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Clinical Studies |
Maine Center for Osteoporosis Research and Education, St. Joseph Hospital (C.J.R.), Bangor, Maine 04401; University of Washington School of Medicine (C.H.C.), Seattle, Washington 98134; and Ostex International (N.J.S.M.), Seattle, Washington 98134
Address all correspondence and requests for reprints to: Clifford J. Rosen, M.D., St. Joseph Hospital, 360 Broadway, Bangor, Maine 04401.
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Abstract |
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionConflict of InterestReferences |
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionConflict of InterestReferences |
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Two hundred and thirty-six postmenopausal women, aged 40–58 yr (mean age, 51 yr), were recruited from eight clinical research sites situated in the major geographical regions of the United States, as described previously (4). Women were randomized if they met the following conditions: 1) natural menopause from 6 months to 3 yr before the study, 2) willingness to be randomized to either calcium carbonate or HRT, and 3) FSH levels above 30 IU/mL at the time of screening. Exclusion criteria included 1) medications that might interfere with bone metabolism (e.g. anticonvulsants, warfarin, or glucocorticoids), 2) presence of a disease known to affect skeletal turnover (e.g. diabetes mellitus, hyper- or hypo-parathyroidism, sarcoidosis, or malignancy), 3) ideal body weight greater than 130%, 4) renal insufficiency (serum creatinine, >2.0 mg/dL), 5) recent fracture or immobilization, 6) positive mammogram within 12 months, or 7) baseline spine or hip BMD more than 4 SD below the mean of young normal subjects.
Experimental design
Upon enrollment, women were randomized for a 1-yr single blind trial to either calcium supplements alone (CS; Oscal 500, once per day, Smith Kline Beecham, St. Louis, MO) or HRT plus one calcium supplement per day (Oscal-500). For the HRT arm, conjugated equine estrogen (0.625 mg; Premarin, Wyeth Ayerst, Philadelphia, PA) or another equivalent estrogen preparation and continuous or cyclic medroxyprogesterone (2.5 mg/day, continuous; 5.0 mg/day, cyclic; Provera, Upjohn Co., Kalamazoo, MI) were administered. In addition, women were instructed to maintain a total calcium intake (dietary plus supplements) of 800-1200 mg Ca/day.
Subjects were followed for 1 yr, with biochemical measurements obtained at baseline and then 1, 3, 6, and 12 months after initiation of treatment. Two hundred and twenty-seven women completed 1 yr of the trial. Nine women did not complete the study; four moved away, two decided to stop taking the drug (one taking calcium and one taking HRT), and three were removed from the study by their primary care physician (two taking calcium and one taking HRT). Institutional review board approval of the study protocol and informed consent were obtained at all sites before recruitment or initiation of treatment.
BMD
Dual energy x-ray absorptiometry of the spine and femoral neck was performed at all eight clinical sites using machines from three manufacturers (Hologic, Waltham, MA; Lunar, Madison, WI; and Norland, Atkinson, WI). The University of Washington Osteoporosis Research Group provided quality control and phantom cross-calibration for the dual energy x-ray absortiometry measurements. The calibration factor from the quality control provided standardization of the results among the eight clinical sites and different manufacturers’ equipment. The reported precision of measurement at the spine was 1.04%, and that at the femoral neck was 2.13% (7). BMD was measured at baseline and 3, 6 and 12 months after treatment.
