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The Journal of Clinical Endocrinology & Metabolism Vol. 83, No. 2 333-338
Copyright © 1998 by The Endocrine Society

Original Studies

The Effect of Gonadotropin-Releasing Hormone Agonist on Type I Collagen C-Telopeptide and N-Telopeptide: the Predictive Value of Biochemical Markers of Bone Turnover

Ernest A. Amama, Michiyoshi Taga and Hiroshi Minaguchi

Department of Obstetrics and Gynecology, Yokohama City University School of Medicine, Kanazawa-ku, Yokohama, 236 Japan

Address all correspondence and requests for reprints to: Dr. Hiroshi Minaguchi, Department of Obstetrics and Gynecology, Yokohama City University School of Medicine, 3–9 Fukuura, Kanazawa-ku, Yokohama, 236 Japan.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
To evaluate the clinical utility of recently developed biochemical markers in the assessment of bone metabolism during GnRH agonist (GnRHa) treatment, we compared five bone resorption markers [C-telopeptide (CTX) and N-telopeptide (NTX) of type I collagen, hydroxyproline (Hpr), pyridinoline (Pyr), and deoxypyridinoline (Dpyr)] and two bone formation markers [total alkaline phosphatase (Alp) and osteocalcin (OC)]. Sixty-eight normally menstruating women were injected with a long-acting GnRHa once a month for 24 weeks for the treatment of endometriosis or leiomyoma.

The mean percentage bone loss at the lumbar spine was 3.79% at the end of treatment. Although levels of all markers increased significantly as the treatment progressed, CTX and NTX exhibited the highest correlation coefficients between bone loss at 24 weeks and the seven markers measured at 0, 4, 12, 16, and 24 weeks of treatment. Serum estradiol levels were similarly suppressed during the treatment in both fast losers (whose bone loss was more than the mean) and slow losers (whose bone loss was less than the mean). However, significantly higher z-scores of bone resorption markers, but not of bone formation markers, were observed in the fast losers at 24 weeks of treatment, suggesting a more accelerated bone resorption in this group. Whereas the three highest z-scores at 24 weeks of treatment were CTX, NTX, and Dpyr (in that order), the highest z-score (P < 0.05) was observed for CTX in the fast losers. The subjects in the highest quartile of CTX, the highest, and second highest quartiles of NTX at 24 weeks of treatment experienced 2.1, 2.2, and 1.7 times more bone loss (P < 0.001), respectively, than those in the lowest quartiles. Furthermore, the subjects in the highest quartile of both CTX and NTX experienced 3.6 times more bone loss (P < 0.001) than those in the lowest quartile of both markers. These results indicate that both CTX and NTX are useful and sensitive markers for bone resorption in a hypoestrogenic state induced by GnRHa.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
GnRH AGONIST (GnRHa), which temporarily down-regulates the pituitary-ovarian axis to induce a pseudomenopausal state, has recently been used to treat several gynecological diseases (1, 2, 3). GnRHa is effective in treating estrogen-dependent diseases, such as endometriosis and leiomyoma (4). However, reduced bone density at some skeletal sites after treatment is a reported side effect caused by estrogen deficiency (5). Thus, during GnRHa therapy, bone metabolism of patients needs to be monitored to identify those requiring an add-back therapy (6) to counter bone loss.

Several markers for bone metabolism have been shown to reflect bone formation and resorption (7, 8, 9, 10). Some of these provide a semiquantitative index of bone resorption but lack specificity and sensitivity (11). The cross-links of mature collagen, pyridinoline (Pyr) and deoxypyridinoline (Dpyr), have been used to monitor bone resorption. They are formed nonenzymatically during maturation of extracellular collagen fibrils, released by bone resorption, and excreted into the urine (12). Several studies have shown that Pyr and Dpyr are sensitive markers for bone resorption in the metabolic bone diseases characterized by increased bone turnover, including osteoporosis (13) and malignancies affecting bone (14, 15).

