Increased Serum Levels of N-Telopeptides (NTx) of Bone Collagen in Postmenopausal Nigerian Women

Serum levels of cross-linked N-telopeptides (NTx) of bone collagen, alkaline phosphatase (ALP), and intact parathyroid hormone (PTH) were determined in 64 premenopausal (PRM) and 86 postmenopausal (PSM) women living in northern Nigeria. Serum NTx values were correlated with ALP activity (r = 0.31–0.58, P < 0.01) and PTH (0.32–0.35, P < 0.01)) in all of the subjects studied, and were also related to age (−0.47, P < 0.001) and body mass index (−0.45, P < 0.001) in PRM women. Menopause had the effect of increasing the circulating concentrations of NTx and ALP activity by 15% (P= 0.001) and 11% (P= 0.02), respectively; however, serum levels of PTH were not different between these two groups of women. Compared with Caucasian counterparts matched for age and body mass index, PSM Nigerian women had significantly increased circulating concentrations of NTx (21.7 versus 16.2 nmol BCE/liter, P= 0.01) and demonstrated a trend towards higher ALP activities and PTH levels. These results indicate that (1) discrete reference intervals should be defined for biochemical markers of bone metabolism in African populations, (2) Nigerian women have relatively higher rates of bone turnover, and (3) further investigation of the implications of increased serum NTx should be undertaken using physical methods such as dual X-ray absorptiometry (DXA) and bone ultrasound attenuation. Received: 16 September 1998 / Accepted: 10 January 1999     

The Effects of 10 Weeks Military Training on Heel Ultrasound and Bone Turnover

To measure the physiological changes in bone in response to strenuous exercise we performed a prospective study of male army recruits over 10 weeks of basic training. Measurements performed at the start and completion of training consisted of ultrasound (US) measurements of the heel: velocity of sound (VOS in m/seconds) and broadband ultrasound attenuation (BUA in dB/MHz) and bone turnover markers; osteocalcin (OC), bone-specific alkaline phosphatase (BALP), and tartrate-resistant acid phosphatase (TRAP). Forty subjects were recruited for the study and 26 completed training. Over the 10-week study period there was a significant 1.7% fall in mean VOS [mean paired difference (mpd) 27.2 m/second, SEM 9.5 (95% CI 7.5–46.8) P= 0.009] and a nonsignificant 3.4% increase in BUA (P= 0.159). There were significant falls in markers of bone formation OC [11.6%, mpd 0.11 μg/liter (95% CI 0.07–0.14) P < 0.001] and BALP [13.3%, mpd 3.49 U/liter (CI 0.80–6.18) P= 0.013] and a nonsignificant 9.5% fall in TRAP a marker of bone resorption. The 10 recruits subsequently injured had a significantly lower VOS on entry [mean difference 24.2 m/seconds (95% CI 4.6–43.7) P= 0.017] and nonsignificantly raised BUA and baseline levels of all bone markers. The ultrasound changes may be accounted for by increase in trabecular separation and a fall in trabecular connectivity due to microfracture. The decrease in bone markers implies a fall in bone turnover. Received: 26 June 1997 / Accepted: 26 August 1998     

The Efficacy and Tolerability of Alendronate in Postmenopausal Osteoporotic Chinese Women: A Randomized Placebo-Controlled Study

