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     

Effect of surgical treatment on physical activity and bone resorption in patients with neurogenic intermittent claudication

The effect of surgical treatment on physical activity and bone resorption was examined in patients with neurogenic intermittent claudication. Nineteen patients, 50–77 years of age, with neurogenic intermittent claudication (mean, 162 m; range, 20–400 m) caused by degenerative lumbar disease were included in the study. Decompressive laminectomy alone was performed for 7 patients with lumbar spinal stenosis (LSS) and 5 patients with degenerative lumbar spondylolisthesis (DLSL), and decompressive laminectomy, with a Graf stabilization system, was performed for 7 patients with DLSL associated with flexion instability. Clinical symptoms and levels of urinary cross-linked N-telopeptides of type I collagen (NTx) were assessed before and 12 months after surgery. Subjective symptoms, including low back pain, leg pain and/or tingling, and gait disturbance, as well as restriction of activities of daily living were significantly alleviated by the surgical treatment, resulting in an increase in physical activity. Urinary NTx levels were significantly decreased by the surgical treatment, from 63.1 ± 16.9 (mean ± SD) nmol BCE/mmol Cr to 52.1 ± 11.2 nmol BCE/mmol Cr (P < 0.05). These findings suggest that surgical treatment appears to alleviate the clinical symptoms and increase physical activity in patients with LSS or DLSL, potentially resulting in the suppression of bone resorption. Surgical treatment may contribute to the prevention of physical inactivity-induced osteoporosis in elderly patients with neurogenic intermittent claudication caused by degenerative lumbar disease. Received: June 22, 2001 / Accepted: September 17, 2001     

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     

Dietary phylloquinone depletion and repletion in postmenopausal women: effects on bone and mineral metabolism

Introduction Vitamin K has been implicated in increased bone fracture risk. Despite a potential role of vitamin K in bone, little is known about the effects of altered dietary phylloquinone intake on the underlying components of bone and mineral metabolism. Methods A 84-day in-house dietary phylloquinone (vitamin K) depletion–repletion study was undertaken in 21 postmenopausal women (mean age: 70 years) to assess the effects of altered vitamin K status on intestinal calcium (Ca) absorption, urinary and serum Ca and phosphorus (P), serum calcemic hormones, and serum biomarkers of bone turnover [osteocalcin and N-telopeptide type 1 collagen cross-links (NTx)] and the response to 1,25-dihydroxyvitamin D treatment (1 μg/day×7 d). Results The group receiving calcitriol treatment (n=11) had higher Ca absorption, urinary Ca, urinary and serum P and serum osteocalcin and lower serum parathyroid hormone (PTH).There were no significant effects of acute (4-week) phylloquinone depletion on response to 1,25-dihydroxyvitamin D treatment or on measures of bone formation or mineral metabolism. However, phylloquinone treatment had a significant effect (p<0.04) on serum NTx. Phylloquinone repletion, up to five times (450 μg phylloquinone per day) the currently recommended adequate intake level of dietary phylloquinone for women, significantly reduced serum NTx (16.8±0.9 nmol bone collagen equivalents (BCE) per liter following repletion vs 18.4±1.1 nmol BCE per liter following depletion; p< 0.01). Conclusions These findings suggest that altering vitamin K status in postmenopausal women by manipulating phylloquinone intake does not have an acute affect on intestinal Ca absorption, renal mineral excretion, or bone formation, but high phylloquinone intake may modestly reduce bone resorption. The impact of high phylloquinone intake on bone mineral density and fracture risk needs to be ascertained in randomized clinical trials.     

