ST (P < 0.05). This study showed that MDCT is able to visualize trabecular bone structure in an in vivo-like setting at skeletal sites within the torso such as the proximal femur. Even though ST scatter compromises image quality substantially, the major characteristics of the trabecular network can still be appreciated and quantified. Funding source Seed grant by the Department of Radiology, University of California, San Francisco, CA, USA     

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     

The Magnitude and Rate of Bone Loss in Ovariectomized Mice Differs Among Inbred Strains as Determined by Longitudinal In vivo Micro-Computed Tomography

Osteoporosis is characterized by low bone mass and a deterioration of bone architecture and likely is influenced by genetic factors. The ovariectomized (OVX) mouse is well suited for osteoporosis research, as shown to date by cross-sectional studies. Here, we investigate longitudinal changes by in vivo micro-computed tomography (micro-CT) to examine the skeletal response to OVX and patterns of change in three inbred strains of mice. We address whether higher baseline bone mass among the strains of mice provides protection against bone loss and if there is a common base level of bone quantity despite genetic background after the effects of OVX have stabilized. Groups of mice (n = 7 or 8/group) from three inbred strains (C3H/HeJ, C57BL/6J, BALB/cByJ) were subjected to OVX or sham OVX surgery at 12 weeks of age. Weekly in vivo micro-CT scans were performed for 5 weeks at the proximal tibia (skipping week 4). Femurs were harvested after week 5 for analysis of the distal metaphysis and midshaft. The baseline bone architecture differed among the three inbred strains of mice, as did the longitudinal patterns of change due to OVX. At the end point, all three strains retained different bone architecture at the proximal tibia, distal femur, and femur midshaft. Rate of bone loss was correlated to amount of baseline bone volume (R = 0.82, P < 0.001). Morphological analysis indicated that trabecular bone loss due to OVX was manifested through reduced connectivity instead of overall thinning and that the quantity and rate of bone loss due to estrogen deficiency were in part genetically regulated.     

Relation of Statin Use and Bone Loss: A Prospective Population-Based Cohort Study in Early Postmenopausal Women

Recent experimental and epidemiologic studies have suggested that the lipid-lowering drugs, statins, may have bone-protective effects. We studied the effects of statin use on the change in bone mineral density (BMD) in a prospective 4.5-year cohort study based on subjects from the Kuopio Osteoporosis Risk Factor and Prevention (OSTPRE) Study, Finland. Six hundred and twenty women aged 53–64 years were divided into four groups: 55 women reported continuous and 63 women occasional statin use during the follow-up; 142 non-users of statins reported hypercholesterolemia whereas 360 non-users did not. Spinal and femoral BMDs were measured by dual-energy X-ray densitometry in 1995–1996 and 1999–2000 and the BMD changes of the four groups were compared. Characteristics of the study population were obtained with postal inquiries. The mean annual spinal and femoral BMD changes of the study groups were 0.29% and −0.50% for the continuous statin users, 0.19% and −0.57% for the occasional statin users, 0.52% and −0.29% for the hypercholesterolemic non-users of statins, and 0.39% and −0.33% for the non-users of statins without hypercholesterolemia, (p= 0.398 and p = 0.404) respectively. The corresponding BMD changes adjusted for age, years since menopause, body mass index, BMD at baseline, calcium intake, estrogen and cortisone therapy, duration of follow-up and statin use before the baseline were −0.20% and −0.47%, 0.19% and −0.54%, 0.54% and −0.32%, 0.47% and −0.33% (p= 0.134 and p= 0.628), respectively. Our results suggest that statins do not protect from early postmenopausal bone loss. Randomized trials are needed to confirm these results. Received: 11 October 2001 / Accepted: 3 January 2002     

Calcium Supplementation Suppresses Bone Resorption in Early Postmenopausal Women

In order to establish whether calcium supplementation suppresses bone resorption in early postmenopausal women and whether any response is related to calcium absorption status, we studied 22 healthy women (median age 52 years) all within 5 years of the menopause. Urine was collected between 9.00 p.m. and 9.00 a.m., and 9.00 a.m. and 9.00 p.m., (2 days) and a fasting blood and spot urine sample was obtained at 9 a.m. On the first day, 5 μCi of ⁴⁵Ca in 250 ml water with 20 mg calcium carrier as the chloride was given at 9.00 a.m. and a further blood sample was obtained at 10.00 a.m. to measure calcium absorption. A 1 g calcium load was given at 9.00 p.m., immediately before the second 24-hour urine collection. There was a rise in plasma ionized calcium (1.18 ± 0.010 mmol/liter versus 1.21 ± 0.011 mmol/liter, P < 0.01) and a fall in plasma PTH (4.2 ± 0.34 pmol/liter versus 3.5 ± 0.31 pmol/liter, P < 0.01) from baseline after the calcium load, and a trend for the magnitude of the change in PTH to be inversely related to calcium absorption (r =−0.33, P= 0.13). In the fasting spot urine samples, there were falls in hydroxyproline (OHPr/Cr; 14.6 ± 0.71 versus 12.6 ± 0.83, P < 0.001), pyridinoline (Pyr/Cr; 75 ± 2.8 versus 70 ± 3.5, P < 0.05), and deoxypyridinoline (Dpd/Cr; 22.7 ± 1.2 versus 19.5 ± 1.1, P < 0.005) after the calcium load. The calcium load suppressed urinary Dpd/Cr between 9.00 p.m. and 9.00 a.m. (P < 0.005), but not between 9.00 a.m. and 9.00 p.m. We conclude that acute administration of a 1 g calcium load suppresses bone resorption in early postmenopausal women, probably by decreasing PTH secretion. Received: 2 December 1996 / Accepted: 21 May 1997     