Biochemical markers of bone turnover and gonadotropins
FSH was measured on one screening visit to assess eligibility (FSH, >30 IU/mL). Retests of subjects who had borderline gonadotropin levels were permitted to reach FSH concentrations above 30 IU/mL before randomization. Serum FSH was also determined at 6 months and 1 yr in all subjects. Two markers of bone formation and two markers of bone resorption were selected as primary end points for this study. Biochemical markers were measured at screening and after randomization but before treatment (day 0). For the subjects receiving treatments, measurements were made 1, 3, 6, and 12 months after therapy. Bone resorption markers were measured while subjects were fasting in the second morning voided urine specimens collected at study visits. Serum formation indicators were collected at the same time as the urine samples (i.e. fasting morning samples). The samples for biochemical markers were initially collected at the individual research site, frozen, shipped to the central laboratory (American Medical Laboratories, Chantilly, VA), aliquoted into vials, and stored (-20 C) until testing at three laboratories: 1) American Medical Laboratories (Chantilly, VA), 2) Endocrine Sciences (Calabasas Hills, CA), and 3) Dynacare Laboratory of Pathology, (Seattle, WA).
Bone resorption indexes
NTx was measured by a commercially available enzyme-linked immunosorbent assay that uses a specific monoclonal antibody directed against the NTx intermolecular cross-linking domain of type I collagen of bone (Osteomark, Ostex International, Seattle, WA) (8). Urinary values were calculated from a standard curve of known NTx concentrations and expressed as bone collagen equivalents (BCE). Levels of BCE reflect the amount of immunoreactive NTx liberated from human bone collagen after bacterial collagenase digestion as measured by hydroxyproline using high performance liquid chromatography. Assay values were corrected for dilution by urinary creatinine analysis and expressed as nanomoles per L BCE/millimoles per L creatinine. The sensitivity of the assay was 20 nmol/L BCE. Intra- and interassay variabilities averaged 7.6% and 4%, respectively. The normal (premenopausal) expected range is 5–65 nmol/L BCE/mol/L creatinine.
Free deoxypyridinoline (fDpd) was measured by a commercially available competitive enzyme-linked immunosorbent assay that uses a monoclonal antibody directed against fDpd (Pyrilinks-D, Metra Biosystems, Mountain View, CA) (9). Cross-reactivity with free pyridinoline is reported as less than 1%, and free pyridinoline/fDpd peptides was less than 2.5% (9). Assay values are corrected for dilution by urinary creatinine analysis and expressed as nanomoles per L/millimoles per L creatinine. Within- and between-run precisions reported by the manufacturer, as determined with three urine samples of varying fDpd concentration, averaged 6.1% and 4.2%, respectively. The reference range for healthy premenopausal women is 3.0–7.4 nmol/L/mol/L.
Bone formation markers
Osteocalcin (OC) was measured by a RIA that uses rabbit antihuman OC antibody and radiolabeled human OC (10). This procedure measures both intact as well as N-terminal fragments. The reported sensitivity is 0.8 ng/mL. Intra- and interassay variabilities of 8.1% and 12% have been reported. The expected normal range for postmenopausal women is 1.5–11.0 ng/mL.
Bone-specific alkaline phosphatase (BSAP) was measured in a kinetic colorimetric assay (11). The bone-specific fraction is determined by inhibition of other fractions by heat and chemicals as well as utilization of highly purified BAP as standard (12). The sensitivity was reported to be greater than 2.5 U/mL, with intra- and interassay variabilities of 18.7% and 6.8%, respectively. Expected values ranged from 2.8–12.0 U/mL.
Data analysis
The variables for the four markers and those for the spine (L1–L4) and femoral neck BMD were analyzed using both their actual values and the percent change from baseline. A paired t test was used to determine the significance of changes from baseline. Comparisons between quartiles of the markers were made using the Wilcoxon rank sum test. The percent change in L1–L4 BMD at 1 yr was used to classify subjects as maintaining/gaining (zero or positive change) or losing (negative change) BMD. Receiver operating characteristic (ROC) curves were used to compare the relationship between the individual markers and a gain or loss in BMD at 1 yr. These curves plot sensitivity vs. one minus specificity, and thus, the area under the curve provides a measure of predictive power. The odds of a gain or loss of BMD for an increase of 1 SD in the individual markers were estimated from logistic regression models in which the dependent variable was the gain or loss in BMD, and the independent variable was the value of the marker at baseline. Data are presented as the mean ± SEM unless otherwise noted. All tests are two-sided; P <0.05 was defined as significant. All analyses were performed using the Statistical Analysis System (SAS Institute, Cary, NC).