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     

Relationships among physical activity, metacarpal bone mass, and bone resorption marker in 70 healthy adult males

The purpose of the present study was to investigate the relationships among physical activity, metacarpal bone mineral density (BMD), and bone resorption marker in healthy active adult men. Seventy healthy men (mean age, 68.4 years, range, 48–85 years) were recruited. The metacarpal BMD of the nondominant hand was measured by computed X-ray densitometry, and the levels of urinary cross-linked N-telopeptides of type I collagen (NTx), as a marker of bone resorption, were measured with an enzyme-linked immunosorbent assay. The relationships among BMD, urinary NTx levels, and activities in leisure time and at work were examined. BMD was 2.77 ± 0.48 (mean ± SD; range, 1.54–3.60) mmAl, and NTx levels were 44.9 ± 21.0 (range, 11.7–91.0) nmol BCE/mmol creatinine. Single regression analysis showed that BMD was significantly correlated with NTx levels and activity at work (r = −0.331 and P < 0.01; r = 0.468 and P < 0.05, respectively), while NTx levels were significantly correlated with activities in leisure time and at work (r = −0.250 and P < 0.01; r = −0.325 and P < 0.01, respectively). NTx levels were decreased and BMD were increased with higher activity at work. The present study shows that increased physical activity as a result of hard work may have the potential to decrease bone resorption and increase BMD in healthy adult men. Received: December 14, 2000 / Accepted: August 3, 2001     

Longitudinal evaluation of a bone resorption marker in elderly subjects

The variability over time in the excretion of a hone resorption metabolite (collagen type I N-telopeptide crosslink, NTx) was evaluated in a cohort of community-dwelling elderly men and women (mean age 73 years). Three annual 24-h urine samples were collected. NTx concentration was measured using an established ELISA. Total (24-h) NTx excretion as well as NTx/creatinine concentration were compared. Men had a significantly lower excretion of NTx/creatinine than women who were not on hormone replacement therapy. Overall, the within-subject long-term coefficient of variability for NTx/creatinine was 26%. The correlation coefficient between the samples taken a year apart was higher for the 24-h NTx excretion (r=0.66) than for the 24-h creatinine excretion (r=0.51). The consistency of NTx excretion over time was also evaluated in all 93 subjects with three yearly samples using Kendall’s rank correlation method; the resulting coefficient of concordance was 0.78 (significant at the 0.01 level). These results indicate that while NTx excretion varies in subject samples collected over a period of 2 years, this variability is not much greater than the daily variation reported for NTx and other bone metabolism markers. The relative reproducibility of NTx excretion over time in this age group was also evident in the coefficient of concordance. The results provide support for stratifying subjects according to level of bone resorption and identifying those subjects with high turnover who may be at greater risk of osteoporotic fracture.     

Urinary Excretion of Type I Collagen Degradation Products in Healthy Women and Osteoporotic Patients with Vertebral and Hip Fractures

We have evaluated both the effect of normal aging and menopause on urinary CrossLaps™ (u-CTx) excretion and the bone resorption status by u-CTx in patients with vertebral fracture and hip fracture. In 246 healthy women, 76 patients with vertebral fracture, and 63 patients with hip fracture, u-CTx excretion was measured by ELISA. The age-related changes of u-CTx in healthy females reflected the marked increase of bone resorption associated with modeling at childhood. The values in the subgroups of postmenopausal women 1–3 years since menopause and ≤10 years since menopause were significantly higher than those in the subgroups of premenopausal adult women. The values in the vertebral fracture group were significantly higher than those in the premenopause group, but not those in the postmenopause groups. The values in the hip fracture group were significantly higher than those in the other groups. Of the 70 postmenopausal subjects aged 45–64 years, 43% had u-CTx values more than 2 SD above premenopausal mean. The corresponding values in the patients with vertebral fracture and those with hip fracture were 58% and 64%, respectively. This marker reflects well the increase of bone resorption associated with bone modeling at childhood and with high bone turnover after menopause. The excretions in the patients with hip fracture were much higher than those in the age-matched subjects and also higher than those in the patients with vertebral fracture. These findings indicate that the abnormality of bone resorption in the patients with hip fracture is more severe than in the patients with vertebral fracture. Received: 30 January 1997 / Accepted: 7 August 1997     

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     

Relationship between serum 25-hydroxyvitamin D and bone resorption markers in vitamin D insufficiency