Osteoporosis is a growing health problem in Asian women and it is expected that half of the world's hip fractures will occur in Asia in 50 years' time. As the use of hormonal replacement therapy (HRT) is extremely low in postmenopausal Asian women, nonhormonal agents will be more acceptable for the treatment and prevention of osteoporosis. The efficacy, tolerability, and acceptability of alendronate, an amino-bisphosphonate, for Asian women was evaluated in 70 osteoporotic southern Chinese women in a prospective, randomized, double-blind study. The subjects were randomized to receive either alendronate 10 mg daily or placebo, plus calcium supplementation 500 mg daily. The baseline L 1–4 and hip bone mineral density (BMD) were similar between both groups. At the end of 1 year, there was an increase of 5.8% in the lumbar spine BMD and 3.4% at the total hip with alendronate treatment when compared with baseline values (P < 0.001). Alendronate treatment for 1 year resulted in significant improvement in BMD at all sites measured when compared with placebo. There was also marked reduction in serum alkaline phosphatase (ALP) and urinary n-telopeptide (NTx) in the alendronate group when compared with the placebo group (ALP 25% versus 2%, NTx 75% versus 14%, both P < 0.005). The changes in ALP and NTx at 6 and 12 months correlated with the change in BMD at all sites measured at 1 year (P all <0.05). Alendronate was well tolerated and accepted, although two cases of gastric ulcer were reported. We conclude that alendronate is an effective and well-accepted agent for the treatment of osteoporosis in Asian women. Received: 30 September 1999 / Accepted 6 April 2000     

Measurement of Bone Mineral Density by Dual X-ray Absorptiometry in Paget's Disease Before and After Pamidronate Treatment

Third-generation bisphosphonates are now currently used in the treatment of Paget's disease of bone. Dual X-ray absorptiometry may make it possible to quantify the action of these bisphosphonates on bone mineral density (BMD) in pagetic and nonpagetic bone. We used Lunar DPX, a total-body software program (automatic analysis and/or manual windows according to the site and bilateral or unilateral pagetic involvement) to study BMD in 28 patients (18 men, 10 women, mean age 69.8 years) with Paget's disease before and 6 months after infusions of 60 mg (alkaline phosphatase <350 IU) or 120 mg (ALP >350 IU) of pamidronate. Before treatment, in the 28 patients, the BMD of trabecular pagetic bone was 25% higher than that of nonpagetic bone; in cortical pagetic bone the BMD was 35% higher. After treatment, the BMD of trabecular pagetic bone increased by only 1.17%. the BMD of cortical pagetic bone increased by 1.37% whereas nonpagetic cortical bone lost 0.84%, independently of the levels of parathyroid hormone or the administration of calcium and vitamin D. Received: 17 March 1998 / Accepted: 12 March 1999     

The Effect of Intermittent Slow-Release Sodium Fluoride and Continuous Calcium Citrate Therapy on Calcitropic Hormones, Biochemical Markers of Bone Metabolism, and Blood Chemistry in Postmenopausal Osteoporosis

A detailed examination of calcitropic hormones and biochemical markers of bone turnover, serum chemistry, and blood hematology was performed in 75 postmenopausal women allocated to two groups: placebo plus calcium citrate (400 mg Ca B.I.D.) (n = 36) or intermittent slow-release sodium fluoride (SRNaF, 25 mg B.I.D.) plus calcium citrate (n = 39). After 2 years of therapy, a significant reduction in serum immunoreactive parathyroid hormone (PTH) was seen for both groups (43 ± 18 SD–30 ± 11 ng/liter, in placebo and 46 ± 24–36 ± 10, in SRNaF P < 0.0001 for both groups). Serum 1,25(OH)₂D significantly fell in placebo-treated patients (91 ± 31–75 ± 34 pmol/liter, P= 0.001) but did not change for SRNaF-treated patients. This difference in response between placebo and SRNaF-treated groups was significant, P= 0.005. Urinary hydroxyproline significantly declined during treatment in both groups (130 ± 61–76 ± 38 μmol/day, for placebo and 138 ± 84–84 ± 38 for SRNaF, P= 0.001). Similar decreases in urinary N-telopeptide of type I collagen were also observed for both groups (305 ± 192–252 ± 197 nmoles BCE/day for placebo and 356 ± 230–220 ± 197, P= 0.0001 for SRNaF). Serum carboxyterminal propeptide of type I collagen (PICP) declined significantly in both the placebo and SRNaF groups (118 ± 38–101 ± 36 μg/liter, and 116 ± 47–105 ± 39, P= 0.0027). Serum osteocalcin did not change significantly for either group, but bone-specific alkaline phosphatase (BS-ALPase), another marker of bone formation, demonstrated a significant fall in the placebo group at 2 years of therapy (16.2 ± 6.7 U/liter–12.1 ± 3.5, P= 0.009) and a small increase in the SRNaF-treated patients (13.0 ± 4.1–15.0 ± 4.5). The observed difference in response of BS-ALPase between the placebo and treated groups was significant (P= 0.007). There were no significant changes within or between treatment groups for blood hematology or serum chemistries. Mean values for all parameters remained within established normal ranges. These findings suggest that administration of calcium citrate inhibited PTH secretion and thereby reduced bone resorption in both groups, indicated by a decline in serum PTH, urinary hydroxyproline, and N-telopeptide. A low turnover state of bone may have been produced in the placebo group taking calcium citrate alone, since serum PICP, BS-ALPase, and 1,25(OH)₂D also decreased. The addition of SRNaF prevented serum 1,25(OH)₂D from falling by an unknown mechanism. However, its anabolic action on the skeleton was best reflected by changes in BS-ALPase. Moreover, SRNaF appeared to exert no deleterious effects on blood chemistries or hematology during 2 years of administration. Received: 28 January 1996 / Accepted: 25 April 1997     