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionConflict of InterestReferences |
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At 12 months BMD increased significantly in HRT-treated women at
both spine (+2.5%; P < 0.0001) and femoral neck (hip;
+1.0%; P < 0.05). Only approximately one third of
women receiving HRT showed suppression of FSH below 30 IU/L even though
more than two thirds had a positive skeletal response to replacement
therapy. The mean FSH for all women treated with HRT at 6 months was
41 ± 23 IU/L. On the other hand, markers of bone remodeling
decreased consistently in response to HRT. A significant decrease was
seen at 1 month with NTx, fDpd, and OC, with mean percent changes from
baseline of -28%, -10%, and -15% (P < 0.0001),
respectively (Fig. 1
). BSAP increased at 2 and 3 months,
but then declined at 6 and 12 months (-25%; P <
0.0001).
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). Stratification of the NTx baseline value
demonstrated a significant difference between the increase in BMD in
those subjects with higher NTx values (Q4) and those with lower NTx
values (Q1; P < 0.05). This was not observed with
fDpd, where the difference between Q1 and Q4 was not statistically
significant. Significant differences were observed between Q1 and Q4
for both OC and BSAP (P < 0.05).
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Although the quartile analysis compared baseline marker values or
response in markers to change in spine BMD, ROC curves were used to
determine whether the percent change at 6 months in a marker could
predict gain or loss of spine BMD after 1 yr of HRT (Fig. 3). Those analyses yielded similar results, with the
percent change in NTx providing a greater discrimination between gain
and loss of BMD than OC, BSAP, or fDpd.
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, the mean baseline resorption marker value for those
gaining spine BMD was compared to that in those losing BMD after 1 yr
of HRT. For the group receiving a skeletal benefit from HRT (n =
84), the gain in spine BMD at 1 yr was +3.9 ± 2.8%, whereas for
those that lost BMD during HRT (n = 22), the loss in spine BMD was
-1.7 ± 1.6%. Mean baseline NTx values were significantly
different between those that gained and those that lost BMD at the
spine (63 nmol/L BCE/mol/L creatinine vs. 42 nmol/L
BCE/mmol/L creatinine; P = 0.0002). However, baseline
fDpd values were not statistically different between the two groups
(6.5 nmol/L Dpd/mmol/L creatinine vs. 5.9 nmol/L Dpd/mmol/L
creatinine).
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). The odds ratios ranged from 6.4 (95% confidence
interval, 2.6–9.99) for OC to 1.2 (95% confidence interval,
0.80–1.73) for fDpd. An increase of 1 SD in the baseline
fDpd value (1.7 nmol/L Dpd/mmol/L creatinine) did not affect the odds
of receiving a skeletal benefit from HRT as measured by a gain in spine
BMD after 1 yr of therapy.
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In the CS group, BMD decreased significantly at the spine and hip
(-1.1%; P < 0.01). Mean resorption marker values did
not change significantly over the 12 months of CS. However, BSAP
increased from baseline to 12 months, whereas OC did not change. The
response to calcium at the spine was stratified into quartiles by the
average on-therapy value for the bone resorption markers (Fig. 5). Comparison of the resorption marker quartile
analysis for the CS group was similar to that for the HRT group.
Subjects with the highest NTx values (>64 nmol/L BCE/mmol/L
creatinine) maintained throughout the study had a significantly greater
decrease in spine BMD (-2.3 ± 0.4%) than subjects with the
lowest NTx values (<38 nmol/L BCE/mmol/L creatinine; +0.2 ±
0.6%; P < 0.005). However, stratification of fDpd
average on-therapy values revealed that loss of BMD in subjects in the
highest quartile (>7.5 nmol/L Dpd/mmol/L creatinine) were not
different from that in subjects in the lowest quartile (<5.3 nmol/L
Dpd/mmol/L creatinine; P = 0.18).
