The Decrease in Serum Bone-Specific Alkaline Phosphatase Predicts Bone Mineral Density Response to Hormone Replacement Therapy in Early Postmenopausal Women

Hormone replacement therapy (HRT) prevents bone loss in postmenopausal women. Up to 20% of women demonstrate no increase in bone mineral density (BMD) on HRT. We examined whether early changes in serum bone alkaline phosphatase (B-ALP) predict long-term BMD changes in postmenopausal women on HRT. Ninety women within 1 year of menopause were randomly assigned to continuous or sequential estrogen/progestin (beta estradiol/norethisterone acetate) if naturally postmenopausal, or beta estradiol if within 1 month of surgical menopause. Spine, femoral neck BMD (DXA), and B-ALP were determined over 2 years. The mean percent BMD changes were 3.8%, 2.9%, 1.6% in the spine and 2.4%, 4.0%, 1.1% in the femoral neck in sequential, continuous, and estrogen alone treatment groups, respectively, significantly different from zero except for femoral neck BMD change in the estrogen alone group. HRT was associated with spine and femoral neck BMD loss in 17.4% and 25.3% of women, respectively. In estrogen/progestin-treated women, baseline B-ALP correlated with spine BMD change (r = 0.42, P < 0.01). At 3 months, B-ALP dropped significantly in the estrogen/progestin-groups with a maximal decrease at 12 months, but no change from baseline in the estrogen alone group. Using quartile analysis, women with the greatest drop in B-ALP (≥50%) at 6 months demonstrated the greatest gain in spine BMD at 2 years. A 40% decrease at 6 months in B-ALP had a 56% sensitivity, 83% specificity, 95% positive predictive value for spine BMD gain at 2 years. The decrease in B-ALP can be used to monitor BMD response to HRT. Received: 6 January 1999 / Accepted: 13 August 1999     

Biochemical Markers of Bone Turnover and Bone Loss at the Lumbar Spine and Femoral Neck: The Taiji Study

The purpose of this study was to ascertain whether biochemical markers of bone turnover predict bone loss. The survey was carried out in Taiji, Wakayama Prefecture, Japan. From a list of inhabitants aged 40–79 years, 400 participants (50 men and 50 women in each of four age groups) were selected randomly. Bone mineral density (BMD) was measured, and blood and urine samples of all participants were examined to obtain values for eight biochemical markers: alkaline phosphatase (ALP), bone Gla protein (BGP), type I procollagen (carboxyterminal peptide of type I procollagen; PICP), cross-linked carboxyterminal telopeptide region of type I collagen (ICTP), and urinary excretion of calcium (Ca), phosphate (P), pyridinoline (Pyr), and deoxypyridinoline (D-Pyr). Each marker was evaluated as a predictor of the rate of bone change in lumbar spine and femoral neck BMD over a 3-year period. The value of Pyr was significantly related to the change of lumbar spine BMD in men (P= 0.009), and that of BGP was found to be significant in women (P= 0.045). By contrast, none of the bone markers significantly correlated with bone loss at the femoral neck. The coefficient of determination at the lumbar spine was 5% and 7% at the femoral neck only. We conclude that biochemical markers of bone turnover cannot predict bone loss rates in middle-aged or elderly Japanese men and women over a 3-year period with sufficient accuracy for use in clinical decision making. Received: 26 January 1998 / Accepted: 9 July 1998     

Effect of Long-Term Growth-Hormone Substitution Therapy on Bone Mineral Density and Parameters of Bone Metabolism in Adult Patients with Growth Hormone Deficiency