The type I collagen degradation products, urinary C-telopeptide (CTX) and N-telopeptide (NTX), are excreted as reproducible fractions of total bone-derived pyridinolines. New immunoassays for CTX and NTX provide a means to measure bone resorption (16, 17, 18, 19, 20). Reported studies suggest that CTX and NTX are more sensitive and more specific indicators of bone resorption than pyridinolines measured by immunoassay (21). NTX is reported to increase in peri- and postmenopausal women (22) and during ovarian suppression by GnRHa (11, 23). Conversely, it is reported to decrease by antiresorptive therapy, such as hormone replacement (24) or bisphosphonate administration (16). Chesnut et al. (25) reported that NTX provides a basis for predicting future bone loss in postmenopausal women and the probable efficacy of hormone replacement therapy. CTX is also reported to increase in postmenopausal women and to decrease in response to bisphosphonate treatment (18, 26). Garnero et al. reported that CTX and Dpyr predict the susceptibility of elderly women to hip fractures (27). The present study was undertaken to compare the clinical utility of CTX, NTX, and other markers for bone remodeling in monitoring bone loss in a hypoestrogenic state induced by GnRHa treatment.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Subjects

Sixty-eight premenopausal, otherwise healthy Japanese women with endometriosis or leiomyoma, 22–45 yr old (mean ± SE age: 34 ± 5 yr) were enrolled in this study. All subjects menstruated regularly; had normal renal and hepatic functions; were not taking medications (other than GnRHa) known to affect urinary calcium, creatinine excretion, or bone metabolism; and had no chronic diseases. Women whose body mass index exceeded 30 were excluded. A therapeutic dose of long-acting GnRHa, either 1.8 mg of busereline microparticles (Hoechst, Frankfurt am Main, Germany; n = 50) or 3.6 mg of gosereline depot (Zeneca, Cheshire, UK; n = 18), was injected sc once a month for 24 weeks. Informed consent was obtained from all subjects before initiating the study.

The patients were divided retrospectively into 2 groups, according to the degree of bone loss after GnRHa treatment. For 36 patients (designated fast losers), bone loss was greater than the mean value of bone loss in all subjects, whereas for 32 patients (designated slow losers), bone loss was less than the mean. Clinical and laboratory characteristics at baseline were not significantly different between the 2 groups.

Biochemical markers

Fasting serum and urine samples were collected just before the beginning of GnRHa treatment and after 4, 12, 16, and 24 weeks of treatment. Serum was frozen at -20 C within 1 h of collection. Urine samples were also stored at -20 C until they were assayed.

Urinary CTX was measured by ELISA (enzyme-linked immunosorbent assay) for CrossLaps (Osteometer A/S, Copenhagen, Denmark), according to the manufacturer’s method. CrossLaps antibody was obtained by immunizing rabbits with the amino acid sequence specific for a part of the C-terminal telopeptide of the {alpha}1 chain of type I collagen (Glu-Lys-Ala-His-Asp-Gly-Gly-Arg). The sensitivity was 50 µg/L. The intra- and interassay variabilities were less than 13% in the concentration range of the calibration curve. Duplicate measurements were performed for each urine sample, and the values were corrected for creatinine (Cr), as measured by standard calorimetric technique.

Cross-linked N-telopeptide of type I collagen, NTX, was quantified directly in unextracted urine by ELISA using a specific monoclonal antibody to NTX (16). The ELISA kit was produced by Mochida Pharmaceutical Co. Ltd. (Tokyo, Japan), according to the modified method of Eyre (16), and was supplied for clinical use. The values were expressed as nanomolar bone collagen equivalent (BCE) per millimolar Cr. The sensitivity of the assay was 20 nmol BCE/L. The intra- and interassay variabilities were 4.6% and 4.1%, respectively.

Serum osteocalcin (OC) was measured with a Mitsubishi Yuka Ltd (Tokyo, Japan) BGP IRMA kit using a mouse monoclonal antibody to human OC. This procedure measures both the intact fragments and N- and C-terminal fragments. The sensitivity of the assay was 1.0 ng/mL. The intra- and interassay variabilities were 3.26% and 7.70%, respectively. Urinary Pyr and Dpyr were measured using high-performance liquid chromatography, with a modification of the method described by Uebelhart et al. (28). An internal standard was used for the high-performance liquid chromatography assay of pyridinolines. The values were expressed as nmol/mmol Cr. The sensitivity of both Pyr and Dpyr was 4 pmol/mL. The intra- and interassay variabilities were 2.22% and 3.11% for Pyr, and 3.50% and 4.12% for Dpyr, respectively. Urine Hpr was measured according to standard colorimetric method. The intra- and interassay variabilities were 3.26% and 3.11%, respectively. Total alkaline phosphatase (Alp) was determined by standard enzymatical procedure. The intra- and interassay variabilities were 0.68% and 0.40%, respectively. Serum estradiol (E2) was measured by RIA.