Differences in Bone Turnover and Skeletal Response to Thyroid Hormone Treatment Between Estrogen-Depleted and Repleted Rats

This study was undertaken to compare the effect of supraphysiological doses of thyroxine (T4) on bone metabolism in SHAM and OVX young adult rats. Female Sprague Dawley rats (220 ± 2 g, approx. 5 months of age) were divided into four groups of eight animals each. The animals were intraperitoneally injected 6 days per week with vehicle (Vh): 0.001 N NaOH/0.9% NaCl (SHAM+Vh and OVX+Vh) or 250 μg of thyroxine/kg/day (SHAM+T4 and OVX+T4) during a 5-week period. Serum T4 and osteocalcin (BGP), urinary pyridinolines (Pyr), and creatinine (creat) were determined. At the beginning and at end of the experiment, skeletal bone mineral content (BMC), bone mineral density (BMD), and area (A) of the total skeleton, femur, spine, and whole tibia, as well as proximal, middle, and distal areas of the tibia were assessed by dual X-ray absorptiometry (DXA) in an ultra-high-resolution mode. T4 treatment of the SHAM rats did not induce significant changes in BGP level or Pyr/creat excretion compared with the SHAM+Vh control group. However, these two biochemical bone markers significantly increased due to T4 treatment in OVX rats compared with both OVX+Vh and SHAM+T4 groups (P < 0.05 and P < 0.001, respectively). The OVX+T4 group had a significantly lower ΔBMD than SHAM+T4 rats in all studied regions (P < 0.05) except for the middle tibia region. OVX+T4 groups presented a significantly lower ΔBMC and ΔA compared with SHAM+T4 animals (P < 0.001). OVX+T4 rats significantly impaired the ΔBMD in the femur (P < 0.01), spine (P < 0.05), whole (P < 0.05) and middle (P < 0.05) tibia whereas T4 treatment of SHAM rats only affected, significantly, the whole (P < 0.05) and the proximal tibia region (P < 0.01). T4 treatment affects bone growth in young adult rats. The effect is significantly greater in the estrogen-depleted than in the estrogen-repleted state. The bone site most adversely affected by T4 treatment depends on the estrogen status. The proximal tibia (principally trabecular bone) was the most affected area in estrogen-repleted rats. Conversely, in OVX rats, the middle tibia (principally cortical bone) presented the greatest decrease in bone density. Received: 20 May 1999 / Accepted: 4 February 2000     

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 Promethazine on Bone Mass and on Bone Remodeling in Ovariectomized Rats: A Morphometric, Densitometric, and Histomorphometric Experimental Study

