The Journal of Clinical Endocrinology & Metabolism Vol. 83, No. 3 751-756
Copyright © 1998 by The Endocrine Society
Effects of the Circadian Variation in Serum Cortisol on Markers of Bone Turnover and Calcium Homeostasis in Normal Postmenopausal Women1
Hassan M. Heshmati,
B. Lawrence Riggs,
Mary F. Burritt,
Carol A. McAlister,
Peter C. Wollan and
Sundeep Khosla
Endocrine Research Unit (H.M.H., B.L.R., C.A.M., S.K.), the
Departments of Laboratory Medicine (M.F.B.) and Biostatistics (P.C.W.),
Mayo Clinic and Mayo Foundation, Rochester, Minnesota 55905
Address all correspondence and requests for reprints to: Sundeep Khosla, M.D., Mayo Clinic, 200 First Street SW, 5–164 West Joseph, Rochester, Minnesota 55905.
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Abstract
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Bone turnover has a circadian pattern, with bone resorption and, to a
lesser extent, bone formation increasing at night. Serum cortisol also
has a circadian pattern and is a potential candidate for mediating the
circadian changes in bone turnover. Thus, we measured bone formation
and resorption markers before (study A) and after (study B) elimination
of the morning peak of cortisol. We also assessed effects of the
circadian cortisol pattern on serum calcium, PTH, and urinary calcium
excretion. Ten normal postmenopausal women, aged 63–75 yr (mean, 69
yr), were studied. Metyrapone was administered to block endogenous
cortisol synthesis and either a variable (study A) or a constant (study
B) infusion of cortisol was given to reproduce and then abolish the
morning cortisol peak. Blood was sampled every 2 h for serum
cortisol, ionized calcium, PTH, and bone formation markers
[osteocalcin and carboxyl-terminal propeptide of type I collagen
(PICP)], and timed 4-h urine samples were collected for measurement of
calcium, phosphorus, sodium, potassium, and bone resorption markers
(N-telopeptide of type I collagen and free
deoxypyridinoline).
During study A, serum osteocalcin had a circadian pattern, with a peak
at 0400 h and a nadir at 1400 h. During study B, however, the
afternoon nadir of serum osteocalcin was eliminated
(P < 0.001 and P < 0.005 for
the difference in the patterns of peak and nadir, respectively, on the
2 study days). In contrast, the circadian patterns of serum PICP and
urinary N-telopeptide of type I collagen and free
deoxypyridinoline were virtually identical during the two studies.
Urinary calcium excretion declined after the cortisol peak, without
differences between the 2 study days in phosphorus or sodium excretion
or in serum PTH. We conclude that the circadian variation in serum
cortisol is responsible for the circadian pattern of serum osteocalcin,
but not that of PICP or bone resorption markers. The physiological
variation in serum cortisol may also reduce urinary calcium excretion.
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Introduction
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BONE TURNOVER has a circadian rhythm in
both animals and humans, with bone resorption and, to a lesser extent,
bone formation increasing at night (1, 2, 3, 4, 5). Eastell et al.
(2) have shown that the bone resorption marker urinary total
deoxypyridinoline (Dpd) increased by 28% at night in normal women,
whereas the bone formation marker serum osteocalcin increased by only
5.3%. As serum osteocalcin reflects mostly, if not entirely,
osteoblast activity (6, 7) and, by inference, bone formation, it is
likely that there is net bone resorption at night, which may contribute
to bone loss. In addition, Eastell et al. (1) also found
that the nocturnal increase in urinary total Dpd excretion was
significantly greater in osteoporotic compared to normal women. Thus,
understanding the mediator(s) of the circadian variation in bone
turnover is important from both a mechanistic and possibly a
therapeutic standpoint.
Several studies have attempted to define the cause of the circadian
pattern of bone turnover. Posture is an obvious candidate, as prolonged
bed rest leads to an increase in bone turnover (8). However, Schlemmer
et al. (8) found that the circadian variation in the urinary
excretion of the bone resorption markers, total pyridinoline (Pyd) and
Dpd, remained unchanged after 5 days of total bed rest. Several
hormones with effects on bone turnover, including PTH, GH, and
cortisol, also exhibit circadian rhythms and could be candidates for
mediating the circadian changes in bone turnover. In previous studies,
however, Ledger et al. (9) found that abolishing the
circadian variation in serum PTH by a continuous iv infusion of calcium
had no effect on the circadian variation in the urinary excretion of
the bone resorption marker, the cross-linked N-telopeptide
of bone type I collagen (NTx). Similarly, the nocturnal increase in
serum osteocalcin was not affected by somatostatin-induced inhibition
of the nocturnal rise in GH (10).