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demonstrated a lack of change in BSAP through the majority of the
study. A significant difference between the percent change in spine BMD
for OC Q1 and Q4 was observed (P < 0.05); subjects
that maintained values above 8.0 ng/mL had a greater decrease in spine
BMD (-1.66 ± 0.64%) than those that maintained values below 5.1
ng/mL (0.06 ± 0.50%). There was a nonsignificant difference
between Q1 BSAP and Q4 BSAP.
The ability of the markers to predict loss of spine BMD in the calcium
group from the average on-therapy value confirmed the quartile results
(Table 1). For NTx and OC, an increase of 1 SD in the
average on-therapy value increased the odds of losing spine BMD by 2.1
and 1.6, respectively.
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionConflict of InterestReferences |
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Several lines of evidence suggest that bone turnover indexes provide clinically relevant information about skeletal remodeling and bone responsiveness to therapy. For instance, all four biochemical markers decreased in a time-dependent manner during 1 yr of HRT. From this study, it is clear that HRT suppresses bone resorption more than formation and, therefore, is almost certainly the mechanism responsible for the modest increase in spine and hip BMD seen in most trials of estrogen replacement therapy. The resultant increase in vertebral and femoral BMD in this trial is also consistent with results from earlier studies as well as the recently completed PEPI (postmenopausal estrogen progesterone intervention) study (3). However, in the PEPI study, the women were older and consequently had been postmenopausal for a longer period (3). As bone turnover is increased in the immediate postmenopausal period, attempts to compare marker responsiveness in our study to those in other studies (e.g. PEPI) could be problematic.
Although all four biochemical markers were suppressed during HRT, the earliest and most significant change from baseline was noted for urinary NTx and serum OC. That trend continued at later time points as well, suggesting that measurement of serum OC or urinary NTx 1–3 months after initiation of therapy can reflect changes in bone remodeling as well as the degree of bone mass responsiveness. ROC curve analysis for change in markers from baseline to 6 months further reinforces these findings.
In addition to changes in bone formation and bone resorption markers
with HRT, there is evidence from this study that a baseline biochemical
marker can predict subsequent bone density in response to intervention.
Using quartile analysis of women treated with HRT, those with the
highest serum OC, BSAP, and urinary NTx excretion exhibited the
greatest increase in spine bone density after 1 yr of treatment,
whereas only fDpd failed to predict a statistically significant change
in BMD. In the same vein, these indexes could be useful in identifying
women who might not have a favorable response to HRT (i.e.
loss of BMD after 1 yr) compared to those who showed an increase in
lumbar BMD. Twenty-two women (20%) receiving HRT had a decline in
spine BMD after 1 yr of HRT (mean, -1.7%, Fig. 4). When gainers of
BMD were compared to losers of BMD by baseline NTx excretion, those
women who gained bone mass had significantly higher mean urinary NTx at
baseline than those who lost BMD. We also noted highly significant odds
ratios for an increase in bone mass during HRT when a single baseline
OC or NTx measurement was 1 or more SD above the
premenopausal normal range. This would confirm earlier observations
that skeletal responsiveness to estrogens and calcitonin is influenced
by the pretreatment status of the bone-remodeling unit (15, 16, 17).
