0021-972X/01/$03.00/0
7
The Journal of Clinical Endocrinology & Metabolism
Copyright © 2001 by The Endocrine Society
Vitamin D Status and Redefining Serum Parathyroid
Hormone Reference Range in the Elderly*
JEAN-CLAUDE SOUBERBIELLE, CATHERINE CORMIER,
CATHERINE KINDERMANS, PING GAO, THOMAS CANTOR,
FRANÇOISE FORETTE, AND ETIENNE EMILE BAULIEU
Laboratoire d’Explorations Fonctionnelles, Hôpital Necker-Enfants Malades (J.C.S., C.K.); Service de
Rhumathologie, Hôpital Cochin (C.C.); Service de Gérontologie, Hôpital Broca (F.F.); and Assistance
Publique des Hôpitaux de Paris, 75015 Paris, France; and Scantibodies Laboratory, Inc. (P.G., T.C.),
Santee, California 92071; and INSERM, U-488 (E.E.B.), 94276 Le Kremlin Bicêtre, France
ABSTRACT
Subclinical vitamin D insufficiency is characterized by mild sec-
ondary hyperparathyroidism and enhanced risk of osteoporotic frac-
ture. However, although low levels of 25-hydroxyvitamin D (25OHD)
are common in otherwise normal elderly people, vitamin D status has
not generally been taken into account in the previously published
reference values for serum PTH. We measured fasting morning serum
(obtained from April through June) PTH, total calcium, albumin,
phosphate, creatinine, bone markers, and 25OHD in 280 healthy
subjects (140 men and 140 women), aged 60 –79 yr. Serum PTH was
measured by means of 2 immunoradiometric assays, the Allegro in-
tact PTH assay (Nichols Institute Diagnostics) and the new CAP
assay (Scantibodies Laboratory, Inc.). We found a high prevalence
(167 of 280; 59.6%) of low 25OHD (ⱕ30 nmol/L) in these otherwise
I T WAS REPORTED recently that the currently used PTH
assays overestimate the true concentration of intact PTH-
(1– 84) because they cross-react with a fragment [PTH-(7–
84)], which lacks the first six amino acids of the intact mol-
ecule (1). Not only has this fragment been shown to be
responsible for up to 50% overestimation of intact PTH, but
Slatopolsky et al. have recently demonstrated that this frag-
ment functions as a biological antagonist to active PTH (2).
A new PTH assay, the CAP assay, that recognizes only the
1– 84 molecule has been considered of better clinical value
than the other commercial assays in patients with renal fail-
ure in whom the 7– 84 fragment is present in large amounts
(3). As determination of the serum PTH concentration is also
of great clinical importance in disorders of calcium metab-
olism other than renal failure, we aimed to establish reference
values for this new assay in normal elderly subjects with
normal renal function. We took particular note of the fact that
although low levels of 25-hydroxyvitamin D (25OHD) are
common in otherwise normal elderly people (4), vitamin D
status had not generally been taken into account in the pre-
Received December 19, 2000. Revision received February 23, 2001.
Accepted March 13, 2001.
Address all correspondence and requests for reprints to: Dr. J. C.
Souberbielle, Laboratoire d’Explorations Fonctionnelles, Hôpital
Necker-Enfants Malades, 149 rue de Sèvres, 75015 Paris, France. E-mail:
Jean-claude.souberbielle@mck.ap-hop-paris.fr.
* The DHEage study was conducted under the hospices of the Fon-
dation Nationale de Gérontologie. The main sponsor of the study was
the Assistance Publique des Hopitaux de Paris.
3086
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Vol. 86, No.
Printed in U.S.A.
healthy individuals. The PTH concentrations (95% confidence inter-
val) obtained in the whole group of 280 subjects ranged from 13– 64
ng/L for the Allegro assay and from 10 – 44 ng/L for the CAP assay.
In the subjects with a serum 25OHD concentration greater than 30
nmol/L, values for both PTH assays were lower, 10 – 46 and 9 –34 ng/L
for the Allegro and the CAP assays, respectively. By using these
values as a reference range, approximately 25% of the subjects with
a serum 25OHD level of 30 nmol/L or less had a high serum PTH level
(whatever the assay), reflecting secondary hyperparathyroidism.
This might be missed if the reference PTH values are those obtained
in the entire group, as is usually done. These results strongly suggest
that vitamin D status should be taken into account when establishing
reference values for serum PTH in elderly subjects. (J Clin Endocrinol
Metab 86: 3086 –3090, 2001)
viously published reference values for the current serum
intact PTH assays (5–9). This omission may seem surprising,
as mild secondary hyperparathyroidism (SHPT) is a classical
feature in patients with subclinical vitamin D insufficiency