The effect of promethazine on bone is debated. We studied the effect of promethazine on bone and the mechanism of action involved by densitometric and histomorphometric measurements in female Wistar rats (100 days old, mean weight 25 ± 20 g). A control group of 15 rats was not manipulated. An experimental group of 15 rats were ovariectomized (OVX) at 100 days of life and fed a diet supplemented with 4.8 mg/kg promethazine hydrochloride (OVX + Prom). The group that underwent OVX and a group of 15 rats that underwent sham ovariectomy (Sham-OVX) were not treated with promethazine. After 30 days, all the rats were killed. Their femur and 5th lumbar vertebra were dissected and cleaned of soft tissue. Femoral length and vertebral height were measured with a caliper and bones were weighed on a precision balance. The bone mineral content (BMC) and bone mineral density (BMD) of the whole right femurs and 5th lumbar vertebras were measured by dual-energy X-ray absorptiometry (DXA). Trabecular bone volume (Cn-BV-TV%), trabecular number (Tb-N mm⁻¹), trabecular thickness (Tb-Th μm), and trabecular separation (Tb-Sp μm) were measured in the femurs by histomorphometric study of nondecalcified bone. Our results showed that promethazine significantly inhibited postovariectomy loss of bone mass (P < 0.0001) by significantly reducing bone resorption, as shown by the smaller trabecular spaces observed in the treated OVX rats (P < 0.0001). Received: 1 June 1998 / Accepted: 17 February 1999     

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

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

Ovariectomy-Induced Bone Loss Can be Affected by Different Intensities of Treadmill Running Exercise in Rats

Fifty-six Sprague-Dawley rats were either ovariectomized (OVX, n= 24), sham-operated (Sham, n= 24), or sacrificed (n= 8) at the beginning of the experiment to serve as a baseline group. The OVX and Sham groups were further randomly divided into control (CTRL), slow running (R10), and faster running (R18) groups. R10 and R18 groups ran for 2 × 30 min/day for 8 weeks at speeds of 10 m/min and 18 m/min, respectively. Exercise did not affect the mechanical or histomorphometric parameters of bone in the sham-operated rats. There was no effect of exercise on body weight gain in the OVX-R10 group, but in OVX-R18 it decreased the gain of body weight. In the OVX–CTRL group the maximal load and energy absorption of the femoral neck were 16.7% (P < 0.001) and 30.0% (P < 0.001) lower than in the Sham–CTRL group, respectively. In OVX animals, slow running had a positive effect on the maximal load of the femoral neck (86.5 N) when compared with OVX–CTRL rats (77.1 N, P < 0.07). 51.7% of the trabecular bone was lost in the distal femur as a result of OVX and exercise reduced this loss to 30.2% (R10) and 39.9% (R18). Ovariectomy increased the bone formation rate (BFR) and the mineral apposition rate (MAR) on the periosteum of the femoral shaft. Exercise decreased the periosteal BFR and MAR in OVX rats, but increased it at the endosteum. Osteoclast numbers in the femoral metaphysis were increased after OVX and running exercise inhibited this effect significantly. The maximal bending load of the humerus increased after OVX by 12.1% (P < 0.05). Exercise enhanced this effect, the slow running being more effective. These results suggest that bone in OVX rats is either more sensitive to exercise than in sham-operated rats or that the higher body weight with slow running induces optimal loading and strengthens the bones. Received: 2 May 1996 / Accepted: 15 October 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     

A Double Blind,Placebo-Controlled Trial of Ipriflavone for Prevention of Postmenopausal Spinal Bone Loss

