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The Journal of Clinical Endocrinology & Metabolism Vol. 84, No. 7 2363-2368
Copyright © 1999 by The Endocrine Society

Original Studies

Monitoring of Alendronate Treatment and Prediction of Effect on Bone Mass by Biochemical Markers in the Early Postmenopausal Intervention Cohort Study1

P. Ravn2, D. Hosking2, D. Thompson2, G. Cizza2, R. D. Wasnich2, M. McClung2, A. J. Yates2, N. H. Bjarnason2 and C. Christiansen2

Center for Clinical and Basic Research (P.R., N.H.B., C.C.), Ballerup 2750, Denmark; Bone and Mineral Unit (D.H.), City Hospital, Nottingham NG5 1PB, United Kingdom; Merck Research Laboratories (D.T., G.C., A.J.Y.), Rahway, New Jersey 07065; Hawaii Osteoporosis Center (R.D.W.), Honolulu, Hawaii 96814; Center for Metabolic Bone Disorder (M.M.), Portland, Oregon 97213

Address all correspondence and requests for reprints to: Pernille Ravn, M.D., Center for Clinical and Basic Research, Ballerup Byvej 222, 2750 Ballerup, Denmark.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Statistical analyses
 Results
 Discussion
 References
 
To establish whether biochemical markers could be used to monitor alendronate (ALN) treatment and predict long-term response in bone mass, we used results from an ongoing, randomized trial of ALN treatment for prevention of postmenopausal osteoporosis (n = 1202). In women treated with ALN (5 mg), change from baseline at month 6 in urine N-telopeptide cross-links of type I collagen (NTX) and osteocalcin (OC) correlated with change from baseline at month 24 in spine, hip, and total body bone mineral density (BMD) [r = -0.28 to -0.31 (NTX) and r = -0.16 to -0.25 (OC), P < 0.001]. This corresponded to a 4- to 5-fold greater increase at month 24 in BMD in the tertiles, with the greatest decrease at month 6 in NTX or OC. In women treated with ALN (5 mg) who had a change at month 24 in spine BMD of at least 0%, 86% (NTX) and 79% (OC) had a decrease at month 6 of at least 40% (NTX) or 20% (OC) (sensitivity). The corresponding specificities were 48% (NTX) and 53% (OC). In conclusion, change at month 6 in NTX and OC, in groups of women treated with ALN, indicated the numeric long-term response in BMD within these groups. In individual women, a decrease at month 6, in NTX or OC below the cut-point, validly identified women who responded, on ALN treatment, with a stabilization or an increase in bone mass. However, lack of decrease below the cut-point in NTX or OC could not be used to identify women with a bone loss during ALN treatment.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Statistical analyses
 Results
 Discussion
 References
 
RECENT STUDIES have indicated that treatment with bisphosphonates, a class of antiresorptive agents, can prevent the early postmenopausal bone loss (1, 2, 3, 4, 5), and that this class of drugs offers an alternative option to hormone replacement therapy in the prevention of postmenopausal osteoporosis. Because postmenopausal osteoporosis is a common and serious disease (6), it is likely that the use of bisphosphonates will increase considerably in the future. It is therefore of interest to find reliable and simple methods to monitor response to treatment. Oral alendronate (ALN, 5 mg) has been suggested as the optimal dose for prevention of postmenopausal bone loss (1, 2). This dose has been shown to induce a 3–5% mean increase in bone mineral density (BMD) at the spine and hip, over 2 yr, to stabilize total body BMD, and to attenuate bone loss at the forearm (1). Changes in BMD of this order of magnitude are only slightly larger than the precision error of dual-energy x-ray absorptiometry at these sites (1–3%) (7), which implies the necessity to await at least 1 yr of treatment before detection of a meaningful effect on BMD is possible.

Response to treatment can also be indirectly estimated by measuring biochemical markers of bone formation and bone resorption. Based on their action at the level of the osteoclast, bisphosphonates cause pronounced decreases in biochemical markers of bone resorption and, because of the coupling of bone formation to bone resorption (8), less pronounced decreases in biochemical markers of bone formation (2, 3, 5, 9, 10). The recently introduced biochemical markers of bone resorption decrease up to 70% during treatment with bisphosphonates and exhibit detectable differences between treatment groups within 3 months after start of therapy (2, 9, 10). Data obtained with other antiresorptive drugs indicate that changes in biochemical markers, observed 3–6 months after start of treatment, are useful predictors of response in bone mass after 1–2 yr (11, 12, 13, 14). In a large randomized trial of ALN treatment for prevention of postmenopausal osteoporosis, we evaluated the accuracy of short-term changes in biochemical markers of bone turnover to predict long-term response in bone mass.