Bone densitometry

Bone mineral density (BMD) of the lumbar spine (L2-L4) was determined by dual-energy x-ray absorptiometry (Hologic, QDR 2000, Waltham, MA) at the beginning of the study and at 24 weeks of treatment. Quality control and phantom cross-calibration were performed each day before measurement. The precision of the measurement in the spine was within 1%.

Statistical analysis

Data were analyzed using a Stat View 2 (Abacus Concepts, Inc. Berkeley, CA) program on a Macintosh computer (Cupertino, CA). Simple regression analysis was performed for each bone metabolic marker during the treatment. Stratification of sample data into quartiles was performed for descriptive purposes.

The statistical significance of correlation was determined with the F test. The statistical significance between the two groups was determined with one-way ANOVA followed by the Scheffe F test. The P values indicate the significance level of the difference between the means at each time point. Probability values less than 0.05 were considered statistically significant.

To evaluate the discrimination power of each assay in a hypoestrogenic state during GnRHa treatment, we compared the z-scores by calculating the difference in SD units between the values at 24 weeks of treatment and the pretreatment baseline means in the fast losers and slow losers of bone mass. The difference between the values of each marker was calculated according to Duncan’s multiple range test.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Changes in E2, lumbar spine BMD, and bone metabolic markers during 24 weeks of GnRHa treatment are presented in Table 1Go. The mean levels of serum E2 were significantly suppressed by 4 weeks of treatment and remained below 30 pg/mL throughout the treatment. The mean value of BMD at 24 weeks of treatment was significantly lower than baseline (P < 0.01), with a mean percentage bone loss of 3.79%. All the mean values for bone formation markers, Alp and OC, as well as for bone resorption markers, Hpr, Pyr, Dpyr, CTX, and NTX, increased as the treatment progressed. The increases in these markers from baseline were all significant at 24 weeks of treatment (P < 0.05 for Hpr and P < 0.01 for the other markers). Among these markers, the percent increase at 24 weeks of treatment from baseline was most marked in CTX (162%), followed by NTX (86%), Dpyr (54%), and OC (42%).


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  		Table 1. Changes in estradiol, lumbar spine BMD (L2–L4) and bone metabolic markers during 24 weeks of GnRHa treatment

 
Table 2Go shows the correlations between the percent decrease of BMD at 24 weeks of treatment from baseline (bone loss) and the seven biochemical markers (upper part) and the correlations among these markers (lower part) during GnRHa treatment. Strong negative correlations were observed between bone loss and CTX (r = -0.651) or NTX (r = -0.606). There were moderate or mild negative correlations between bone loss and the other markers, except Hpr. Significant correlations were obtained among these seven markers themselves.


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  		Table 2. The correlations between percent changes of lumbar spine BMD and biochemical markers (upper part) and the correlations between markers (lower part) during GnRHa treatment

 
Figure 1Go shows the comparisons of E2 levels, percent changes of BMD, and percent changes of CTX and NTX from the pretreatment levels between the fast losers and slow losers during 24 weeks of treatment. Serum E2 levels were similarly suppressed and remained under 30 pg/mL after 4 weeks of treatment in both groups; the two groups were not significantly different. The mean percent loss in BMD at 24 weeks of treatment was 5.87 ± 0.26% in the fast losers, which was significantly greater (P < 0.0001) than in the slow losers (1.45 ± 0.34%). Whereas CTX and NTX levels continued to increase during the treatment in both fast losers and slow losers, the percent increases at 24 weeks of treatment from baseline in the fast losers were significantly greater (P < 0.01) than in the slow losers. Figure 2Go shows the comparison of the percent increases in the seven markers at 24 weeks of treatment from pretreatment levels between the slow losers and fast losers. The percent increases in Alp, Dpyr, CTX, and NTX in the fast losers were significantly higher than in the slow losers, whereas increases in OC, Hpr, and Pyr were not significantly different between the two groups.