(10).
Therefore, to establish and validate appropriate reference
ranges, we measured serum PTH using the new CAP Scanti-
bodies assay and another widely used assay, the Nichols
Allegro assay, in healthy elderly subjects with serum 25OHD
concentrations above 30 nmol/L. We compared these values
with those obtained in normal elderly persons with serum
25OHD levels of 30 nmol/L or less.
Subjects and Methods
Subjects
We obtained fasting morning blood samples in 280 healthy subjects
(140 men and 140 women), aged 60 –79 yr, at baseline (April through
June) of a 1-yr, double blind, placebo-controlled trial involving oral
dehydroepiandrosterone, the so-called DHEage study for which pre-
liminary results have been already published (11). All blood samples
were collected at the Center d’Investigation Clinique, Hôpital Necker-
Enfants Malades (Paris, France). The subjects had consulted in a geriatric
polyclinic for various symptoms related to aging, such as asthenia,
memory loss complaint, pain, and anxiety, but were otherwise consid-
ered to be in good health. There was no severe or evolutive disease or
antecedent of hormone-dependent cancer. None of the women was
taking hormone replacement therapy, and none of the subjects was
taking drugs known to affect bone or calcium metabolism, such as
bisphosphonates, calcitonin, fluoride, thiazides, or vitamin D supple-
ments. The protocol was approved by an ethical committee, and all the
subjects gave written informed consent.
 VITAMIN D STATUS AND SERUM PTH IN THE ELDERLY
Assays
All blood samples were immediately centrifuged, and sera were
aliquoted and frozen at ⫺20 C until assayed. Serum total calcium (tCa),
phosphate (PO4), creatinine, and albumin (Alb) were measured (Ar-
senazo III method, phosphomolybdic acid method, modified Jaffé
method, and bromocresol purple method, respectively) by means of an
automated chemistry analyzer (Synchron CX4, Beckman Coulter, Inc.,
Brea, CA). Serum 25OHD was measured by a competitive protein bind-
ing assay using tritiated 25OHD (Amersham Pharmacia Biotech, Little
Chalfont, UK) after a modified extraction procedure allowing microde-
termination (12). We measured two markers of bone formation, serum
osteocalcin (Elsa-Osteo, Cis Bio, Gif-sur-Yvette, France) and serum bone
alkaline phosphatase (Tandem R-ostase, Hybritech, Brea, CA), and one
marker of bone resorption, serum C-terminal telopeptide of type I col-
lagen (serum Cross-laps One Step Elisa, Cis Bio, Gif sur Yvette, France).
Serum PTH was measured by means of two immunoradiometric assays.
The first one recognizes the intact PTH-(1– 84) molecule and the PTH-
(7– 84) fragment equally (Allegro Intact PTH, Nichols Institute Diag-
nostics, San Juan Capistrano, CA). The other PTH assay is a new im-
munoradiometric assay exclusively specific for the intact molecule
(CAP, Scantibodies Laboratory, Inc., Santee, CA). For this CAP assay, we
found the intraassay coefficient of variation evaluated on 300 samples
assayed in duplicate to be 11.2 ⫾ 1.9%, 4.3 ⫾ 0.6%, and 1.2 ⫾ 0.4% for
concentrations of 0 –20, 21–100, and more than 100 pg/mL, respectively.
Interassay coefficient of variation (nine different batches) was 8.3% at 31
pg/mL and 3.4% at 359 pg/mL. The detection limit (concentration
corresponding to the mean signal ⫹ 3 sd of 10 determinations of the zero
standard) was less than 3 pg/mL. We did not find any loss of immu-
noreactivity after four freeze-thaw cycles as well as in samples which
were let 4 h at room temperature before being frozen (⫺20 C).
Expression of results and statistical analysis
The data are expressed as the mean ⫾ sd, with a 95% confidence
interval in parentheses when appropriate. Total calcium corrected for Alb
(tCaalb corr) was calculated as follows: tCaalb corr(mmol/L) ⫽ tCa ⫹ 1 ⫺
Alb/40 where tCa is in millimoles per L and Alb in grams per L.
Creatinine clearance was estimated by the Cockcroft and Gault formula
(13), which takes serum creatinine (micromoles per L), weight (kilo-
grams), age (years), and gender into account: estim.Clcreat ⫽ (140 ⫺
age) ⫻ weight ⫻ k/creatinine (estim.Clcreat, estimated creatinine clear-
ance; k ⫽ 1.24 for men and 1.04 for women). The concentration of
PTH-(7– 84) fragment was calculated by subtracting the CAP value from
the Allegro value. The proportion of the 7– 84 fragment was calculated
by 1 ⫺ [CAP/Allegro] and expressed as a percentage. Normality was
assessed with the Kolmogorov-Smirnov test. Groups were compared by