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

The Early Postmenopausal Intervention Cohort study is an ongoing randomized, double-blind, placebo-controlled trial of ALN treatment for prevention of postmenopausal osteoporosis. All participants were 45–59 yr of age and at least 6 months past the menopause at baseline, were in good general health, and had no clinical or laboratory evidence of confounding systemic disease (1). The study is being carried out at 4 centers (Copenhagen, Denmark; Nottingham, UK; Honolulu, Hawaii; and Portland, Oregon). The 1609 enrolled participants were randomized to placebo, ALN (2.5 mg), or ALN (5 mg; Merck Research Laboratories). All participants consented, in writing, after oral and written information. The protocol was approved by the local ethics committees and institutional review boards. In the present analyses, we excluded women who did not have baseline-, 6-, and 24-months values of urine N-telopeptide cross-links of type I collagen (NTX) and spine BMD measurements available, leaving a total of 1202 evaluable participants (Denmark, n = 306; UK, n = 304; Hawaii, n = 303; Oregon, n = 289). All women adhered to therapy (had taken at least 80% of the tablets, confirmed by tablet count).

Methods

Bone densitometry. Measurements of BMD were performed at baseline and then annually by dual-energy x-ray absorptiometry (Hologic 2000; Hologic, Inc., Waltham, MA). To ensure that the majority of the participants had normal bone mass at baseline, enrollment was restricted, at each center, to include at least 90% study participants with a spine BMD of at least 0.8 g/cm2 (which approximately corresponded to a spine BMD above -2 SD of the young normal mean value). The short-term precision errors for BMD measurements at the different skeletal regions ranged from 0.7–1.9%.

Biochemical parameters. Blood and morning second-void urine samples were collected after an overnight fast at baseline and every 6 months thereafter. NTX was measured by an enzyme-linked immunosorbent assay (Osteomark, Ostex International, Inc., Seattle, WA) (15) and corrected for creatinine excretion. The assay measures the concentration of the cross-linked N-telopeptides of type I collagen, which are breakdown products of bone. The intra- and interassay coefficients of variation were less than 8% and 9%, respectively, and the detection limit was 10 pmol/mL.

Osteocalcin (OC) OC was measured by an RIA (Human Osteocalcin Kit, Nichols Institute Diagnostics, San Juan Capistrano, CA) (16) and is a marker of bone formation. The intra- and interassay coefficients of variation were less than 5% and 7%, respectively, and the detection limit was 0.05 ng/mL.


   Statistical analyses
Top
 Abstract
 Introduction
 Subjects and Methods
 Statistical analyses
Results
 Discussion
 References
 
Percent changes from baseline for BMD and for biochemical markers (100 x (on-treatment value - baseline value)/baseline value) were calculated at months 6, 12, and 24. Month 24 was the primary BMD end-point of the study. At each time-point, treatment effects on biochemical markers were evaluated by an ANOVA model, with percent change from baseline as the response variable and with treatment, group, and study center as factors. Spearman’s correlation was used to assess associations between continuous variables. For ease of presentation, continuous variables were categorized by tertiles to demonstrate the relationship between two variables. Sensitivity, specificity, positive predictive value, and negative predictive value were used to assess the accuracy of changes from baseline, at month 6, in biochemical markers, in predicting the prevention of bone loss at month 24. Significance was accepted at the P <= 0.05 level. All analyses were done centrally and independently of study centers using Statistical Analyis System procedures.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Statistical analyses
 Results
Discussion
 References
 
Baseline characteristics, bone mass values, and biochemical markers were similar among women randomized to placebo, ALN (2.5 mg), or ALN (5 mg) (Table 1Go).


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  		Table 1. Baseline demographic data, bone mass values, and biochemical markers in the study groups (mean ± SD)

 
NTX and OC revealed a dose-related pattern with significant differences between the study groups 6 months after start of ALN treatment (Table 2Go). NTX decreased about 60% below baseline, 6 months after start of treatment with ALN (5 mg), whereas the decrease in OC was more gradual over a period of 12 months, to a level 40% below baseline. In the placebo group, there was a small decrease of about 15% in both biochemical markers during the course of the study.