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  		Figure 1. Changes in serum level of E2 and percent changes from pretreatment levels in lumbar spine BMD, CTX, and NTX in the fast losers and slow losers during 24 weeks of GnRHa treatment. Solid lines indicate the fast losers and dotted lines indicate the slow losers. The values are expressed as the mean ± SE. *, P < 0.01, as compared with the values of slow losers.

 


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  		Figure 2. Comparison in percent increases of seven markers from the pretreatment levels between the slow losers and fast losers of bone mass at 24 weeks of GnRHa treatment. The values are expressed as the mean ± SE. *, P < 0.05; **, P < 0.01, as compared with the values of slow losers.

 
To evaluate the discrimination power of the seven markers in bone loss in a hypoestrogenic state during GnRHa treatment, the z-score for each of the seven markers at 24 weeks of treatment was calculated against the pretreatment level (Table 3Go). Whereas the z-scores were highest for CTX, NTX, and Dpyr (in that order) in both fast losers and slow losers, the highest z-score (P < 0.05) was observed for CTX (3.68 ± 2.57) in the fast losers. NTX (2.53 ± 1.93) and Dpyr (1.91 ± 1.69), in the fast losers, had moderate scores, whereas the z-scores of Alp, OC, Hpr, and Pyr were low. The z-scores of CTX, NTX, Dpyr, and Pyr, in the fast losers, were significantly greater than those in the slow losers, whereas the z-scores of Alp, OC, and Hyr were not significantly different between the two groups.


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  		Table 3. Z-scores of markers in the slow losers and fast losers of bone mass at 24 weeks of GnRHa treatment compared with pretreatment levels

 
To further analyze the relationship between bone loss caused by GnRHa administration and each of CTX and NTX, we tried a stratification of CTX and NTX levels at 24 weeks of treatment into quartiles. As shown in Fig. 3aGo, the subjects in the highest quartile of CTX (475~655 µg/mmol Cr) experienced a significantly greater spinal BMD loss (2.1 times more) than the subjects within the lowest quartile of CTX (120~226 µg/mmol Cr) (-5.72 ± 0.50% vs. -2.72 ± 0.67%, P < 0.001). Similarly, the subjects belonging to the highest (93~145 nmol BCE/mmol Cr) and second highest quartile (66~93 nmol BCE/mmol Cr) of NTX demonstrated 2.2 times (P < 0.001) and 1.7 times (P < 0.05) more spinal BMD loss, respectively, than the subjects within the lowest quartile of NTX (25~50 nmol BCE/mmol Cr) (-5.87 ± 0.46% and -4.44 ± 0.73% vs. -2.68 ± 0.80%, respectively) (Fig. 3bGo). As illustrated in Fig. 3cGo, the subjects in the highest quartile of both CTX and NTX experienced 3.6 times more bone loss than the subjects in the lowest quartile of both CTX and NTX (-6.17 ± 0.71% vs. -1.69 ± 0.88%, P < 0.001). This magnitude of bone loss in the highest quartile of both CTX and NTX was also significantly greater (P < 0.01) than in the highest quartile of either CTX or NTX, and 10.3% and 8.8% of all subjects were coincident in the highest and lowest quartile of both CTX and NTX, respectively.



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  		Figure 3. Percent bone loss at the lumbar spine by the quartiles of CTX (3a), NTX (3b), and by the highest and lowest quartiles of both CTX and NTX (3c) at 24 weeks of GnRHa treatment. The values are expressed as the mean ± SE. *, P < 0.05; **, P < 0.001, as compared with Q1 (the lowest quartile) of either CTX, NTX, or both CTX and NTX.

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
GnRHa is widely used in the treatment of estrogen-dependent gynecological disorders, such as endometriosis and uterine fibroids (29, 30). The disadvantage of this treatment is a risk of bone loss associated with a GnRHa-induced hypoestrogenic state. The magnitude of bone loss has been observed to vary from 0–6% by dual-energy x-ray absorptiometry (31) and 4.6% to 11.8% by quantitative computed tomography (32, 33) in the spine. In this study, we used a long-acting GnRHa, which suppresses estrogen more effectively than the nasal formula. Previous reports on biochemical markers during GnRHa treatment demonstrated an increase in urinary Hpr, Pyr, and Dpyr excretions (34, 35, 36), as well as an increase in urinary NTX excretion (11, 23). In the present study, all seven markers of both bone formation and bone resorption, including CTX and NTX, were significantly elevated during GnRHa therapy, confirming that bone metabolic turnover is enhanced in the hypoestrogenic state induced by GnRHa. Among these markers, the percent increase from baseline at 24 weeks of treatment was most marked in CTX, followed by NTX. The calculated correlation coefficients between the percent change of BMD and biochemical markers show that CTX and NTX correlate well with bone loss. Thus, CTX and NTX more sensitively detect increased bone resorption caused by a rapidly induced estrogen deficiency than do pyridinoline cross-links.