Reduced bone mineral density (BMD) and the prevalence for osteoporotic vertebral fractures are symptoms of growth hormone deficiency (GHD) syndrome, and GH replacement therapy is now available for GH-deficient adults. We investigated the long-term effects of GH replacement therapy on bone mineral density (BMD) and bone metabolism in 19 adult patients with GHD over a period of 18 months. In response to GH treatment, the initially decreased IGF-I concentrations rose significantly during 18 months of therapy to levels within the normal range (matched for sex and age) (mean change 158.1 ± 50.8 ng/ml, P < 0.001). Parameters of bone formation such as osteocalcin (OC) and procollagen I-C-Peptide (PICP) showed a significant increase in the first 6 months of therapy, followed by a slight decrease in the next months. Markers of bone resorption (Crosslaps^R and deoxypyridinoline (D-Pyr) also increased significantly with a peak value after 6 months and all parameters except PICP remained above baseline values after 18 months. BMD of the femoral neck (FN) showed an increase after 18 months of therapy (mean change 0.01 ± 0.03 g/cm² after 18 months, n.s.). However, the increase in BMD was significant only in the lumbar spine (LS) (mean change 0.03 ± 0.04 g/cm², P < 0.05 after 18 months). We conclude that GH replacement therapy in adult patients with GHD over a period of 18 months causes a pronounced increase in bone turnover mainly during the first 12 months of therapy and increases BMD of the lumbar spine and the femoral neck after 18 months. Received: 13 March 1997 / Accepted: 7 August 1997     

Short-Term Effect of Vitamin K Administration on Prednisolone-Induced Loss of Bone Mineral Density in Patients with Chronic Glomerulonephritis

Glucocorticoid-induced osteoporosis has been reported to be caused by enhanced bone resorption and suppressed bone formation. To clarify whether administration of vitamin K, which enhances bone formation, prevents prednisolone-induced loss of bone mineral density (BMD), a randomized, prospective, controlled study was conducted on 20 patients with chronic glomerulonephritis scheduled for treatment with prednisolone. All patients were initially treated with 0.8 mg/kg body weight/day of prednisolone (maximum of 40 mg) for 4 weeks, tapering to 20 mg/day over approximately 6 weeks. Ten patients received prednisolone alone (Group 1), and the other 10 patients received prednisolone plus 15 mg of menatetrenone, vitamin K, three times per day (Group 2). BMD of the lumbar spine measured by dual-energy X-ray absorptiometry (DXA) and biochemical markers of bone metabolism in blood and urine were evaluated before and 10 weeks after administration of prednisolone alone or with menatetrenone. In Group 1, treatment with prednisolone significantly reduced BMD of the lumbar spine from 1.14 ± 0.12 to 1.10 ± 0.11 g/cm² (P= 0.0029). Serum intact osteocalcin and procollagen type I C-peptide (PICP) concentrations, biochemical markers of bone formation, were markedly reduced. A biochemical marker of bone resorption, urinary excretion of deoxypyridinoline, was significantly reduced. In Group 2, prednisolone-induced reduction of BMD was prevented by menatetrenone administration (1.09 ± 0.09 to 1.07 ± 0.07 g/cm², P= 0.153). Menatetrenone prevented reduction of PICP concentration by prednisolone but not in serum intact osteocalcin concentration and urinary excretion of deoxypyridinoline. Thus, treatment with prednisolone resulted in loss of BMD of the lumbar spine associated with suppression of both bone formation and bone resorption. Menatetrenone is a useful agent in preventing prednisolone-induced loss of BMD. Received: 7 July 1998 / Accepted: 13 August 1999     

Acute Alteration in Bone Mineral Density and Biochemical Markers for Bone Metabolism in Nephrotic Patients Receiving High-Dose Glucocorticoid and One-Cycle Etidronate Therapy