means of unpaired t tests. P ⬍ 0.05 was considered significant.
Results
In the whole group of 280 healthy elderly subjects, the
distribution of serum PTH values for both assays was log-
normal and skewed to the right with a tail of high values. The
PTH concentrations obtained with both assays were highly
correlated (r ⫽ 0.92; P ⬍ 0.0001). The mean ⫾ sd concentra-
tion of PTH and 95% confidence interval (nonparametric
method) in serum from the 280 subjects were 35 ⫾ 20 ng/L
(13– 64 ng/L) and 25 ⫾ 16 ng/L (10 – 44 ng/L) with the
Allegro assay and the CAP assay, respectively. With both
assays, serum PTH was negatively correlated with serum
25OHD (r ⫽ ⫺0.31; P ⬍ 0.0001 and r ⫽ ⫺0.26; P ⬍ 0.0001 with
the Allegro assay and the CAP assay, respectively). No cor-
relations were found between PTH and age, creatinine, PO4,
tCaalb corr, Oc, bone alkaline phosphatase, and CTx in the
entire group.
We found that 167 (59.6%) of these 280 healthy individuals
had a serum 25OHD level of 30 nmol/L or less, only 113
subjects having thus a concentration more than 30 nmol/L
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3087
(see Fig. 1). These 113 subjects were younger, had similar
estim.Clcreat, Alb, tCaalbcorr, Oc, and bone alkaline phospha-
tase, but lower serum PO4, CTx, and PTH than their vitamin
D deficient counterparts (Table 1). When using the values of
the subjects with a 25OHD level greater than 30 nmol/L as
a reference for both PTH assays, the corresponding 95%
confidence intervals were rather different than that found in
the entire group (10 – 46 ng/L and 9 –34 ng/L with the Al-
legro and the CAP assay, respectively). Using different (high-
er) cut-off values for serum 25OHD did not change the PTH
reference range (see Table 2). With both assays approxi-
mately 25% of the subjects with a serum 25OHD of 30
nmol/L or less had a serum PTH above the 97th percentile
of the subjects with a serum 25OHD more than 30 nmol/L,
reflecting SHPT. Although the absolute concentration of
PTH-(7– 84) fragment was different according to vitamin D
status (7.6 ⫾ 4.6 ng/L for serum 25OHD ⬎30 nmol/L and
10.5 ⫾ 6.5 ng/L for serum 25OHD ⱕ30 nmol/L; P ⬍ 0.001),
its proportion was not correlated with serum 25OHD in the
entire group of 280 subjects. This proportion was highly
variable from one subject to another (from 0 – 0.71), and the
proportions were 28.4 ⫾ 1.2% and 26.5 ⫾ 1.4% in the subjects
with 25OHD of 30 nmol/L or less and more than 30 nmol/L,
respectively, with no significant difference between groups.
Discussion
In the present study we found a high prevalence (almost
60%) of low serum level of vitamin D (serum 25OHD, 30
nmol/L) in a group of 280 elderly subjects representative of
the healthy age-related French general population. In this
group we found that the 95% confidence interval for serum
PTH (13– 64 ng/L) measured with a largely used assay, the
Nichols Allegro assay, was very close to what is stated by the
manufacturer (10 – 65 ng/L) as a reference range and to what
was found in other studies to be the normal reference range
(5, 14). The PTH range obtained with the new Scantibodies
CAP assay was lower (10 – 44 ng/L), consistent with the
specificity of this assay.
Although patients with subclinical vitamin D insufficiency
usually do not have a mineralization defect such as found in
osteomalacia, statistically they have mild SHPT, increased
bone turnover, decreased bone mineral density at the hip,
and enhanced risk of osteoporotic fracture in comparison
with vitamin D-sufficient subjects (10). As pointed out above,
vitamin D status had not generally been taken into account
in previously published normative data for serum PTH (5–9).
In fact, the only study that included women with a normal
25OHD concentration (14) as participants in a reference pop-
ulation found a reference range for healthy postmenopausal
women that is not different from what was found by others
with the same PTH kit in subjects of unspecified age and
vitamin D status (5, 6). However, in this study by Sokoll et
al. (published in 1988), the cut-off used to define normal
serum 25OHD was not specified. In fact, the acceptance of the
concept of subclinical vitamin D insufficiency (i.e. the serum
25OHD level below which SHPT statistically occurs in a
population) is relatively recent. Before the early 1990s vita-
min D insufficiency was usually identified as a serum
25OHD level below 12–15 nmol/L (that is the third or fifth
3088 SOUBERBIELLE ET AL. JCE & M • 2001
Vol. 86 • No. 7