It is known that nursing-home patients with vitamin D insufficiency have elevated serum parathyroid hormone (PTH) as well as raised serum alkaline phosphatase (ALP). Although it is well known that vitamin D insufficiency and secondary hyperparathyroidism are common among the elderly in western countries, there is continuing controversy over the level of serum 25-hydroxyvitamin D [25(OH)D] necessary for bone health. We approached this issue by examining the relationships between serum 25(OH)D, ionized calcium, PTH, and ALP and the urinary bone resorption markers hydroxyproline, pyridinoline, and deoxypyridinoline, corrected for creatinine (OHPr/Cr, Pyd/Cr, and Dpd/Cr, respectively), in 486 postmenopausal women of mean age 63 (SD 9.5) years, who were referred to our osteoporosis and menopause clinics for investigation. When the patients were divided into two groups with 25(OH)D above and below 20 nmol/L, 30 nmol/L, 40 nmol/L, 50 nmol/L, 60 nmol/L, or 70 nmol/L, the most significant differences between the two groups thus derived was found at a serum 25(OH)D level of 60 nmol/L (P < 0.001 for all markers). The most significant difference between groups for serum PTH was found when the patients were divided at a serum 25(OH)D of 50 nmol/L. PTH, OHPr/Cr, Pyd/Cr, and ALP were inversely related to serum 25(OH)D. PTH was inversely related to serum ionized calcium. There was a trend for ionized calcium to be positively related to 25(OH)D, but this did not reach statistical significance. We conclude that rises in three bone resorption markers and ALP can be detected in postmenopausal women when the serum 25(OH)D level falls below 60 nmol/L. Levels above this may be required for optimal bone health.     

Application of a New Serum Assay for Type I Collagen Cross-Linked N-Telopeptides: Assessment of Diurnal Changes in Bone Turnover With and Without Alendronate Treatment

Biochemical markers of bone turnover are finding increased application in the investigation and management of skeletal diseases such as osteoporosis. The present study assessed for the first time the diurnal variation of serum type I collagen cross-linked N-telopeptides (NTx), a new serum-based marker of bone resorption, and the effect of antiresorptive therapy with alendronate on this marker in elderly osteopenic women. The concentrations of serum NTx were monitored over 24 hours in a randomly selected subset of 38 women (placebo n = 13, 69 ± 3 (SD) year; alendronate n = 25, 69 ± 3 year), who had completed 12–15 months of a larger (n = 120) randomized, double-blind, parallel group, placebo-controlled trial with alendronate 5 mg/day. Blood was obtained every 4 hours for measurement of serum NTx using a new chemiluminescent-based immunoassay. There was a significant diurnal variation of serum NTx (p = 0.001) in both the placebo and alendronate groups. Mean peak levels occurred at ∼0504 h with a mean nadir at ∼1320 h in the placebo group, with no significant difference on alendronate. Serum NTx was ∼25% lower in the alendronate group over the entire 24-hour period. Mean (SE) daytime (0800–2000) and nighttime (2200–0800) serum NTx values were 6.40 ± 0.30 versus 8.45 ± 0.58 nmol BCE/liter, and 7.42 ± 0.23 versus 10.01 ± 0.53 nmol BCE/liter for alendronate versus placebo, respectively (P≤ 0.003 for both comparisons). Combining the data of both treatment groups, serum NTx was significantly (P < 0.05) correlated with serum osteocalcin (r = 0.753) and urine NTx (r = 0.628) measurements previously obtained over the entire 24-hour period. Serum NTx has a significant diurnal variation and is responsive to antiresorptive therapy with alendronate. Alendronate reduces the amplitude but maintains the pattern of the 24-hour serum NTx profile. These data suggest that serum NTx may be a useful new marker of bone resorption. Received: 13 March 1997 / Accepted: 15 October 1997     

Acute Effects of Calcitonin Nasal Spray on Serum C-telopeptide of Type 1 Collagen (CTx) Levels in Elderly Osteopenic Women with Increased Bone Turnover