The mechanism responsible for the observed relationship between NTx and skeletal response or nonresponse to HRT is unclear, although the relatively young age (mean age, 51 yr) of our cohort may be important. However, other possibilities could explain the relatively high proportion of our cohort who did not respond to 0.625 mg conjugated equine estrogen and progesterone. First, early postmenopausal women may be undergoing greater changes in bone turnover than older women and, hence, may respond by decreasing their rate of bone loss rather than increasing their BMD. Second, there may be a relatively fixed proportion of postmenopausal women who exhibit either skeletal resistance to conventional doses (0.625 mg) of conjugated equine estrogens or are rapid metabolizers of estrogen. Third, we cannot exclude the possibility of noncompliance with HRT. This phenomenon is quite common in clinical practice and has been noted in other studies, although in our trial almost all women receiving HRT had a significant suppression of NTx from baseline, suggesting some drug effect from estrogen. Finally, it is uncertain whether changes in BMD at 1 yr are sufficient to determine final skeletal responsiveness to HRT. As all markers demonstrated a time-dependent decrease, we cannot exclude the possibility that further suppression of bone turnover with a subsequent increase in BMD could occur. Despite these possibilities, questions concerning the proper replacement dose for an individual and identification of nonresponders before treatment are likely to persist.
In contrast to women receiving HRT, women randomized to calcium alone exhibited a significant decrease in femoral and lumbar BMD at the end of 1 yr. However, by stratification of average marker values across the study year, only NTx and OC values could predict the subsequent loss of bone, whereas fDpd and BSAP could not; i.e. when considering fDpd, women that maintained over 1 yr the highest values of fDpd did not lose significantly more bone than those with the lowest fDpd. Furthermore, the value of a marker for identifying a pretreatment risk for bone loss in postmenopausal women supplemented with calcium alone is strengthened by the relatively high odds ratio for bone loss for serum OC and urinary NTx. In addition, all markers showed relatively stable values over the course of the study in the calcium-supplemented women. Hence, this trial provides further comparative data on the predictive value of the four most commonly used biochemical markers of turnover in early postmenopausal women treated with either calcium or estrogen/progesterone.
There were several limitations to this randomized calcium-controlled study. First, our population had recently entered menopause. Thus, results from this study may not be applicable to other women more than 3 yr after menopause. Second, as noted previously, it was unclear (pill counts were not performed) what percentage of women receiving HRT in this trial was not compliant with the regimen. Suppression of FSH levels can be useful in determining which women are taking HRT, but changes in FSH concentrations did not predict the skeletal response to HRT in this study or in other earlier studies. Third, during the course of the study there was significant intrasubject variability. However, a 20–25% coefficient of variation for NTx (Osteomark) and fDpd (Pyrilinks-D) in an individual subject is not unexpected and is similar to reports in other studies (5, 13, 14, 15, 18). This variability almost certainly relates to fluctuations in creatinine excretion as well as biological variation. However, when subjects’ coefficient of variation were compared to the percent change in the markers after the initiation of HRT, the mean change in NTx due to therapy was always greater than the biological variability, even at the early time points. This was not the case for fDpd. As an example, after 1 month of HRT, the mean percent change in NTx was -28% compared to the mean change in fDpd of -10%. After 6 months, the mean change in NTx was -42% compared to that in fDpd, which was -22%. Finally, it should be noted that women recruited for this study were healthy and were not overtly osteoporotic (mean T scores in spine and hip were normal). Therefore, it is unclear if the same degree of estrogen resistance or skeletal responsiveness to calcium supplementation would be seen in women suffering from postmenopausal osteoporosis.
In conclusion, we have demonstrated that biochemical markers of bone turnover can be used to determine skeletal responsiveness to HRT, and that select baseline biochemical markers in postmenopausal women provide clinically useful information about future changes in bone mass after therapeutic intervention. From this study, urinary NTx and serum OC provided the greatest sensitivity and specificity for change in bone density with either calcium supplementation or HRT. Confirmation of these data by other longitudinal studies will lead to greater utilization of selected biochemical markers of remodeling in conjunction with bone mass measurements to guide clinical decision making for postmenopausal women.
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Conflict of Interest |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionConflict of InterestReferences |
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Acknowledgments |
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Footnotes |
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Received January 22, 1997.
Revised February 27, 1997.
Accepted March 5, 1997.
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionConflict of InterestReferences |
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