FIG. 1. Relationship between serum

25OHD and PTH measured with the
Allegro assay (top) and with the CAP
assay (bottom). On both figures, the
gray area represents the above normal
PTH values with a reference range ob-
tained in the entire group of 280 sub-
jects, whereas the hatched area repre-
sents the additional zone of high PTH
values with a reference range obtained
in the 113 subjects with a serum
25OHD level above 30 nmol/L. The hor-
izontal line is the low level of the ref-
erence range (subjects with 25OHD
⬎30 nmol/L).

percentile of an apparently normal population). It is thus some degree of vitamin D insufficiency and SHPT, and there-
plausible that in the study by Sokoll et al. (14), at least some fore that the upper limit of their PTH reference range may
of their 245 healthy postmenopausal women had, in fact, have been overestimated. Indeed, a concentration of 30

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 VITAMIN D STATUS AND SERUM PTH IN THE ELDERLY 3089

TABLE 1. Biochemical values of the 280 healthy elderly subjects, according to vitamin D status

250HD ⱕ30 nmol/L 250HD ⬎30 nmol/L

P
(19.0 ⫾ 8.5 nmol/L) (43.3 ⫾ 10.3 nmol/L)
n 167 113
Women/men 78/89 62/51
Age (yr) 70.2 ⫾ 4.5 68.6 ⫾ 4.5 0.04
tCaalb corr (mmol/L) 2.29 ⫾ 0.08 2.29 ⫾ 0.07 0.52
PO4 (mmol/L) 1.12 ⫾ 0.15 1.05 ⫾ 0.14 0.004
Albumin (g/L) 42.1 ⫾ 2.5 42.7 ⫾ 2.7 0.10
Estimated creatinine clearance (mL/min䡠1.73 m2) 67.1 ⫾ 15.9 66.3 ⫾ 14.6 0.57
Oc (␮g/L) 18.7 ⫾ 6.4 19.1 ⫾ 6.3 0.66
bAP (mg/L) 10.4 ⫾ 4.0 10.3 ⫾ 4.2 0.98
sCTx (pM) 3621 ⫾ 1687 3236 ⫾ 1492 0.05
Allegro PTH (ng/L) 35.4 ⫾ 14.6 28.6 ⫾ 10.6 ⬍0.0001
CAP PTH (ng/L) 25.0 ⫾ 1.5 21.1 ⫾ 7.9 0.002
PTH-(7– 84) (ng/L) 10.5 ⫾ 6.5 7.6 ⫾ 4.6 ⬍0.001
PTH-(7– 84) (% of total) 28.4 ⫾ 1.2 26.5 ⫾ 1.4 0.19