Salmon calcitonin is a potent inhibitor of osteoclastic activity. The effect of calcitonin in elderly women with high bone turnover at higher risk of developing osteoporosis has not been studied. To investigate acute effects of calcitonin treatment on bone resorption markers in elderly women, we conducted a randomized trial in women >65 years of age with high bone turnover assessed as urinary N-telopeptide of type-I collagen (NTx) levels 1 SD higher than mean premenopausal levels, which was irrespective of bone density. A total of 98 elderly women were randomly assigned to receive either 200 IU calcitonin nasal spray (n = 75) with calcium (500 mg) and vitamin D (200 IU) or calcium and vitamin D (n = 23) alone for 6 months. Blood and urine samples were collected at 0, 2, 4, and 6 months and analyzed for urinary NTx and serum C-telopeptide of type-1 collagen (CTx). At baseline, mean age was 72.1 ± 4.7 (mean ± SD) in the calcitonin group and 72.2 ± 6 years in the control group. The spine and total hip BMD, serum PTH levels and urinary calcium/creatinine ratios were similar in both groups. Mean BMD was in the osteopenic range in both groups. Calcitonin treatment resulted in significant decreases in serum CTx levels, 2, 4 and 6 months after treatment as compared to baseline, and after 4 and 6 months as compared to controls. A maximum decrease from baseline of 33% was seen at 6 months. The urinary resorption marker, urine NTx, showed a significant decrease in the calcitonin group when compared to baseline only at the 6-month time point. Analysis of least significance change (LSC) showed that 70% of calcitonin patients were categorized as responders using serum CTx after 6 months of treatment. We conclude that 200 IU calcitonin effectively decreases bone resorption within 60 days of therapy, thus preventing further bone loss in elderly women who are at a high risk of developing osteoporosis.     

Alteration of the circadian rhythm of intact parathyroid hormone and serum phosphate in women with established postmenopausal osteoporosis

Several studies have established that the circulating concentration of intact parathyroid hormone, PTH (1–84), over 24 h follows a circadian rhythm. The importance of this circadian rhythm is not known although some authors have detected alterations in the rhythm in metabolic bone disease and following dietary manipulation. We have studied the circadian rhythm of PTH (1–84) in 8 premenopausal women, 8 postmenopausal women with established osteoporosis and 8 postmenopausal women with no evidence of osteoporosis. Blood samples were obtained at 30-min intervals over a 24-h period and significant differences were found in the profiles of PTH (1–84) and serum phosphate in the three groups studied. Premenopausal women possessed a nocturnal/early morning increase in PTH (1–84) and phosphate (between 2200 and 0700 hours), as did postmenopausal women without osteoporosis. In postmenopausal women with osteoporosis the nocturnal increase in PTH (1–84) and serum phosphate was absent and PTH (1–84) decreased during the period 2200-0700 hours. A shift in acrophase is observed between premenopausal and postmenopausal women without osteoporosis. No acrophase was found in postmenopausal women with osteoporosis for either PTH (1–84) or serum phosphate. No circadian rhythm, acrophase or significant amplitude was observed in serum adjusted calcium or ionized calcium in any group studied. Alterations in the circadian rhythms for PTH (1–84) and serum phosphate occur in patients with postmenopausal osteoporosis that suggest the normal dynamics of PTH (1–84) secretion may play a role in both calcium and phosphate metabolism and the bone remodelling process. Whether these changes are causative or a response to the pathology will require further investigation.     