Several studies have examined the role of cortisol in mediating the
circadian rhythm of bone turnover, with somewhat conflicting results
(11, 12, 13, 14). Studies using pharmacological agents such as prednisone (11)
or metyrapone (12) have found that these agents did alter the circadian
pattern of serum osteocalcin. In addition, Kendler et al.
(13) found that dexamethasone administration altered the circadian
pattern of urinary total Dpd excretion. In contrast, Schlemmer et
al. (14) reported that hydrocortisone administered orally in
divided doses to hypoadrenal subjects did not prevent the nocturnal
increase in bone resorption.
In addition to having effects on bone turnover, cortisol may have
significant effects on overall calcium homeostasis, including PTH
secretion (15) and renal calcium handling (16, 17). It remains unclear,
however, whether these are pharmacological effects or whether the
normal circadian variation in serum cortisol also alters PTH secretion
or renal calcium handling.
The aim of this study was to use the most rigorous design possible in
normal subjects to test for a role for the circadian variation in serum
cortisol in determining the circadian variation in bone turnover. We
also sought to define the effects of the circadian variation in serum
cortisol on overall calcium homeostasis. Thus, we inhibited endogenous
cortisol synthesis using metyrapone and infused cortisol at either a
variable rate (to mimic the physiological circadian variation in serum
cortisol) or at a constant rate (to eliminate the cortisol rhythm) and
assessed the circadian variation in bone formation and bone resorption
as well as in serum calcium, PTH, and renal calcium handling under the
two conditions.
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Subjects and Methods
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Subjects
After approval of the protocol by the Mayo Institutional Review
Board, 10 untreated normal postmenopausal women, aged 63–75 yr (mean,
69 yr), were studied. The mean duration of menopause was 19 yr (range,
11–29 yr), and the mean body mass index was 27.7 (range, 21.7–36.1).
All subjects gave informed consent. Based on medical history, physical
examination, and hematological and biochemical tests, subjects with
significant medical diseases such as osteoporosis, renal failure
(creatinine, >1.5 mg/dL), adrenal dysfunction, malabsorption, active
malignancy, congestive heart failure, hypotension, and psychiatric
disorders were excluded from the study. We also excluded nightshift
workers and subjects who recently traveled across several time zones.
No subject was taking any medication known to affect bone metabolism or
adrenal function.
Study protocol
Throughout the study period, subjects were maintained on their
habitual calcium intake, which was assessed by a trained dietitian
using a food frequency questionnaire (18). Each subject was studied
before (study A) and after (study B) elimination of the morning peak of
cortisol as an in-patient at the General Clinical Research Center. For
each study (A or B), subjects were admitted to the General Clinical
Research Center at 1500 h on day 1 and were dismissed at 0900
h on day 3 (see Fig. 1
, A and B, for outline of study protocol). Meals
were served at 0800, 1200, and 1800 h and were consumed within 30
min. Subjects were ambulant (sitting or walking) from 0700–2300 h and
were recumbent from 2300–0700 h (sleeping hours), except to urinate.
During study A, metyrapone (750 mg, orally, every 4 h for 24
h) was administered to block endogenous synthesis of cortisol, and a
variable infusion of hydrocortisone (0.1–1.1 µg/kg·min) was used
to reproduce the normal circadian pattern of cortisol. During study B,
metyrapone, as described above, plus a constant, low dose infusion of
hydrocortisone (0.2 µg/kg·min), was given to eliminate the
endogenous circadian rhythm of cortisol (Fig. 1) (19). Blood was sampled through an
indwelling catheter every 2 h for measurement of serum cortisol,
ionized calcium, PTH, osteocalcin, and carboxyl-terminal propeptide of
type I collagen (PICP). Timed 4-h urine samples were collected for
measurement of calcium, phosphorus, sodium, potassium, NTx, and free
Dpd (f-Dpd).
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Figure 1. Outline of study protocol. The times of the
blood and urine samples are shown in A, and the patterns of the
variable and continuous cortisol infusions are shown in B.