Inhibition of Bone Resorption by Divided-Dose Calcium Supplementation in Early Postmenopausal Women

We have previously shown that a calcium (Ca) supplement of 1000 mg given in the evening reduces the overnight and early morning, but not the daytime, excretion of bone resorption markers in postmenopausal women within five years of the menopause. In the present study, we have looked at the effect of splitting the Ca into two doses of 500 mg each given in the morning and evening. We studied 19 healthy women (median age 53 years) who were all within 5 years of the menopause. On the 2 study days, urine was collected from 9 a.m. to 9 p.m. (day collection), and from 9 p.m. to 9 a.m. (night collection); a further fasting (spot) urine sample was obtained at 9 a.m. at the end of the night collection. The first day was a control day; on the second day the subjects ingested 500 mg Ca as the carbonate at 9 a.m. and 9 p.m. We measured pyridinoline cross-links excretion in all the samples, as well as hydroxyproline in the fasting urine. The Ca supplements lowered urinary excretion of the markers during the day (P < 0.01), had only a marginal effect during the night, but reduced excretion significantly in the fasting urine (P < 0.001). In the whole 24-hour period, the falls in resorption markers were small but comparable to those seen after the ingestion of 1 g of Ca in the evening. We conclude that the acute administration of 0.5 g Ca in the morning and evening reduced the markers of bone resorption in early postmenopausal women during the day but not during the following night, whereas the single 1 g supplement had the reverse effect. Over the 24-hour period, there was nothing to choose between the two regimes. Women at this stage in their life cycle probably require a larger Ca supplement if they are not taking estrogen. Received: 5 April 2000 / Accepted: 27 July 2000 / Online publication: 2 November 2000     

Bone Mineral Density of the Lumbar Spine is Associated with TNF Gene Polymorphisms in Early Postmenopausal Japanese Women

We investigated the relationships between tumor necrosis factor (TNF) gene polymorphism, circulating TNF-alpha (TNF-) concentrations, and bone mineral density (BMD) in the lumbar spine. TNF gene polymorphisms studied were the Nco I polymorphism within the first intron of TNF-beta (TNF-) and three single nucleotide polymorphisms in the promoter region of the TNF- gene, at positions –857, –863, and –1031. Allelic variants of the TNF gene were identified using restriction fragment length polymorphism (RFLP) analysis in 177 postmenopausal Japanese women within 10 years after menopause, aged 56.4 ± 4.5 years (mean ± SD). A significantly higher prevalence of the alleles TNF--863A (20.3% versus 9.9%) and TNF--1031C (21.3% versus 12.4%) was seen in the low BMD group (Z-score < 0, n = 91) than in the high BMD group (0 Z-score, n = 86). In genotype analysis, although difference did not reach a significant level, women with the rarest allelic variants, i.e., homozygous TNFb1, TNF--863A, and TNF--1031C, showed the lowest BMD Z-scores. Women with another rarest allelic variant, TNF--857T/T had significantly lower BMD Z-scores than did women with TNF--857C/T or –857C/C. The BMD Z-score decreased significantly with an increase in the total number of such rare alleles. Serum concentrations of TNF- did not differ significantly among groups divided by genotypes. Multiple linear regression analysis revealed that the total number of rare alleles, in addition to the body mass index and the number of years since menopause, was an independent predictor of the BMD. These presumptive functional polymorphisms of the TNF gene may be associated with the lumbar spine BMD in early postmenopausal Japanese women.     