Bone loss, in response to an estrogen deficiency, is reported to be heterogeneous in each individual (37, 38). In our study, a 14% variability was noted in bone loss during 24 weeks of GnRHa treatment, a result not unexpected, because of the various factors that affect bone loss. When the subjects were divided into two groups based on the degree of bone loss after GnRHa administration (fast losers and slow losers), the levels of spinal BMD and all markers before treatment were not different between the two groups. E2 levels were suppressed similarly in both groups during the treatment, and the extent of suppression was not significantly different between the two groups. However, at 24 weeks of treatment, the levels of Alp, Dpyr, CTX, and NTX in the fast losers were significantly higher than in the slow losers. Moreover, z-scores of all bone resorption markers in the fast losers, except Hpr, were significantly higher than in the slow losers, whereas z-scores of the bone formation markers, Alp and OC, were not different between the two groups. Therefore, it is likely that bone resorption is more accelerated in the fast losers during treatment. Whereas the z-scores were highest for CTX, NTX, and Dpyr (in that order) at 24 weeks of treatment in both fast losers and slow losers, the highest z-score among these markers was noted for CTX in the fast losers. The z-score estimates the discrimination power of the assay, because it indicates a degree of difference under its baseline variability (39). Thus, the new markers, CTX and NTX (especially CTX), were considered to be better markers for monitoring the risk of bone loss during GnRHa therapy.

The evidence that bone loss is not completely recovered after the cessation of treatment is important when treating endometriosis or leiomyoma patients with GnRHa (40). The adverse effect of GnRHa on bone mass has led to the use of an add-back therapy with low doses of estrogen and/or progestogen to minimize the side effects (41, 42). Certain concomitant prescriptions of nasal calcitonin or parathyroid hormone have also been suggested to prevent bone loss caused by GnRHa administration (43). CTX and NTX measurements could be used clinically to monitor these medications.

An accurate biochemical marker for the detection of postmenopausal women at risk of osteoporosis has been sought for years (44). NTX is reported to predict future bone loss and the therapeutic effects of hormone replacement therapy in postmenopausal women (25). In our current study, the subjects in the highest quartile of CTX, in the highest, and in the second highest quartile of NTX at 24 weeks of treatment experienced 2.1, 2.2, and 1.7 times more bone loss, respectively, than the lowest quartile. Furthermore, the subjects in the highest quartile of both CTX and NTX lost 3.4 times more bone mass than those in both lowest quartiles. Both CTX and NTX are cross-linked peptides derived from type I collagen; CTX originates in the carboxy-terminal nonhelical part (telopeptide) (45), and NTX originates in the amino-terminal telopeptide (16). The present study indicates that the concomitant measurements of both CTX and NTX may further increase the ability to evaluate bone loss. However, the present study indicates that neither CTX nor NTX can predict a risk of bone loss, because a significant difference in bone resorption markers between the fast losers and slow losers was observed only at the end of treatment. The failure to observe such a difference during treatment is possibly caused by the short period of GnRHa administration and the abrupt onset of estrogen deficiency. The clinical applications of concomitant measurements of CTX and NTX, in the management of postmenopausal women at risk of osteoporosis or osteopenia, need to be studied further.

In conclusion, the present results indicate that CTX and NTX are useful and sensitive markers for bone resorption in a hypoestrogenic state induced by GnRHa. Both CTX and NTX can be used to monitor the changes in bone metabolism and bone loss during GnRHa treatment.


   Acknowledgments
 
We extend our sincere thanks to the many researchers who participated in this clinical study.

Received July 23, 1997.

Revised October 24, 1997.

Accepted October 31, 1997.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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