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Assay methods
Serum cortisol was measured by an immunochemiluminometric assay
[Sanofi, Chaska, MN; inter- and intraassay coefficients of variation
(CVs), 6.8% and 5.2%, respectively], serum osteocalcin was measured
by an enzyme-linked immunosorbent assay (ELISA; CIS US, Bedford, MA;
inter- and intraassay CVs, 13.6% and 3.9%, respectively), serum PICP
was determined by ELISA (Metra Biosystems, Mountain View, CA; inter-
and intraassay CVs, 9.9% and 4.7%, respectively), urinary NTx was
determined by ELISA (Ostex International, Seattle, WA; inter- and
intraassay CVs, 13.1% and 7.6%, respectively), and urinary f-Dpd was
measured by ELISA (Metra Biosystems; inter- and intraassay CVs, 14.0%
and 5.4%, respectively). Serum intact PTH was measured by an
immunochemiluminometric assay (20) (inter- and intraassay CVs, 8.0%
and 6.0%, respectively). The serum ionized calcium concentration was
measured with a Radiometer ICA 2 Analyzer (Radiometer America,
Westlake, OH; inter- and intraassay CVs, 1.6% and 0.8%, respectively)
(21), and these values are reported corrected to a pH of 7.40. Urinary
phosphorus, sodium, potassium, and serum and urinary creatinine were
measured by routine automated methods (Hitachi 911 Analyzer,
Boehringer Mannheim, Indianapolis, IN). Urinary calcium was
measured by an atomic absorption spectrophotometry. The glomerular
filtration rate was assessed by measuring creatinine clearance, and the
urinary parameters were normalized per dL glomerular filtrate (GF).
Statistical analysis
All data are reported as the mean ± SEM. A
variety of statistical analyses have been used to identify or test for
circadian rhythm, including trigonometric regression, power spectrum
analysis, Kalman filters, nonparametric regression, and deconvolution
(22, 23, 24). All of these methods, however, have difficulties handling
data consisting of a single cycle of an unspecified functional form. We
have chose to employ a method, O’Brien’s extended t test
(25), which does not test for any specific form of cycle, but, rather,
tests for the difference in pattern between the location of the maximum
and the location of the minimum concentration within each subject’s
responses. A significant effect (P < 0.05) under this
test can be interpreted as evidence of a cycle of some form, consistent
across subjects.
O’Brien’s test was used to compare within-subject time of peak
concentration to the time of minimum concentration, within studies A
and B separately, to test for circadian rhythm. Also, the same test was
used to compare the time of peak and the time of nadir between study A
and study B to test for an effect of cortisol suppression. In addition,
for each parameter, the magnitude of the variable at a given time point
was compared between study A and study B using the Wilcoxon rank sum
test.
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Results
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Circadian changes in serum cortisol
Figure 2 shows the serum cortisol
levels in the study subjects during either the variable cortisol
infusion or the continuous infusion days. During the variable infusion,
serum cortisol levels peaked in all 10 subjects at 0800 h, whereas
on the continuous infusion day, cortisol levels did not have an early
morning peak, but, rather, there was a gradual increase over the course
of the day (P < 0.0001 and P < 0.02
for the differences in the times of peak and nadir on the 2 days,
respectively).
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Figure 2. Serum cortisol levels as a function of clock
time during either the variable cortisol infusion (solid
circles) or the continuous cortisol infusion (open
circles). The times of the peak and nadir were both
significantly different (P < 0.0001 and
P < 0.02, respectively) between the 2 study days
(*, P < 0.05; **, P < 0.01;
***, P < 0.001 for differences in the magnitude of
serum cortisol levels between the 2 study days).
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Circadian changes in bone turnover markers
Figure 3 shows the serum osteocalcin
and PICP levels in the study subjects during either the variable
cortisol infusion or the continuous infusion days. The cortisol peak at
0800 h resulted in a daytime nadir in serum osteocalcin levels,
which was absent on the continuous infusion day (Fig. 3A;
P < 0.001 and P < 0.005 for the
differences in the times of peak and nadir on the 2 days,
respectively). In contrast, serum PICP levels showed a persistent
daytime nadir on both the variable and continuous cortisol infusion
days (Fig. 3B). Toward the end of the study period, however, serum PICP
levels tended to be higher on the continuous cortisol infusion day than
those on the variable cortisol infusion day, although the differences
in the magnitude of PICP levels at the individual time points were not
statistically significant.
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Figure 3. Serum osteocalcin (A) and PICP (B) levels as
a function of clock time during either the variable cortisol infusion
(solid circles) or the continuous cortisol infusion
(open circles). The times of the peak and nadir in serum
osteocalcin were both significantly different (P <
0.001 and P < 0.005, respectively) between the 2
study days, whereas these were not different for serum PICP.
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To assess the effects of the circadian variation in cortisol on bone
resorption, we measured urinary NTx, which is an assay for one of the
peptide fragments released during bone resorption, and f-Dpd, which
measures the free, nonpeptide-bound bone collagen cross-linking
molecule. As shown in Fig. 4A, the
circadian variation in urinary NTx excretion was virtually identical
during the variable cortisol infusion and the continuous cortisol
infusion days. For f-Dpd, the circadian pattern was present during both
study days (Fig. 4B), although there was a broader peak with a smaller
magnitude (P = 0.08) during the continuous infusion
vs. the variable infusion days.