Urinary Cross-linked N-telopeptides of Type I Collagen Levels in Patients with Rheumatoid Arthritis

Osteoclastic activation rather than suppression of bone formation has been suggested to be the dominant process leading to bone loss in rheumatoid arthritis (RA). Although many studies have already shown the correlation of urinary pyridinoline (PYD) and deoxypyridinoline (DPD) levels with RA-related bone loss, urinary cross-linked N-telopeptides of type I collagen (NTx), a more specific marker of bone-derived type I collagen fragments in urine than urinary PYD and DPD in RA, has not been adequately studied. The purpose of the present study was to determine clinical factors that are associated with an increase in urinary NTx levels in patients with RA. One hundred and eighty-four patients with RA and 185 sex- and age-matched controls were enrolled in the study: 71 men, 37-68 years of age (RA: 31, controls: 40); 129 premenopausal women, 30-48 years of age (RA: 67, controls: 62), and 169 postmenopausal women, 48-69 years of age (RA: 86, controls: 83). The correlations of urinary NTx levels, measured by enzyme-linked immunosorbent assay with anatomic grade in the wrist, functional class, duration of disease, steroid use, modified health assessment questionnaire (HAQ) score for the upper and lower extremities, the levels of serum c-reactive protein and rheumatoid factor (RF), erythrocyte sedimentation rate, and/or years since menopause were examined by multiple regression analysis. Urinary NTx levels (nmol BCE/mmol Cr) did not differ significantly between men with RA and controls (53.2 +/- 29.6 vs 41.0 +/- 19.6, respectively), whereas urinary NTx levels were significantly higher in pre- and postmenopausal women with RA than in respective controls (premenopausal women: 57.1 +/- 36.6 vs 42.3 +/- 21.3, P <0.01; women: 76.2 +/- 27.3 vs 57.1 +/- 28.3, P <0.001). In men with RA, no clinical factors were significantly correlated with urinary NTx levels. In premenopausal women with RA, functional class, HAQ score for the upper extremities, and RF were significantly correlated with urinary NTx levels (all P <0.05); in postmenopausal women with RA, functional class and RF were significantly correlated with urinary NTx levels (both P <0.05). These findings suggest that urinary NTx levels were significantly higher only in women with RA than in age-matched controls, and a RA-related increase in urinary NTx levels may be associated with physical inactivity and disease activity.     

Change of cross-linked telopeptide of type I collagen (ICTP) and other bone resorption markers in patients with bone fragility fractures

Background The serum concentration of cross-linked telopeptide of type I collagen (ICTP) has been reported to be a useful marker and for both diagnosis and monitoring of bone metastasis. This study was performed to clarify the changes in various bone turnover markers, including ICTP, after bone fragility fracture. Methods Seventy-six bone fragility fracture patients (14 men and 62 postmenopausal women; mean age, 77.0 years) were evaluated for bone resorption markers, including serum ICTP. We measured urinary N-terminal telopeptides of type I collagen (NTX) several times after fracture. Furthermore, serum ICTP, serum NTX, urinary deoxypyridinoline (DPD), and urinary C-telopeptide-cross-linked type I collagen (CTX) were measured at the times of both minimum and maximum urinary NTX. Results Urinary NTX was increased significantly from 86.4 ± 57.9 to 214.3 ± 137.2 nmol BCE/mmol Cr following fracture. Serum ICTP showed a similar significant increase from 7.6 ± 4.7 to 10.4 ± 5.5 ng/ml in bone fragility fracture patients. Furthermore, other markers also showed similar increases. The level of increase in urinary NTX (148.0%) was especially high compared with other bone resorption markers. On the other hand, the level of increase in serum ICTP (36.8%) was similar to that in serum NTX (39.8%). Serum ICTP levels were significantly correlated with other bone resorption markers, with an especially strong correlation between serum ICTP and serum NTX (r = 0.647, P < 0.001). The percentage of cases in which ICTP exceeded the cutoff value for suspected bone metastasis in postmenopausal women was 73.6%. Conclusions The value of ICTP increases with bone fragility fracture and is correlated with other bone resorption markers, and ICTP obviously exceeded the reference value as compared with other bone resorption markers.     