Suppression of Bone Resorption in Early Postmenopausal Women by Intranasal Salmon Calcitonin in Relation to Dosage and Basal Bone Turnover

In the present study, we assessed the ability of increasing doses of intranasal calcitonin to suppress urinary deoxypyridinoline cross-link (DPD), a specific biochemical marker of bone resorption, in early postmenopausal women. Subjects consisted of 30 healthy Thai women within 5 years of postmenopause, randomly assigned to 50, 100, or 200 IU of intranasal calcitonin 5 days/week for 3 months. Calcium supplementation by calcium carbonate capsules at 750 mg of elemental calcium per day was given to all subjects. Twenty four-hour urine for DPD and creatinine assays was collected at baseline, 1 month, and 3 months after treatment. All DPD values were corrected with urinary creatinine before analyses. Data were expressed as mean ± SEM. DPD decreased significantly 1 month after intranasal calcitonin treatment (P < 0.01). However, at 3 months, DPD increased when compared with the values at 1 month (P < 0.01), suggesting that there may be a reduction in the suppression of bone resorption after prolonged calcitonin therapy. Using a stepwise multiple regression model to address whether dosage and DPD at baseline influence the response to intranasal calcitonin, it was found that DPD suppression after intranasal calcitonin was not related to dosage but was strongly associated with baseline DPD (P < 0.0001). Suppression of bone resorption in early postmenopausal women by intranasal calcitonin is determined more by the state of bone turnover at baseline than the dosage of calcitonin. Received: 10 March 1997 / Accepted: 14 November 1997     

Colles' Fracture of the Wrist as an Indicator of Underlying Osteoporosis in Postmenopausal Women: A Prospective Study of Bone Mineral Density and Bone Turnover Rate

Colles' fracture has been shown to be associated with an increased risk of hip fracture. The incidence of low bone mineral density (BMD) and high bone turnover in such patients is uncertain. The aim of this study was to prospectively assess BMD and bone turnover in a cohort of consecutive postmenopausal Colles' fracture patients. BMD (spine, hip and contra-lateral radius) was measured by dual-energy X-ray absorptiometry (DXA) within 2 weeks of fracture. Bone turnover was assessed within 4 days by measurement of serum osteocalcin, total alkaline phosphatase (TALP), bone-specific alkaline phosphatase (BSAP) and urine hydroxyproline. We recruited 106 (71%) of 149 consecutive patients. Fifty-one per cent of subjects had a history of previous fracture, and 25% a past history of wrist, hip or vertebral body fracture. The incidence of osteoporosis was 21%, 42% and 22% at the spine, hip and radius respectively. Fifty per cent of subjects had osteoporosis of at least one of these sites. When compared with the values expected for their age the patients were found to have higher BMD than expected at the spine, and slightly lower BMD at the hip and distal radius. Patients aged 65 years or less had lower hip BMD than expected from the age-matched normal range (p < 0.01). Osteocalcin and TALP levels did not differ from the normal ranges, but BSAP and hydroxyproline levels were significantly elevated (p < 0.001), within 37% and 25% of patients having levels above the respective normal ranges. We conclude that osteoporosis is common in patients with Colles' fracture; however, in older patients BMD is not lower than would be expected in the normal population. In patients aged 65 years or less BMD is lower than expected at the hip. Bone turnover rate is high in many such patients. Intervention to prevent future fracture would be appropriate in women aged 65 years or less with Colles' fracture.     

Estimation of the Architectural Properties of Cortical Bone Using Peripheral Quantitative Computed Tomography

We assessed the volumetric bone mineral density (vBMD) and cross-sectional architecture of cortical bone at the distal radius by peripheral quantitative computed tomography (pQCT). The volumetric bone mineral density [integral bone mineral density (BMDi), trabecular bone mineral density (BMDt) and cortical with subcortical bone mineral density (BMDsc)] and the architectural parameters [cortical bone area (CBA), cortical thickness (C-th), moment of inertia (Im) and polar moment of inertia (Ip)] were measured in 115 healthy premenopausal women, 48 osteoporotic postmenopausal women and 78 age-matched healthy postmenopausal women. Age-matched healthy women had higher values of vBMD and architectural parameters at the distal radius than osteoporotic women. Premenopausal women had higher values of vBMD and architectural parameters at the distal radius than postmenopausal women. The differences in the architectural parameters between age-matched healthy women and osteoporotic women were more pronounced when only the high density area (threshold 0.70 cm^–1) was included. However, the differences in architectural parameters between premenopausal women and postmenopausal women were significant using even the lowest threshold value of 0.50 cm^–1 in the calculation. Receiver operating characteristic (ROC) curves were constructed and the areas under the curves calculated to evaluate the discriminating power of vBMD and architectural parameters. Comparison of the different ROC curves showed no statistical significance. In conclusion, our results suggest that both the density and mass distribution of the radius were clearly different between the healthy women and osteoporotic women. The differences in architectural parameters were more useful for studying the pathopysiology of osteoporosis than for contributing to the diagnosis. Determination of the cross-sectional mass distribution of bone combined with BMD should offer more information than BMD alone in the study of the pathophysiology of osteoporosis. Received: 22 December 1998 / Accepted: 2 June 1999