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Figure 4. Urinary NTx (A) and f-Dpd (B) excretion as a
function of clock time during either the variable cortisol infusion
(solid circles) or the continuous cortisol infusion
(open circles). For urinary NTx, the times of the peak
and nadir were identical on the 2 study days, whereas the time of the
peak was different (P < 0.02) for urinary f-Dpd.
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Circadian changes in serum ionized calcium, PTH, and renal calcium
and phosphorus handling
Serum ionized calcium and PTH values were virtually identical
during the variable and continuous cortisol infusion days (Fig. 5, A and B). The pattern over time in
urinary calcium excretion was, however, significantly different between
the 2 study days; the morning peak of cortisol was followed by a
decrease in urinary calcium between 1200–2000 h, whereas there was a
late afternoon rise in urinary calcium excretion on the continuous
infusion day (Fig. 6A; P
< 0.05 for the timing of the peak in urinary calcium excretion on the
2 study days). Urinary phosphorus excretion, however, was similar on
the 2 days (Fig. 6B). The differences in renal calcium handling were
not due to differences in sodium handling, as sodium excretion was also
not different between the 2 study days (Fig. 7A). Potassium excretion, however, was
significantly different between the 2 study days; the cortisol peak was
followed by a peak in potassium excretion, which was not present during
the continuous infusion (Fig. 7B; P < 0.0001 for the
timing of the peak in potassium excretion on the 2 study days),
although potassium excretion tended to increase over the course of the
continuous infusion day, perhaps reflecting the gradually rising
cortisol levels (Fig. 2
). Neither the pattern nor the magnitude of the
glomerular filtration rate was significantly different between the 2
study days (data not shown).
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Figure 5. Serum ionized calcium (A) and PTH (B) levels
as a function of clock time during either the variable cortisol
infusion (solid circles) or the continuous cortisol
infusion (open circles). The times of the peak and nadir
were similar for both variables on the 2 study days. The
asterisk indicates a significant difference
(P < 0.05) in serum ionized calcium level between
the 2 study days.
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Figure 6. Urinary calcium (A) and phosphorus (B)
excretion as a function of clock time during either the variable
cortisol infusion (solid circles) or the continuous
cortisol infusion (open circles). The time of the peak
in urinary calcium excretion was significantly different
(P < 0.05) between the 2 study days, whereas the
pattern of urinary phosphorus excretion was identical on the 2 study
days.
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Figure 7. Urinary sodium (A) and potassium (B)
excretion as a function of clock time during either the variable
cortisol infusion (solid circles) or the continuous
cortisol infusion (open circles). The pattern of urinary
sodium excretion was identical on the 2 study days, whereas the time of
the peak in urinary potassium excretion was significantly different
(P < 0.0001) between the 2 study days (**,
P < 0.01; ***, P < 0.001 for
differences in the magnitude of urinary potassium excretion between the
2 study days).
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Discussion
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Our findings clearly show that the morning rise in serum cortisol
is responsible for the daytime nadir in serum osteocalcin levels. The
nocturnal increase in serum osteocalcin levels, then, is a consequence
of the declining cortisol levels in the evening and nighttime hours.
Previous studies using pharmacological agents, such as prednisone (11)
or metyrapone (12) in normal subjects and hydrocortisone in a
heterogeneous group of hypoadrenal subjects (with primary and secondary
adrenal insufficiency) (14), had indicated a possible role for cortisol
in determining the circadian pattern of serum osteocalcin. Our studies,
however, by first reproducing and then eliminating the circadian rhythm
of cortisol, provide the most direct demonstration of the critical role
of cortisol in determining the circadian pattern of serum
osteocalcin.
In contrast to osteocalcin, serum PICP levels showed a persistent
circadian variation in the presence or absence of the cortisol peak.
The discrepancy between the changes in serum osteocalcin and PICP are
not surprising, as bone formation involves multiple steps, and the two
serum markers represent different aspects of osteoblast function (26).
Thus, these data would be consistent with a cortisol-induced inhibition
of osteocalcin synthesis, without effects of the physiological
variation in cortisol on type I collagen synthesis by bone cells.
Previous studies have shown that serum osteocalcin levels are the most
sensitive marker of glucocorticoid inhibition of osteoblast function
compared to either PICP or bone alkaline phosphatase levels (26, 27).