Biochemical Variables in Pre- and Postmenopausal Women: Reconciling the Calcium and Estrogen Hypotheses

There is controversy as to whether the rise in urinary calcium at the menopause is the cause or the result of the rise in bone resorption at that time. In an attempt to resolve this issue, we have compared the relevant biochemical variables in 102 premenopausal volunteers (mean age 37 years; range 21–52) and 86 apparently normal postmenopausal women (mean age 55 years; range 40–60). We measured the fasting serum calcium, creatinine, proteins, electrolytes and intact parathyroid hormone (PTH), and the urinary calcium and creatinine both after an overnight fast and in a 24-h collection. We calculated serum calcium fractions, creatinine clearance and the notional tubular maximum reabsorptive capacity for calcium. Creatinine excretion and clearance were lower in the post- than in the premenopausal women after correction for surface area and age. Total serum calcium was higher in the post- than in the premenopausal women but this was accounted for by the higher ligand concentrations in the former. Fasting and 24-h urinary calcium were also higher in the post- than in the premenopausal women due in part to the former’s higher filtered load of calcium (due to their higher serum complexed calcium) but mainly to their reduced tubular reabsorption of calcium despite their slightly raised serum PTH. Our analysis resolves the rise in urinary calcium at the menopause into its two components: increased filtered load and reduced tubular reabsorption. The changes in these two variables, neither of which can be attributed to increased bone resorption, produce an increase in calcium requirement that is sufficient to account for postmenopausal bone loss. However, the translation of this menopausal increase in calcium requirement into an increase in bone resorption at near-normal serum PTH levels requires some menopause-dependent change in the responsiveness of the bone to calcium demand. We suggest that this change may occur at the level of the osteoclasts and that estrogen may modify the calcium feedback setpoint in these cells in a manner analogous to calcitonin. This model resolves the apparent conflict between the estrogen and calcium hypotheses and explains the synergism between these two treatment modalities. Received: 8 June 1998 / Accepted: 5 September 1998     

Isosorbide mononitrate increases bone formation and decreases bone resorption in postmenopausal women: a randomized trial.

NO regulates bone remodeling in cellular and animal models. We examined the effect of administering ISMO, a NO donor, on bone turnover in 144 postmenopausal women. After 3 months, women randomized to ISMO had a greater decrease in bone resorption and a greater increase in bone formation compared with placebo. NO donors may prevent postmenopausal bone loss. INTRODUCTION: NO both stimulates bone formation and inhibits bone resorption in vitro. NO donors (nitrates) are inexpensive and widely available, but their value for postmenopausal osteoporosis has never been evaluated in a randomized trial. MATERIALS AND METHODS: We randomly assigned 144 healthy postmenopausal women with a hip BMD T score between 0 and -2.5 to 5 or 20 mg/day of isosorbide mononitrate (ISMO) or placebo for 12 weeks. We measured urine N-telopeptide (NTx), a marker of bone resorption, and serum bone-specific alkaline phosphatase (BSALP), a marker of bone formation. Markers were measured immediately before randomization and after 12 weeks of treatment. We calculated the percent change in NTx and BSALP for each of the treatment groups (placebo, 5 mg ISMO, and 20 mg ISMO). Our primary outcome was the percent change in NTx and BSALP in the 5- and 20-mg ISMO groups compared with placebo. RESULTS AND CONCLUSIONS: Compared with women randomized to placebo, women randomized to 20 mg of ISMO had a 45.4% decrease in NTx (95% CI, 25.8-64.9) and a 23.3% increase (95% CI, 8.9-37.8) in BSALP. Women randomized to 5 mg of ISMO had a 36.3% decrease in NTx (95% CI, 14.8-57.8) and a 15.9% increase in BSALP (95% CI, 1.1-30.7). ISMO decreases bone resorption and increases bone formation. These findings suggest that nitrates may be useful for the prevention of postmenopausal osteoporosis.     