One hundred ninety-eight postmenopausal women (aged 50–65 years) with vertebral bone density (VBD) 1 SD below the mean value for normal, age-matched, postmenopausal subjects were enrolled in six Italian centers and 134 completed 2 years of treatment. All subjects were randomly allocated to a 2-year treatment with oral ipriflavone (200 mg t.i.d.) or a matching placebo, according to a double-blind, parallel group design. All patients also received an oral daily calcium supplement of 1 g as calcium carbonate. VBD and markers of bone turnover were measured at baseline, and every 6 months. A complete routine analysis of liver and kidney functions along with hematological parameters were measured before and at the end of treatment period. The valid completers analysis showed a significant increase of VBD in ipriflavone-treated women with average percent changes of +1.4 after 1 year, and +1% at the end of treatment period (P < 0.05). The placebo group presented a significant decrease of VBD after 2 years of treatment (P < 0.05). The difference between treatments was significant (P < 0.01). The intention to treat analysis confirmed the significant decrease of VBD in the placebo group, with no changes in ipriflavone-treated women. Skeletal ALP significantly decreased in ipriflavone-treated women (P < 0.05). Serum BGP and urine HOP/Cr showed a significant decrease only in ipriflavone-treated women, suggesting an inhibitory effect on bone turnover rate. Adverse reactions, mainly gastrointestinal, occurred to a similar extent in the two treatment groups. The evaluation of patients' compliance, assessed by residual tablets count, revealed a drug intake of more than 80% after 2 years in 92.5% and 92.8% of patients treated with ipriflavone or placebo, respectively. This study demonstrates that ipriflavone can prevent bone loss in postmenopausal women with low bone mass. Received: 1 April 1996 / Accepted: 5 March 1997     

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

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

Bone Mineral Density and Bone Size in Men With Primary Osteoporosis and Vertebral Fractures

The bone mineral density (BMD) at the lumbar spine, proximal femur, and total skeleton was evaluated in 38 men with primary osteoporosis and vertebral fractures. BMD of the patients was significantly reduced over all skeletal areas compared with controls. The Z-score of the lumbar spine (−2.8 ± 0.9) was less than that of the other areas (P < 0.001) except the legs (−2.5 ± 1.1) (p.n.s.) showing that bone loss had a tendency to be greater over the axial skeleton. Vertebral dimensions compared with age-matched controls were as follows: projected L2–L4 area (cm 2): 45.7 ± 5.6 versus 53.7 ± 3.6 (P < 0.001); vertebral width (cm): 4.37 ± 0.44 versus 4.90 ± 0.36 (P < 0.001). Serum biochemical parameters and testosterone levels were similar between osteoporotic and control men. We conclude that men with vertebral osteoporotic fractures have reduced vertebral BMD and vertebral dimensions compared with age-matched controls. Thus, these findings indicate that the achievement of a reduced bone size at the end of the growth period or a failure of periosteal increase during adult life is likely to contribute to the pathogenesis of the vertebral fractures observed in older men. Received: 31 January 1997 / Accepted: 2 July 1997     

Geographic Differences in Bone Turnover: Data from a Multinational Study in Healthy Postmenopausal Women

Biochemical markers of bone metabolism (bone markers) are used increasingly to monitor response to therapy and may be predictors of bone loss and fractures. The relationship between fracture rates, which differ between countries, and the rate of bone turnover has not been examined. Therefore, we explored the geographic variability of bone turnover in a selected, healthy study population of 619 postmenopausal women, ages 40–61, participating in a clinical trial of raloxifene hydrochloride for osteoporosis prevention. The subjects were distributed among 38 investigative sites in 10 countries (9–211 subjects/country) on four continents (North America, n = 277, Europe, n = 168, Australia, n = 125, and Africa, n = 49). Specimens for serum osteocalcin (OC), bone-specific alkaline phosphatase (BSAP), and urine type I collagen fragment/urinary creatinine ratio (CTX) were handled in a uniform fashion and assayed in a central laboratory. Mean levels of OC (P < 0.001), BSAP (P= 0.006), and CTX (P < 0.001) varied significantly by country (ANOVA), with the lowest values typically in German and Spanish subjects and the highest in American and Canadian subjects. The consistent pattern and wide ranges of mean bone marker values (OC 1.6-fold, BSAP 1.7-fold, CTX 3.1-fold) between countries suggest clinically significant differences in bone turnover. Geographic differences in bone markers were not explained by the determined potential confounders of age, years posthysterectomy, total serum cholesterol, and serum follicle stimulating hormone (FSH). We conclude that bone marker values vary substantially by country in this selected study population, suggesting systematic geographic differences in bone metabolism that potentially relate to osteoporotic fracture rates. Received: 28 November 1997 / Accepted: 23 March 1998     

Bone Mineral Densitometry Substantially Influences Health-Related Behaviors of Postmenopausal Women