It is widely known that glucocorticoids induce and accelerate osteoporosis. High-dose glucocorticoids are administrated daily to patients in the acute phase of nephrotic syndrome. It could be inferred that high-dose glucocorticoids rapidly decrease patients' basal bone mineral density (BMD) and this accelerates the natural progress of osteoporosis associated with aging or menopause. Nine nephrotic patients (male/female: 5/4) without previous prednisolone administration were chosen to measure BMD and the level of the markers for bone turnover before and after treatment for 3 months (total prednisolone administration: 4.5 ± 0.0 g). Twenty-three patients under remission with prednisolone administration (male/female: 14/9) were included in the long-term treatment group. Patients in this group whose %YAM in the lateral lumbar spine was less than 89% were classified into a low BMD group (n = 10, male/female: 3/7). They were administered etidronate disodium at 200 mg/day for 14 days. BMD and % of young adult mean (YAM) in the lumbar spine (L2-L4 in lateral objection) and other regions were measured by dual-energy X-ray absorptiometry. As markers of bone metabolism, the urinary level of deoxypyridinoline (Dpd) was determined to evaluate osteogenesis, and serum osteocalcin was measured to evaluate bone resorption. BMD of the lumbar spine significantly decreased in the 3-month treatment group (752 ± 96 mg/cm², 7 ± 4% reduction) compared with the pretreatment group (810 ± 85 mg/cm²). BMD in the long-term treatment group decreased continuously (683 ± 135 mg/cm²). No significant differences were noted in other measurement sites. BMD in the etidronate treatment group increased significantly (597 ± 55 mg/cm²) compared with the pretreatment group (549 ± 76 mg/cm²). Etidronate did not change BMD at the sites with a normal BMD. Among the biochemical markers (BM) examined, the urinary level of Dpd (nMol/liter · Cr) significantly increased in the 3-month treatment group (8.6 ± 5.1 nMol/liter·Cr) compared with the pretreatment group (5.8 ± 2.0 nMol/liter · Cr). No significant differences were seen in the BMs measured in the long-term treatment group. The urinary Dpd level of the etidronate treatment group decreased (3.9 ± 1.4 nMol/liter · Cr) compared with the pretreatment group. These data indicate that etidronate could improve the accelerated bone resorption. In conclusion, high-dose glucocorticoid therapy causes rapid bone resorption and accelerates the natural progress of osteoporosis associated with aging or menopause. Etidronate administration prevents the progress of osteoporosis in nephrotic patients. Preventive treatment should be performed when the estimated BMD in 3 months falls below the baseline by more than 7 ± 4%, reaching the therapeutic range. Received: 31 March 1999 / Accepted: 29 September 1999     

Relationships Between Bone Mass Measurements and Lifetime Physical Activity in a Swedish Population

Lifetime occupational and leisure time activities were assessed by a questionnaire in order to evaluate their relationship to bone mass measurements and biochemical markers of bone metabolism in a population of 61 women and 61 men, randomly selected from a Swedish population register, to represent ages between 22 and 85 years. We also considered possible confounders by using questions about smoking habits, milk consumption, hormone replacement therapy (HRT), and menopausal age. Bone mineral density (BMD) and bone mineral content (bone mass, BMC) of the total body, lumbar spine, and proximal femur (neck, trochanter, Ward's triangle) were measured by dual energy X-ray absorptiometry (DXA), and BMD of the forearm with single energy X-ray absorptiometry (SXA). In addition, both DXA and SXA provided information on bone area. Quantitative ultrasound measurements (QUS) at the heel were performed to assess the speed of sound (SOS) and broadband ultrasound attenuation (BUA). Fasting blood samples were analyzed for biochemical markers of bone metabolism as well as parathyroid hormone (PTH) and total serum calcium. After adjustment for confounding factors, neither BMD nor QUS measurements were consistently related to lifetime leisure time or occupational activities; nor were there any consistent patterns relating biochemical markers of bone metabolism to bone mass measurements. However, physical activity seemed to influence bone mass, area, and width more than density. In men, high levels of leisure time activity were associated with raised values for lumbar spine area (6.2%) and width (3.3%) as well as for femoral neck area (5.5%) compared with their low activity counterpart. Men exposed to high levels of occupational activity demonstrated lower lumbar spine BMD (10.9%) and area (5.3%) than men with low activity levels. Within an unselected Swedish population, estimation of lifetime occupational and sport activities as well as bedrest, using a questionnaire, demonstrated no major effects on bone density. However, the association between high levels of lifetime activity and raised values for bone mass, area, and width indicate that geometrical changes in bone may provide better estimations of mechanically induced bone strength than bone density, at least in men. Received: 20 May 1997 / Accepted: 15 October 1997     

Cytokine Production and Bone Mineral Density at the Lumbar Spine and Femoral Neck in Premenopausal Women