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  		Table 2. Percent change (SEM) from baseline at months 6 and 24 in the biochemical markers

 
Baseline values of NTX and OC were weakly correlated with percent change from baseline at month 24 in BMD in the placebo group (r = -0.12, P < 0.01 to r = 0.07, not significant) and in the group treated with ALN 5 mg (r = -0.09, not significant to r = 0.17, P < 0.001).

In the ALN-treated groups, percent change from baseline at month 6, in NTX and OC, correlated with percent change from baseline at month 24 in BMD in all skeletal regions (r = -0.28 to -0.31 (NTX) and r = -0.16 to -0.25 (OC), P < 0.001) (Table 3Go). The correlations were weakest with forearm BMD (r = -0.12 to -0.17, P < 0.01). A regression analysis (not shown) revealed the correlation between percent change at month 6 in NTX and OC and percent change at month 24 in BMD to be dependent on treatment group (P = 0.016 for the association between NTX and spine BMD), which explained the slightly higher coefficients of correlation when data from all three study groups were pooled.


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  		Table 3. Coefficients of correlation between change from baseline at month 6 in the biochemical markers and change from baseline at month 24 in BMD at different skeletal regions

 
Figure 1Go shows the mean percent changes from baseline, at month 24, in spine and hip BMD by tertiles of percent changes from baseline at month 6 in NTX (A and B) and OC (C and D). Women in the tertiles with the greatest decrease at month 6 in NTX or OC experienced a 4- to 5-fold greater increase at month 24 in spine and hip BMD, as compared with women in the tertiles with the least decrease at month 6 in NTX or OC.



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  		Figure 1. Percent change from baseline at month 24 in lumbar spine (A and C) and total hip BMD (B and C) by tertiles of percent change from baseline at month 6 in NTX (A and B) and OC (C and D) [the group treated with ALN (5 mg) only].

 
The accuracy of percent change, from baseline at month 6 in NTX and OC, to predict prevention of bone loss at month 24 (defined as a change from baseline at month 24 in BMD of at least 0%) in individual patients treated with ALN (5 mg) is shown in Figs. 2Go and 3Go. The cut-points for NTX and OC were a decrease from baseline of 40% and 20%, respectively. These cut-points were found to achieve the highest possible sensitivities and specificities and to reflect that NTX decreased about twice as much as OC during ALN treatment. Eighty-one percent (NTX) and 74% (OC) of the women had a decrease at month 6 below the cut-point (A+D). In women with an increase at month 24 in spine BMD, 86% (NTX) and 79% (OC) had a decrease at month 6 in NTX or OC below the cut-point (sensitivity). In women with a decrease in spine BMD at month 24, 48% (NTX) and 53% (OC) had a change at month 6 in NTX or OC above the cut-point (specificity). In women with a decrease in NTX or OC at month 6 below the cut-point, 92% had an increase at month 24 in spine BMD (positive predictive value). In women with a change at month 6 in NTX or OC above the cut-point, 33% (NTX) and 37% (OC) had decreased at month 24 in spine BMD (negative predictive value). With these cut-points, NTX and OC revealed similar accuracies to predict changes in spine, hip, and total body BMD, but a lower accuracy to predict change in forearm BMD.



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  		Figure 2. Percent change from baseline at month 6 in NTX vs. percent change from baseline at month 24 in lumbar spine BMD (A), total hip BMD (B), total body BMD (C), and ultradistal forearm BMD (D).

 


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  		Figure 3. Percent change from baseline at month 6 in OC vs. percent change from baseline at month 24 in lumbar spine BMD (A), total hip BMD (B), total body BMD (C), and ultradistal forearm BMD (D).

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Statistical analyses
 Results
 Discussion
References
 
The study demonstrated that short-term prospective determinations of biochemical markers of bone turnover could be used to monitor ALN treatment and predict long-term change in bone mass.

The dose-related decrease in the biochemical markers during ALN treatment was reflected as a dose-related increase in bone mass, consistent with numerous previous studies of bisphosphonate treatment in postmenopausal women (2, 9, 10, 17, 18, 19, 20, 21). The presently applied biochemical markers were more responsive to ALN treatment than traditional biochemical markers, such as deoxypyridinoline (17, 18, 19, 20, 21), and revealed significant differences between the study groups 6 months after start of treatment, reflecting the higher sensitivity of these newer markers (2, 9, 10).