However, as glucocorticoids also inhibit osteocalcin gene transcription
(28, 29), it is possible that at least part of the decline in
circulating osteocalcin levels after the cortisol peak is related to a
direct inhibition of osteocalcin gene expression by cortisol.
Our results also show that the circadian variation of cortisol is not
responsible for the circadian variation in bone resorption, as assessed
by two different bone resorption markers. Thus, elimination of the
morning peak of cortisol had no effect on the circadian variation in
urinary NTx excretion. The circadian pattern in f-Dpd excretion was
also present on both days, although the peak was somewhat broader and
of a smaller magnitude when the cortisol peak was absent. Although not
affecting the circadian pattern of f-Dpd excretion, cortisol may alter
the relative amount of f-Dpd released during collagen breakdown and/or
alter the metabolism or clearance of f-Dpd.
Our findings regarding the effects of cortisol on the circadian
variation of bone resorption are in contrast to the results of Kendler
et al. (13), who administered a pharmacological dose of
dexamethasone and found that this eliminated the circadian variation in
urinary total Dpd excretion. Similarly, Lakatos et al. (30)
reported that the circadian rhythm of in vitro
bone-resorbing activity in human serum was altered by the
glucocorticoid antagonist, RU486. In contrast, Schlemmer et
al. (14) found, in agreement with our results, that oral
hydrocortisone administered in divided doses to hypoadrenal subjects
did not prevent the circadian variation in urinary total Pyd excretion.
Again, by first reproducing and then eliminating the cortisol peak, our
study provides the most definitive test of the hypothesis that cortisol
is responsible for the circadian variation in bone resorption. As noted
earlier, previous studies have excluded posture (8) or PTH (9) as
mediators of this circadian pattern in bone resorption. As cortisol
does not mediate this effect either, the cause of the circadian
variation in bone resorption remains unclear at present. Studies in
rats have shown that the frequency of feeding may influence the
circadian changes in bone resorption (31); whether this is also true in
humans is unknown and requires further study.
To the extent that changes in serum osteocalcin reflect changes in bone
formation, the demonstration that the morning peak of cortisol
depresses osteocalcin production during the day has potential
implications for diseases associated with even mild derangements in the
hypothalamic-pituitary-adrenal axis. Recent studies indicate, for
example, that depression is associated with reduced bone mineral
density (32) as well as with alterations in 24-h cortisol secretion
rates and the circadian variation in serum cortisol (33). Similarly,
anorexia nervosa is also associated with osteopenia (34) and with
alterations in the circadian pattern of cortisol secretion (35). Our
data suggest that these alterations in cortisol rhythmicity by
themselves may significantly impair osteoblast function.
Our data also indicate that the circadian variation in serum cortisol
has significant effects on urinary calcium excretion. Thus, calcium
excretion declined after the cortisol peak compared to the day without
the cortisol peak, when there was a rise in calcium excretion. These
results are somewhat surprising, as pharmacological glucocorticoid
therapy in humans is generally associated with hypercalciuria (16, 17).
Our findings, however, suggest that the physiological variation in
serum cortisol results in renal calcium conservation. This does not
appear to be due to increased PTH secretion, because PTH levels were
similar on the 2 study days. The effect appears to be relatively
specific for renal calcium handling, as phosphorus excretion was not
different on the 2 study days. The decrease in calcium excretion is
also not due to alterations in renal sodium handling, as that was also
similar on the 2 days, although potassium excretion was different,
perhaps reflecting a small mineralocorticoid effect of the variable
cortisol infusion. Taken together, therefore, these data indicate that
the physiological variation in serum cortisol may have an independent
effect on renal tubular calcium reabsorption that requires further
study.
In summary, our data show that the circadian variation in serum
cortisol is responsible for the circadian pattern of serum osteocalcin,
but not that of PICP or bone resorption markers. The etiology of the
circadian variation in bone resorption remains unclear at present and
requires further investigation. These studies also define the effects
of the circadian variation in serum cortisol on overall calcium
homeostasis, including possible direct effects of cortisol on renal
calcium handling.
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Acknowledgments
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We thank the patients who volunteered to participate in this
study; Joan M. Muhs for recruiting the patients; the nurses and the
dietitians of the General Clinical Research Center (Mayo Clinic and
Foundation) for performing the study and for nutritional assessment;
Roberta A. Soderberg, Debra M. Hanson, Sandra H. Showalter, and Don W.
Heser for technical assistance; and Nurit Geller for illustrations.
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Footnotes
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1 This work was supported by NIH Grants AG-04875 and RR-00585. 
Received August 27, 1997.
Revised November 17, 1997.
Accepted November 25, 1997.
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Abstract
Introduction