Cytokines such as interleukin-1 (IL-1β), interleukin-6 (IL-6) and tumor necrosis factor (TNF-α) can influence both bone resorption and bone formation. The objective of this cross-sectional study was to examine the relationship between cytokine production by peripheral blood mononuclear cells (PBMC) and bone mineral density (BMD); the annual rate of change in BMD was examined. Subjects participating in a randomized clinical trial entitled the Women's Healthy Lifestyle Project in Allegheny County, Pennsylvania were used. They included 50 healthy premenopausal women, aged 45–52 years, who had regular menses within the past 3 months and were not on replacement estrogens. Dual-energy X-ray absorptiometry measurements at the AP lumbar spine and femoral neck were made at baseline and at the first annual exam using a Hologic QDR 2000 densitometer. Cytokine production of IL-1β, IL-6, and TNF-α by PBMC was measured at the annual exam. The median values for stimulated cytokine production by PBMC were 3.92 ng/ml, 31.3 ng/ml, and 1.05 ng/ml, for IL-1β, IL-6, and TNF-α, respectively. There were modest correlations between cytokine production and cross-sectional BMD, ranging from r =−0.30 to r =−0.13. Trends of greater spinal bone loss were observed in women with ``high' (≥75th percentile) cytokine production of stimulated IL-1β and IL-6 (IL-1β: ``high' =−1.56% ± 0.70 versus ``low' (<75th percentile) =−0.56% ± 0.35, P= 0.21). In contrast, greater annual gains in femoral neck BMD were observed in those with high cytokine production of IL-1β and IL-6 (IL-1β: high = 3.39% ± 1.16 versus low =−0.85 ± 0.58, P= 0.002). There was no association between stimulated TNF production and annual change in BMD. In this population of healthy premenopausal women, the relationship between cytokine production by PBMC and the rate of change in BMD was significantly different for the lumbar spine and femoral neck, possibly reflecting differences in the proportion of trabecular and cortical bone at these sites. Received: 5 February 1997 / Accepted: 11 May 1998     

Effects of Risedronate Treatment on Bone Density and Vertebral Fracture in Patients on Corticosteroid Therapy

Men and women (n = 518) receiving moderate-to-high doses of corticosteroids were enrolled in two studies with similar protocols and randomly assigned to receive either placebo or risedronate (2.5 or 5 mg) for 1 year. All patients received daily calcium supplementation (500–1000 mg), and most also received supplemental vitamin D (400 IU). The primary endpoint was the difference between the placebo and active groups in lumbar spine bone mineral density (BMD) at 1 year; changes in BMD at other sites, biochemical markers of bone turnover, and the incidence of vertebral fractures were also assessed. In the overall population, the mean (SE) lumbar spine BMD increased 1.9 ± 0.38% from baseline in the risedronate 5 mg group (P < 0.001) and decreased 1.0 ± 0.4% in the placebo group (P= 0.005). BMD at the femoral neck, trochanter, and distal radius increased or was maintained with risedronate 5 mg treatment, but decreased in the placebo group. Midshaft radius BMD did not change significantly in either treatment group. The difference in BMD between the risedronate 5 mg and placebo groups was significant at all skeletal sites (P < 0.05) except the midshaft radius at 1 year. The 2.5 mg dose also had a positive effect on BMD, although of a lesser magnitude than that seen with risedronate 5 mg. A significant reduction of 70% in vertebral fracture risk was observed in the risedronate 5 mg group compared with the placebo group (P= 0.01). Risedronate was efficacious in both men and women, irrespective of underlying disease and duration of corticosteroid therapy, and had a favorable safety profile, with a similar incidence of upper gastrointestinal adverse events in the placebo and active treatment groups. Daily treatment with risedronate 5 mg significantly increases BMD and decreases vertebral fracture risk in patients receiving moderate-to-high doses of corticosteroid therapy. Received: 11 October 1999 / Accepted: 1 May 2000 / Online publication: 27 July 2000     

Risk Factors for the Development of Vertebral and Total Skeleton Osteoporosis in Patients with Primary Biliary Cirrhosis