Although bone mineral density measurements are helpful in predicting future risk for osteoporotic fractures, there is limited information available on how the results of bone densitometry influence a woman's use of therapeutic alternatives. To assess the role of bone mineral densitometry in influencing postmenopausal women to change health behaviors associated with osteoporosis, we prospectively followed, for an average of 2.9 years, 701 postmenopausal women over 50 years of age referred to an osteoporosis prevention program in a large metropolitan area. Assessments included bone mineral densitometry by dual-energy X-ray absorptiometry (with classification of skeletal health), medical history, use of hormone replacement therapy, calcium intake, caffeine intake, exercise, smoking habits, and fall precaution measures. Women classified at baseline with moderate low bone mass were twice as likely (33%), and women with severe low bone mass more than three times as likely (47%) to start hormone replacement therapy compared with women with a normal result (13%, P < 0.001). This was true regardless of whether they had taken hormone replacement therapy in the past. Below-normal BMD was a strong predictor of a woman's initiation of hormone replacement therapy (OR 4.2; 95% CI 2.7–6.4; P < 0.05) even after adjustment for age, education, history of osteoporosis or fracture, and medical condition related to osteoporosis. Women with moderate or severe low bone mass were also much more likely to start calcium supplements (81–90% versus 67%), increase dietary calcium (71–82% versus 60%), decrease use of caffeine (44–60% versus 34%), start exercising (61–76% versus 52%), and quit smoking (22–24% versus 11%) relative to their behaviors prior to testing (P < 0.01). In conclusion, postmenopausal women report that the results of bone densitometry substantially influence the decision to begin hormone replacement therapy and calcium supplements, increase dietary calcium, decrease caffeine, increase exercise, decrease smoking, and take precautions to prevent falls. More studies are needed to measure the long-term effects of this influence. Received: 19 March 1999 / Accepted: 13 August 1999     

Effects of Age on Serum Dehydroepiandrosterone Sulfate, IGF-I, and IL-6 Levels in Women

Data from animal and in vitro studies suggest that the growth-promoting effects of the adrenal androgen dehydroepiandrosterone sulfate (DHEAS) may be mediated by stimulation of insulin-like growth factor-I (IGF-I) and/or inhibition of interleukin 6 (IL-6), a cytokine mediator of bone resorption. This study tests the hypotheses that there are effects of age on serum DHEAS, IGF-I, and IL-6 levels, and that levels of IGF-I and IL-6 are related to DHEAS levels. The study included 102 women: 27 premenopausal and 75 postmenopausal, including 35 postmenopausal women with osteoporosis, as defined by bone mineral density scores by dual X-ray energy absorptiometry. DHEAS levels decreased significantly with age (r =−0.52, P < 0.0001) and IGF-I levels decreased significantly with age (r =−0.49, P < 0.0001). IL-6 levels increased significantly with age (r = 0.36, P= 0.008). IGF-I was positively correlated to DHEAS levels (r = 0.43, P < 0.0001, n = 102) and IL-6 levels were negatively correlated to DHEAS levels (r =−0.32, P= 0.021, n = 54). Levels of DHEAS and IGF-I were correlated with T scores of the spine and some hip sites. In a multiple variable model to predict DHEAS, age was an important predictor (P < 0.001), but osteoporosis status, IGF-I, and IL-6 were not. The median DHEAS level was lower in the postmenopausal osteoporotic women (67 μg/dl, n = 35) than in the nonosteoporotic postmenopausal women (106.3 μg/dl, n = 40, P= 0.03), but this was not significant after correction for age. Age accounted for 32% of the variance in DHEAS levels. In summary, DHEAS levels decreased with age and had a positive association with IGF-I levels and a negative association with IL-6 levels. DHEA deficiency may contribute to age-related bone loss through anabolic (IGF-I) and anti-osteolytic (IL-6) mechanisms. Received: 28 June 1999 / Accepted: 11 January 2000     

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     

Specific Changes of Urinary Excretion of Cross-Linked N-Telopeptides of Type I Collagen in Pre- and Postmenopausal Women: Correlation with Other Markers of Bone Turnover