Change from baseline at month 6 in biochemical markers was significantly correlated with change from baseline at month 24 in BMD. This corresponded to 4- to 5-fold differences in increase in BMD between the extreme tertiles of biochemical markers: a 3–5.5% increase in BMD in the tertiles of women who decreased at least 70% in NTX, and an only 0.5–2% increase in BMD in the tertiles of women where NTX decreased less than 50%. Similarly, treatment with ALN (5 mg) caused a mean 6-month decrease in NTX of 60%, which corresponded to an increase in spine and hip BMD of 2–4% over 2 yr. This indicated that the numeric short-term changes in the biochemical markers in groups of women treated with ALN reflected the numeric long-term response in BMD within these groups. This is of use in clinical trials, where it is crucial to have an early clue suggesting whether the applied doses are sufficient in terms of treatment effect. However, it should also be noted that associations based on means of subgroups do not reflect the dispersions between percent change in biochemical markers and percent change in BMD, which limit the use of the numeric decrease in a biochemical marker to predict numeric long-term response in BMD in individual patients. Furthermore, an inaccuracy was introduced by the 2-yr BMD changes being in the range of the precision error of the BMD measurements. Change in spine BMD was thus closest correlated with change in biochemical markers, because the response to ALN treatment was most pronounced at this skeletal region. Similarly, change in biochemical markers and change in forearm BMD were only weakly associated, probably because of the vague response to ALN treatment at this skeletal region (1, 2).

We selected a spine BMD above or below baseline, at month 24, as threshold for the analysis of predictive capacity of the biochemical markers in individual patients, because stabilization of bone mass was the therapeutic goal in this population. By using this reference, the positive predictive values of the biochemical markers were up to 92%. This indicated that women with a decrease in NTX or OC below the cut-point (a decrease of 40% for NTX and 20% for OC) had a 92% probability of a positive 2-yr response in spine BMD during treatment with ALN (5 mg). Thus, a decrease in NTX or OC below the cut-point was a valid predictor of long-term prevention of bone loss (stable or increasing BMD) during ALN treatment. In contrast, the low negative predictive values of 30–40% implied that a change in NTX or OC above the cut-point was a poor predictor of bone loss during ALN treatment. This limited the use of NTX and OC to identify women with a decrease in BMD during ALN treatment. However, recent studies have suggested that fracture prevention does not solely depend on BMD values but is also influenced by the decrease in bone turnover per se (22, 23, 24). Because osteoporotic fractures are uncommon in recently postmenopausal women with normal BMD, fracture incidence was not a feasible study end-point in the current study. Long-term ongoing studies in osteoporotic women will further clarify the importance of BMD and biochemical markers as predictors of fracture risk.

There were only weak associations between biochemical markers at baseline and bone loss in the placebo group, which indicated weak associations between high baseline bone turnover and high spontaneous postmenopausal bone loss. The stronger association previously reported from long-term studies (25) was, however, not expected, because the 2-yr spontaneous bone loss was in the range of the precision error of the BMD measurements. Similarly, we found weak associations between baseline bone turnover and response to ALN treatment. This indicated a tendency towards a more pronounced response to ALN treatment in women with higher baseline bone turnover.

Finally, we observed a small decrease in both biochemical markers in the placebo group. Although we cannot definitely account for this unexpected finding, we hypothesize that the decreases might be caused by changes in diet or life style. Although subjects were not prescribed calcium supplements, nevertheless the majority of them received counselling on methods to increase their dietary calcium through either calcium-rich foods or supplements. Because we did not observe major changes, over the 2-yr study period, in body weight or composition, concomitant medications, diet, smoking, or physical activity, we are unable to point to other putative factors.

In conclusion, short-term changes in NTX and OC, in groups of women treated with ALN, indicated the numeric long-term response in BMD within these groups. In individual women, a short-term decrease in NTX or OC below the cut-point of 40% (NTX) or 20% (OC) during ALN treatment was a valid indicator of long-term prevention of bone loss. However, a change in NTX or OC above the cut-point was a poor indicator of bone loss during ALN treatment.


   Footnotes
 
1 This work was supported by funds from Merck Research Laboratories. A part of the data was presented at the European Congress on Osteoporosis, Berlin, Germany, September 1998, by oral presentation and in the book of abstracts (Osteoporos Int, 1998, [Suppl 3] 8:9) in the form of an abstract containing less than 400 words. Back

2 Authors represent the Early Postmenopausal Intervention Cohort Study Group. Back

Received October 1, 1998.

Revised January 28, 1999.

Revised March 31, 1999.

Accepted April 8, 1999.


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

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