The objectives of this work was to (1) study the bone mineral density (BMD) of the lumbar spine, total skeleton, and body composition in patients with primary biliary cirrhosis (PBC) and (2) evaluate the risk factors (premature menopause, stages of the disease, hyperbilirubinemia) and bone and liver biochemical parameters for the development of osteoporosis. We studied 23 women with a compatible diagnosis of PBC. The BMD and body composition were evaluated by X-ray absorptiometry (Lunar DPX-L). The average age of the population was 56.7 ± 10.2 years. The BMD of the lumbar spine and of the total skeleton was 1.3 SDs below the normal population matched for sex and age. In the total skeleton, the legs were the most severely affected area (Z score −1.5). The body composition showed no significant difference compared with the normal population. The BMD of 56% of the patients was less than −2.5 SDs from the average normal young values. Patients with a history of vertebral fractures had diminished mineral density of the lumbar spine, as did those who had had no fractures. Of the risk factors studied, patients with premature menopause had a lower bone mass compared with patients with normal menopausal age (Z score of the total skeleton was −2.1 ± 1.8 versus −1.1 ± 1.0) but the difference did not reach statistical significance. The bone mass was not affected in patients with regular menstrual cycles. There were no statistically significant differences in high levels of bilirubin, advanced stages of the disease, or the biochemical variables studied. It is concluded that patients with primary biliary cirrhosis present diminished cortical and trabecular bone mass, whereas body composition was unaffected. Premature hormone deficit, possibly triggered by the chronic hepatic pathology, is a contributing factor to the osteoporosis in this population. Received: 21 October 1997 / Accepted: 5 March 1998     

Dissimilar Spine and Femoral Z-Scores in Premenopausal Women

The purpose of this study was to determine if differences exist in premenopausal women between z-scores for lumbar spine and proximal femoral bone mineral densities (BMD). Participants were 237 women ranging in age from 20 to 45 years. BMDs of the lumbar spine and proximal femur (femoral neck, Ward's area, and trochanter) were assessed using dual-energy X-ray absorptiometry (Lunar DPX). Mean (±SD) age, height, and weight of the participants were 29.4 ± 6.9 years, 164.4 ± 6.1 cm, and 64.9 ± 12.1 kg, respectively. Lumbar spine BMD and BMD at the femoral neck, Ward's area, and trochanter were significantly correlated with large SEEs (r = 0.59–0.65; SEE = 0.09–0.11). No positive correlation with age and BMD at any site was seen in this population but a significant negative correlation with age was seen in the proximal femur beginning at age 30. Twenty to 24% of the 20–29-year-olds exhibited a difference in z-scores of greater than 1 between the spine and sites in the proximal femur. This percentage increased to 32–46% in the 30–45-year-olds but the nature of the observed differences changed. The differences in spine and proximal femoral z-scores that are seen in the older age group appear to be the result of the earlier onset of bone loss in the proximal femur rather than an initial difference in peak bone mass which has been maintained. Received: 28 August 1996 / Accepted: 25 April 1997     

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

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

Increased Bone Mineral Density after Prolonged Electrically Induced Cycle Training of Paralyzed Limbs in Spinal Cord Injured Man

Spinal cord injured (SCI) individuals have a substantial loss of bone mass in the lower limbs, equaling approximately 50% of normal values in the proximal tibia, and this has been associated with a high incidence of low impact fractures. To evaluate if this inactivity-associated condition in the SCI population can be reversed with prolonged physical training, ten SCI individuals [ages 35.3 ± 2.3 years (mean ± standard error [SE]); post injury time: 12.5 ± 2.7 years, range 2–24 years; level of lesion: C6–Th4; weight: 78 ± 3.8 kg] performed 12 months of Functional Electrical Stimulated (FES) upright cycling for 30 min per day, 3 days per week, followed by six months with only one weekly training session. Bone mineral density (BMD) was determined before training and 12 and 18 months later. BMD was measured in the lumbar spine, the femoral neck, and the proximal tibia by dual energy absorptiometry (DEXA, Nordland XR 26 MK1). Before training, BMD was in the proximal tibia (52%), as well as in the femoral neck, lower in SCI subjects than in controls of same age (P < 0.05). BMD of the lumbar spine did not differ between groups (P > 0.05). After 12 months of training, the BMD of the proximal tibia had increased 10%, from 0.49 ± 0.04 to 0.54 ± 0.04 g/cm² (P < 0.05). After a further 6 months with reduced training, the BMD in the proximal tibia no longer differed from the BMD before training (P > 0.05). No changes were observed in the lumbar spine or in the femoral neck in response to FES cycle training. It is concluded that in SCI, the loss of bone mass in the proximal tibia can be partially reversed by regular long-term FES cycle exercise. However, one exercise session per week is insufficient to maintain this increase. Received: 30 July 1996 / Accepted: 31 December 1996     

