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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
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{at}mck.ap-hop-paris.fr
Abstract
Subclinical vitamin D insufficiency is characterized by mild secondary
hyperparathyroidism and enhanced risk of osteoporotic fracture.
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 intact 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
(
30 nmol/L) in these otherwise healthy individuals. The PTH
concentrations (95% confidence interval) 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.
IT 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 molecule (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 fragment 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 failure 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 metabolism 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 previously published reference values for the current serum intact PTH assays (5, 6, 7, 8, 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 Scantibodies 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 preliminary 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 considered 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 supplements. The protocol was approved by an ethical committee, and all the subjects gave written informed consent.
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 (Arsenazo 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 binding assay using tritiated 25OHD (Amersham Pharmacia Biotech, Little Chalfont, UK) after a modified extraction procedure allowing microdetermination (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 collagen (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 Diagnostics, San Juan Capistrano, CA). The other PTH assay is a new immunoradiometric 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 immunoreactivity 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 (kilograms), age (years), and gender into account: estim.Clcreat = (140 - age) x weight x k/creatinine (estim.Clcreat, estimated creatinine clearance; 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 concentration 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 correlations 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 (see Fig. 1
). These 113 subjects were younger, had
similar estim.Clcreat, Alb,
tCaalbcorr, Oc, and bone alkaline
phosphatase, 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 Allegro and the CAP assay, respectively). Using different
(higher) cut-off values for serum 25OHD did not change the PTH
reference range (see Table 2). With both
assays approximately 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 30
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.
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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, 6, 7, 8, 9). In fact, the only study that included women with a normal 25OHD concentration (14) as participants in a reference population 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 vitamin D insufficiency was usually identified as a serum 25OHD level below 12–15 nmol/L (that is the third or fifth percentile of an apparently normal population). It is thus plausible that in the study by Sokoll et al. (14), at least some of their 245 healthy postmenopausal women had, in fact, some degree of vitamin D insufficiency and SHPT, and therefore that the upper limit of their PTH reference range may have been overestimated. Indeed, a concentration of 30 nmol/L is now frequently accepted as the threshold for vitamin D insufficiency by many researchers, mostly Europeans (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) Americans. Furthermore, the nature of the 25OHD assay (competitive binding protein assay, high performance liquid chromatography, 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 consensus on this topic. Nevertheless, whatever the cut-off chosen, 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 pathogenesis of senile osteoporosis is well known, as is the positive effect of vitamin D supplementation on the decrease in osteoporotic fracture incidence in the elderly (22, 23). Approximately 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 independent 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 hyperparathyroidism (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 example, 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 specificity. 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 variable 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 reference 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 Nichols Allegro intact PTH assay and the CAP assay, respectively. The lower reference range with the Scantibodies CAP assay reflects the absence of PTH-(7–84) fragment interference. These new reference values should improve the diagnosis of primary and secondary hyperparathyroidism and subsequent therapeutic indication.
Acknowledgments
We address special thanks to V. Faucounau (coordinator of the 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, Hôpital Necker-Enfants Malades, Paris, France) for collection and conservation of the blood samples. The geriatricians must be acknowledged for inclusion of the subjects: F. Forette and F. Latour (Hôpital Broca, 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-Observatoire de l’Age), and D. Elia and M. C. Léaud (Mutuelle des PTT-Center J. Senet).
Footnotes
1 The DHEage study was conducted under the hospices of the Fondation
Nationale de Gérontologie. The main sponsor of the study was the
Assistance Publique des Hopitaux de Paris. 
Received December 19, 2000.
Revised February 23, 2001.
Accepted March 13, 2001.
References
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