TABLE 2. Serum PTH (mean ⫾ SD) measured with two
immunoassays in subjects with serum 250HD above different
thresholds
Cut-off value for Allegro PTH CAP PTH
n
250HD (nmol/L) (ng/L) (ng/L)
ⱕ30 113 28.6 ⫾ 10.6 21.1 ⫾ 7.9
ⱕ32.5 99 27.5 ⫾ 9.2 20.2 ⫾ 7.2
ⱕ35 85 27.7 ⫾ 9.1 20.2 ⫾ 6.9
ⱕ37.5 67 27.7 ⫾ 9.2 20.3 ⫾ 6.7
ⱕ50 22 27.8 ⫾ 10.7 21.4 ⫾ 8.6
With a given assay, no difference was found according to these
different cut-off values.
nmol/L is now frequently accepted as the threshold for vi-
tamin D insufficiency by many researchers, mostly Europe-
ans (4, 10, 15, 16), and was used in the present study. It should
be stressed however, that higher cut-off values, such as 37.5
nmol/L (17), 50 nmol/L (18), and up to 80 nmol/L or more
(19), are preferred by others, mostly (but not only) Ameri-
cans. Furthermore, the nature of the 25OHD assay (compet-
itive binding protein assay, high performance liquid chro-
matography, or RIA) as well as the complexity of the
extraction procedure play an important role in the selection
of the cut-off value below which PTH rises (20, 21). These
discordances are an indication that there is not yet a con-
sensus on this topic. Nevertheless, whatever the cut-off cho-
sen, our goal was to demonstrate that the reference range for
serum PTH may depend on the vitamin D status.
Thus, in the present study we considered only the 113
subjects with a serum 25OHD level above 30 nmol/L as our
normal reference population. The normal range for serum
PTH with both assays then became lower than the currently
used normal values. This difference does not seem to be due
to differences in renal function between the two groups, as
the estimated creatinine clearance was similar in both groups
(although definite limitations of the Cockcroft and Gault
formula must be underlined). It is noteworthy that increases
in the cut-off value for serum 25OHD did not change the
range of serum PTH. It must be emphasized, however, that
in the present study only one subject had a 25OHD level
above 75 nmol/L. so that high cut-off values such as 80
nmol/L have not been tested.
The importance of vitamin D deficiency in the pathogen-
esis of senile osteoporosis is well known, as is the positive
effect of vitamin D supplementation on the decrease in os-
teoporotic fracture incidence in the elderly (22, 23). Approx-
imately one quarter of our (otherwise normal) subjects with
a serum 25OHD level less than 30 nmol/L had a serum PTH
level above the range for persons with a 25OHD of 30 nmol/L
or more, reflecting SHPT. This is an important information,
as high normal serum PTH has been identified as an inde-
pendent risk factor of fracture in postmenopausal women
(24). It may be missed, however, if the reference values for
PTH are obtained from a group that does not separate the
subjects according to their vitamin D status.
Another area in which our reference values for serum PTH
may be relevant is the diagnosis of primary hyperparathy-
roidism (PHPT). Indeed, some patients with surgically
proven PHPT have a serum PTH level that is normal but not
in concordance with observed hypercalcemia (25). For ex-
ample, as reported by Nussbaum et al. (5), the lowest PTH
level in PHPT was 50 ng/L with the Allegro assay; that is a
high normal concentration for the usual reference values, but
a clearly high level for our data obtained for subjects with a
serum 25OHD level above 30 nmol/L. It should be stressed,
however, that although the frequency of normal PTH levels
in PHPT patients should be decreased with the use of our
PTH reference range, PTH levels as low as 17 ng/L with the
Allegro assay have been reported in surgically documented
PHPT (26).
Finally, as a secondary, but not directly related, matter, we
have compared two PTH assays that differ in terms of spec-
ificity. As the new CAP assay has been said to be of better
clinical value in patients with renal failure than the other
commercially available PTH assays (3), it may become used
in clinical practice in the near future. It is thus relevant to
obtain information on this new assay in nonrenal patients as
reference data. It is noteworthy that 1) although highly vari-
able from one subject to another, the proportion of PTH-(7–
84) was not dependent on vitamin D status; and 2) ensuring
the adequacy of serum 25OHD before defining the normal
range for PTH is equally valid for the two assays.
In conclusion, our results strongly suggest that vitamin D
status should be taken into account when establishing ref-
erence values for serum PTH, especially in elderly subjects.
By doing so, we found reference ranges for serum PTH in
subjects aged 60 –79 yr of 10 – 46 and 9 –34 ng/L with the

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3090 SOUBERBIELLE ET AL.
Nichols Allegro intact PTH assay and the CAP assay, re-
spectively. The lower reference range with the Scantibodies 9.
CAP assay reflects the absence of PTH-(7– 84) fragment in-
terference. These new reference values should improve the
diagnosis of primary and secondary hyperparathyroidism 10.
and subsequent therapeutic indication.
11.
Acknowledgments
We address special thanks to V. Faucounau (coordinator of the 12.
DHEage study) and C. Chaffaut (statistics). We thank P. Bonnet, C.
Ferret, P. Frotte, and P. Herviaux for their excellent technical work, and
the staff of the Center d’Investigation Clinique (Prof. J. L. Bresson, 13.
Hôpital Necker-Enfants Malades, Paris, France) for collection and con-
14.
servation of the blood samples. The geriatricians must be acknowledged
for inclusion of the subjects: F. Forette and F. Latour (Hôpital Broca, 15.
Paris, France), B. Forette and A. Mokrane (Hôpital Sainte-Perine, Paris,
France), R. Moulias and L. Girard (Hôpital C. Foix, Ivry, France), M. P.
Hervy and C. Verny (Hôpital de Bicètre), R. Sebag-Lanoé and C. Trivalle
(Hôpital P. Brousse), J. P. Aquino, and H. Piti-Ferrandi (Center Mederic- 16.
Observatoire de l’Age), and D. Elia and M. C. Léaud (Mutuelle des
PTT-Center J. Senet). 17.
18.
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