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

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

Allogeneic Bone Marrow Transplantation is Associated with a Preferential Femoral Neck Bone Loss

Osteoporosis is a major complication of organ transplantation. Little is known about the risk of developing osteoporosis in bone marrow transplant (BMT) recipients. We studied early and late changes in bone mineral density (BMD), as well as biochemical markers of bone remodeling, in patients at the time of allogeneic BMT (alloBMT) and up to 13 years thereafter. In a cross-sectional study, 102 patients (40 women, 62 men, mean age ± SEM, 38.9 ± 1.6 years) were segregated into a first group (A, n= 48) and evaluated before or during the first weeks (mean ± SD 0.3 ± 0.1 month, range –0.5 to 3 months) following alloBMT, and a second group (B, n= 54) studied 60.1 ± 5.6 months (range 6–156 months) following alloBMT. Lumbar spine (LS) BMD was similar in groups A and B and was within normal limits. In contrast, femoral neck (FN) Z- and T-scores were significantly decreased in group B compared with group A (–0.68 ± 0.14 vs –0.03 ± 0.14 SD and –0.84 ± 0.14 vs –0.22 ± 0.14 SD, respectively; p≤0.002). Osteopenia (T-score between –1 and –2.5 SD) was present in 35% of group A and 43% of group B patients (NS). Osteoporosis (T-score <–2.5 SD) was detected in 7% of group B patients, but in none of those in group A (p= 0.05). In a longitudinal study, 56 subjects were evaluated at the time of alloBMT, and 33 and 23 were studied 6 or 12 months later, respectively (13 women, 20 men, 37.5 ± 1.6 years). All were treated with supplements of calcium and vitamin D. Amenorrheic women received hormone replacement therapy (HRT). Three-monthly pamidronate infusions were given to 15 men and 10 non-amenorrheic women who were osteopenic/osteoporotic or had elevated baseline bone turnover markers. Mean baseline LS and FN Z- and T-scores were within normal range. Six months after BMT, FN BMD decreased by 4.2 ± 0.7% (p<0.001), and whole body BMD and bone mineral content by 1.5 ± 0.4% and 3.1 ± 0.6%, respectively (p≤0.0001). Twelve months after the graft, there was no further significant bone loss and only FN BMD decrease remained significantly different compared with baseline (–5.6 ± 1.1%, p≤0.0001). These results indicate that the risk of decreased BMD is higher for the femoral neck than the lumbar spine and whole body levels in patients with allogeneic bone marrow transplantation, and that bone loss occurs mainly during the first 6 months after the graft. Received: 9 February 2001 / Accepted: 23 May 2001     

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     

Randomized, Double-masked, 2-year Comparison of Tibolone with 17β-Estradiol and Norethindrone Acetate in Preventing Postmenopausal Bone Loss

In this 2-year, randomized study, we compared the efficacy and tolerability of tibolone 2.5 mg (n= 75), tibolone 1.25 mg (n= 76) and estradiol 2 mg plus norethindrone acetate 1 mg (E₂/NETA; n= 74) for preventing bone loss in postmenopausal women. Bone mineral density (BMD), measured by dual-energy X-ray absorptiometry, and bone remodeling markers were assessed every 6 months. Side-effects were assessed quarterly. After 24 months, the mean increase (± SD) in lumbar spine BMD from baseline was 3.6%± 2.9%, 1.9%± 3.5% and 6.8%± 4.5% in the tibolone 2.5 mg, tibolone 1.25 mg and E₂/NETA groups, respectively. All pairwise differences were significant. The proportion of responders (women with a change from baseline in lumbar spine BMD of ≥−2% after 2 years) was 95.7%, 89.0% and 98.5% with tibolone 2.5 mg, tibolone 1.25 mg and E₂/NETA, respectively. Similar results were obtained for femoral BMD, although the difference between tibolone 2.5 mg and E₂/NETA was not significant at 24 months. Decreases in bone remodeling markers were similar in the three groups. Vaginal bleeding was more common in the E₂/NETA group (33.8%) than with tibolone 2.5 mg (12.0%) or tibolone 1.25 mg (9.2%), as was breast pain (23.0%, 2.7% and 2.6%, respectively). Each treatment effectively prevented bone loss. Overall, tolerability of tibolone was better than with E₂/NETA, because of less frequent vaginal bleeding and breast pain. This may promote long-term adherence. Received: 6 July 2001 / Accepted: 3 October 2001     