Urinary excretion of cross-linked N-telopeptide of type I collagen (NTx) has been reported to be a specific marker of bone resorption [18]. We assessed a new immunoassay for NTx as an indicator of changes in bone resorption caused by spontaneous menopause and compared cross-sectionally the levels of urinary NTx, hydroxylysylpyridinoline (HP), lysylpyridinoline (LP), hydroxyproline (OH-Pr), other serum biochemical indices, and lumbar spine and proximal femur bone mineral density (BMD). Eighty-one Japanese women aged 22–77 participated in this study; 36 were premenopausal and 45 were postmenopausal. Urinary HP, LP, and NTx stayed at low levels in the premenopausal period and rose 21%, 30%, and 67% in the postmenopausal period, respectively. The rise in LP and NTx was statistically significant (P < 0.01), suggesting that NTx is mostly released from bone matrix when bone resorption is accelerated. When premenopausal women were divided into two age groups and postmenopausal women were divided into two groups according to years since menopause (YSM) there were significant differences in LP and NTx between women <4 YSM and women aged <40 and those women aged 41+ (P < 0.01 and P < 0.05, respectively). A significant 110% increase in urinary NTx and a 48% increase in urinary LP were observed in postmenopausal women compared with age-matched premenopausal women aged 45–55. All biochemical markers other than serum PTH correlated significantly with each other (r = 0.243–0.858, P < 0.05–0.0001). Urinary NTx inversely correlated with lumbar spine BMD. When postmenopausal women were divided into three groups, the correlation between bone resorption and formation markers in women 0-1 YSM was greater than in women 2–10 YSM and in women 11 + YSM, indicating that resorption and formation are coupled at the early postmenopausal period. We conclude that urinary NTx is responsive to changes in bone metabolism caused by estrogen deficiency and may be a more sensitive and specific marker than HP, LP, or OH-Pr in the early postmenopausal years. Received: 15 February 1995 / Accepted: 18 October 1996     

Loss of Bone Mineral Density in Women Athletes During Aging

Total and regional bone mineral density (BMD) by dual-energy-X-ray absorptiometry (DXA) and bone turnover were tested in 50 highly trained women athletes and 21 sedentary control women (18–69 years; BMI < 25 kg/m²). VO_2max (ml · kg⁻¹· min⁻¹) and lean tissue mass (DXA) were significantly higher in the athletes versus controls (both P < 0.0001). Total body BMD did not decline significantly with age in the athletes whereas lumbar spine (L₂–L₄) BMD approached statistical significance (r =−0.26; P= 0.07). Significant losses of the femoral neck (r =− 0.42), Ward's triangle (r =−0.53), and greater trochanter BMD (r =−0.33; all P < 0.05) occurred with age in the athletes. In the athletes, total body BMD, L₂–L₄ BMD, and BMD of all sites of the femur were associated with lean tissue mass (r = 0.32 to r = 0.57, all P < 0.05) and VO_2max (r = 0.29 to r = 0.48, all P < 0.05). Femoral neck and greater trochanter BMD were higher in the athletes than in controls (both P < 0.05) and lumbar spine and Ward's triangle BMD approached statistical significance (both P= 0.07). Bone turnover was assessed by serum bone-specific alkaline phosphatase (B-ALP), urinary deoxypyridinoline cross-links (Dpd), and urinary aminoterminal cross-linked telopeptides (NTX). There were no relationships between B-ALP or Dpd with age whereas NTX increased with age (r = 0.46, P < 0.05) in the entire group. Levels of B-ALP and NTX were negatively associated with total body, L₂–L₄, femoral neck, Ward's triangle, and greater trochanter BMD (P < 0.05). B-ALP and Dpd were not significantly different between athletes and controls whereas NTX was lower in the athletes than in controls (P < 0.001). The high levels of physical activity observed in women athletes increase aerobic capacity and improve muscle mass but are not sufficient to prevent the loss of bone with aging. Received: 28 November 1997 / Accepted: 8 April 1998