The value of desoxypyridinoline in the diagnostics of loosened arthroplasty

According to several reports in the last few years, desoxypyridinoline (Dpd) in urine increases significantly in cases of loosened arthroplasty. Therefore, this marker was suggested as useful in the diagnostics of implant loosening. In this study, the level of Dpd was determined in 69 patients with arthroplasty of the hip or the knee joint. Thirty-four of these patients received revision surgery following implant loosening. In 35 of these 69 patients, there were no clinical or radiological signs of loosening (control group). The mean age of the patients with loosened implants (22 women, 13 men) was 67.9 years and of the control group (22 women, 12 men) 66.9 years. In the group with arthroplastic loosening, as well as in the control group, 14 patients had increased levels of Dpd. There were 20 patients in the group with loosened arthroplasty and 19 patients in the control group that had normal levels of Dpd. The female patients had a mean Dpd level of 8.6 nmol/mmol creatinine (4.3–24 nmol/mmol creatinine) in the urine in cases of loosening and 10.1 nmol/ mmol creatinine (2–33 nmol/mmol creatinine) in the control group. The male patients had a mean Dpd level of 7.8 nmol/mmol creatinine (3.2–19.2 nmol/mmol creatinine) in the urine in cases of loosening and 5.8 nmol/mmol creatinine (0.3–11.7 nmol/mmol creatinine) in the control group. In conclusion there was no significant increase in Dpd in patients with implant loosening compared with the control group. Furthermore, older patients often suffer from diseases causing increased bone resorption that may falsify the test results. We cannot confirm that Dpd is helpful in the diagnostics and screening of implant loosening. Received: 14 January 2000     

Comparison of Serum and Urine Assays for Biochemical Markers of Bone Resorption in Postmenopausal Women with and without Hormone Replacement Therapy and in Men

Biochemical markers of bone resorption have been used to characterize metabolic bone disease and assess therapeutic response. Most studies have used the urinary measurement of collagen crosslinks, but serum assays have recently been developed that may have less analytic and biologic variability. In the present study, we measured urine and serum N- and C-terminal crosslinked telopeptides of type I collagen (NTX and CTX) and serum bone sialoprotein (BSP) in postmenopausal women with or without hormone replacement therapy (HRT) and in men of similar age. In these populations, the variability of serum and urine markers was similar, except that serum NTX showed somewhat lower variability in postmenopausal women. Urine and serum assays correlated well with one another and were significantly lower in postmenopausal women on HRT compared with untreated women. The difference in women on HRT was similar for sNTX, uNTX and BSP (35–40%) and greater for sCTX and uCTX (52–53%). There was an inverse correlation between markers and bone mineral density, largely attributable to the high correlation in women not on HRT. Fractional excretion of NTX and CTX were estimated at 0.20 ± 0.07 and 0.44 ± 0.11, respectively. These values were independent of the concentration of the marker or of creatinine in the urine. We conclude that serum markers are useful measures of bone resorption in these populations, in whom the use of such markers is likely to be helpful in the management of osteoporosis. Received: 23 August 1999 / Accepted: 30 November 1999     

Effects of a low sodium diet on bone metabolism

Osteoporosis is a serious public health problem, and dietary interventions may potentially be helpful in preventing this disorder. The purpose of this study was to determine the effects of a low sodium diet on bone metabolism in postmenopausal women. This was a longitudinal study to determine the effects of a low sodium (2-g/day) diet on bone. Forty postmenopausal African–American and Caucasian women were enrolled in a 2-g/day sodium diet for 6 months. Sodium and calcium excretion, bone turnover, and calcitropic hormones (intact parathyroid hormone (PTH) and 1,25 dihydroxyvitamin D) were measured before and 6 months after the intervention. In women who had baseline sodium excretions equal to or greater than the average sodium intake in the United States (≥3.4 g/day), the low sodium diet resulted in significant decreases in sodium excretion (P = 0.01), in calcium excretion (P = 0.01), and in a biomarker of bone turnover, aminoterminal propeptide of type I collagen (P = 0.04). However, there were no significant changes in calcitropic hormones, including intact PTH (P = 0.97) or 1,25 dihydroxyvitamin D (P = 0.49) with the low sodium diet. These findings suggest that in postmenopausal women with sodium intakes ≥3.4 g/day, a low sodium diet may have benefits for skeletal health.