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

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

Once-weekly teriparatide reduces serum sclerostin levels in postmenopausal women with osteoprosis

Once-weekly teriparatide treatment is widely used in the treatment of osteoporosis in Japan but the mechanisms causing the increase in bone mineral density (BMD) of the lumbar spine remain unknown. Methods: This prospective study examined the effects of once-weekly teriparatide treatment on the serum levels of sclerostin, osteocalcin, and bone formation markers as well as BMD of the lumbar spine and femoral neck in 32 postmenopausal women with osteoporosis. Results: The mean age of subjects was 76.3 ± 7.0 years old. Teriparatide significantly reduced serum sclerostin levels at 12 and 18 months in postmenopausal women with osteoporosis, and significantly increased serum osteocalcin levels at 3,12 and 18 months and PINP levels at 1 and 3 months, respectively. Teriparatide treatment significantly increased BMD of the lumbar spine at 6, 12, and 18 months, but did not affect BMD of the femoral neck. Examination of the relationships between percent changes in bone metabolic indices and BMD of the lumbar spine during the teriparatide treatment showed serum sclerostin changes at 3 months were negatively correlated with BMD changes of the lumbar spine at 6, 12, and 18 months. Serum osteocalcin changes were not correlated with BMD changes in the lumbar spine at 12 months. Conclusions: The present study showed that once-weekly teriparatide treatment reduced serum sclerostin levels in postmenopausal women with osteoporosis. The effects of teriparatide on sclerostin may be associated with the response of the BMD of the lumbar spine.     

Diurnal Variation of Bone Mineral Turnover in Elderly Men and Women

The diurnal variation of markers of bone mineral metabolism have been documented in pre- and early postmenopausal women. Such rhythms have clinical implications for timing of sample collection and assessment of therapeutic intervention. To examine the diurnal variation of bone turnover in the elderly, we examined markers of bone formation [serum osteocalcin (OC) and bone-specific alkaline phosphatase (B-ALP)]; a marker of bone resorption (urinary N-telopeptide cross-linked collagen type 1 [NTX]); and serum calcium and parathyroid hormone (PTH) over 24 hours. Subjects were healthy community-dwelling elderly who were on no medications known to significantly alter bone mineral metabolism. Subjects included 14 women [74 ± 6 years (mean ± SD)] and 14 men (80 ± 5 years). Over the 24-hour sampling period, mean serum OC, B-ALP, and calcium values were similar in elderly men and women. However, mean serum PTH was significantly higher in elderly men compared with women (P < 0.05). The magnitude of the diurnal variation of urinary NTX was significantly higher in women compared with men (P < 0.05). There was a significant diurnal variation for serum OC, B-ALP, calcium, PTH, and urinary NTX in both elderly men and women. The magnitude of the diurnal variation was approximately 10–20% of mean value for OC and B-ALP, 30% for PTH, and up to 40% for urinary NTX. We conclude that there is significant diurnal variation in the markers of bone mineral metabolism for elderly men and women. The peak value, which on average would be 20% higher than the mean value for urinary NTX, highlights the importance of the timing of sample collection for appropriate interpretation of therapeutic response. In addition, gender-related differences, including relatively higher levels of serum PTH and lower levels of urinary NTX in elderly men, may help explain differences in rates of bone loss in this age group. Received: 21 June 1996 / Accepted: 18 October 1996     

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

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