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Original Studies |
INSERM, U-403; and Hôpital Neuro-Cardiologique (B.C.), 69437 Lyon, France; and Société de Secours Minière de Bourgogne (F.M.), 71300 Montceau les Mines, France
Address all correspondence and requests for reprints to: Prof. Pierre D. Delmas, INSERM, U- 403, Hôpital Edouard Herriot, place d’Arsonval, 69437 Lyon, France. E-mail: delmas{at}lyon151.inserm.fr
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Abstract |
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In summary, we found in a cross-sectional analysis of a cohort of men that low levels of bio-17ßE2 are associated with high bone turnover and low BMD. These data suggest that the age-related decrease in bio-17ßE2 contributes to bone loss in elderly men by increasing bone turnover. Low 17ßE2 levels may be an important risk factor for osteoporosis in men.
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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In young men, 17ßE2 seems to be necessary for growth, acquisition of peak bone mass, and consolidation of growth cartilage (2). In elderly men, a correlation between BMD and serum 17ßE2 was positive and significant, in contrast to the correlations of BMD with total testosterone (T), free T, androstenedione, and sex hormone-binding globulin (SHBG) (5, 6, 7). Elderly men with low levels of 17ßE2 had a higher prevalence of vertebral deformities (8). Although age- and body weight-adjusted partial correlations were significant, they were relatively weak, suggesting that 17ßE2 levels explain only a small percentage of the variability in BMD in elderly men. The biological impact of 17ßE2 concentration, i.e. difference in BMD between the men with the highest and those with the lowest levels, is not well known (7). Finally, data concerning correlations of 17ßE2 with biochemical markers of bone turnover in elderly men are scarce (6).
The aim of the study was to verify whether 17ßE2 and its bioavailable fraction (bio-17ßE2) are correlated with the levels of bone biochemical markers and to evaluate the impact of 17ßE2 on BMD and biochemical bone marker levels in a large cohort of elderly men.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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The MINOS study is a prospective study of osteoporosis and its determinants in men that was initiated in 1995. It is a collaboration between INSERM (National Institute of Health and Medical Research) and Société de Secours Minière de Bourgogne (SSMB) in Montceau les Mines, France. Montceau les Mines is a town of about 35000 inhabitants situated 130 km northwest of Lyon in the Department (District) of Saône et Loire. SSMB is one of the largest health insurance companies in this district. A detailed description of the cohort was published recently (9). Invitations to our study with explanations of the aim of the study were sent to a random sample of men, aged 51–85 yr, who were insured by SSMB. All men responded to an epidemiological questionnaire covering demographic and behavioral information as well as detailed medical history (diseases, accidents, and medications) of conditions that could influence bone mass and metabolism. Informed written consent was obtained from all participants. From this analysis we excluded 106 men with diseases or receiving treatment known to affect bone metabolism (Paget’s disease, rheumatoid arthritis, ankylosing spondyloarthritis, primary hyperparathyroidism, Cushing’s disease, hemochromatosis, liver cirrhosis, gastrectomy, and Klinefelter’s syndrome; treatment with fluoride, bisphosphonate, T4, or oral corticosteroids). This analysis was performed in a group of 596 men, aged 51–85 yr, who had all the diagnostic tests and all the hormonal measurements performed. The 79 men who had to be excluded because of a in insufficient volume of serum did not differ from the main cohort based on the comparisons of age, body weight, body height, bone mineral density, levels of hormones, and levels of biochemical markers of bone turnover.
Bone mass measurement
BMD was measured at the lumbar spine, right hip, and whole body using pencil-beam dual energy x-ray absorptiometry (QDR-1500, Hologic, Inc., Waltham, MA) and at the distal and ultradistal nondominant forearm using single energy x-ray absorptiometry (DTX 100, Osteo-meter, Rodovre, Denmark). Antero-posterior spine BMD was measured at lumbar vertebrae 2–4. At the hip, five regions of interest were evaluated: femoral neck, trochanter, intertrochanter region, Ward’s triangle, and total hip. At the forearm, two regions of interest were evaluated. The distal site includes 24 mm of ulna and radius situated proximally to the site where the spacing between the two bones is 8 mm. The ultradistal region comprises only the most distal part of the radius. Details concerning quality assurance have been recently described (9).
Biochemical measurements
Fasting serum as well as 24-h urine were collected and stored at -80 C until assayed. Serum total osteocalcin (OC) was measured with a human-specific two-site immunoradiometric assay (ELSA-OSTEO, CIS BioInternational, Bagnols/Ceze, France), which recognizes a large N-terminal midfragment in addition to the intact molecule (10). Intra- and interassay coefficients of variation are less than 4% and 6%, respectively, and the sensitivity is 0.08 nmol/L. Serum bone-specific alkaline phosphatase (BAP) was measured with an immunoassay using a monoclonal antibody directed against BAP purified from human SAOS-2 osteosarcoma cells as a standard followed by a conventional colorimetric detection using paranitrophenyl phosphate (Alkphase-B, Metra Biosystems, Inc., Mountain View, CA) (11). This assay has a low cross-reactivity with circulating liver, placental, and intestinal isoenzymes (<15%). The sensitivity of the assay is 0.7 U/L. Intra- and interassay coefficients of variation are less than 6% and 8%, respectively. Serum N-terminal extension propeptide of type I collagen (PINP) was measured by a RIA that recognizes the intact circulating form of PINP (intact PINP; Farmos Diagnostica, Uppsala, Sweden) (12). Intra- and interassay coefficients of variation are below 5% and 8%, respectively, and the detection limit is 1 ng/mL.
Urinary ß-isomerized C-terminal telopeptide of collagen type I
(ßCTX) was measured with a enzyme-linked immunoassay (ELISA;
CrossLaps ELISA, Osteometer) as described previously (13, 14). The antigen Glu-Lys-Ala-His-ß-Asp-Gly-Gly-Arg is a
fragment of C- telopeptide of the 
1-chain
of type I collagen. The sensitivity of the assay is 0.5 µg/L. Intra-
and interassay coefficients of variation are less than 10% and 15%,
respectively. This assay does not react with free cross-links, and its
cross-reactivity with CTX is less than 1%. Serum ß-isomerized
C-terminal telopeptide of collagen type I (ßCTX) was measured by
ELISA (CrossLaps One Step ELISA, Osteometer) as described previously
(15, 16). The sensitivity of the assay is 0.092 nmol/L.
Intra- and interassay coefficients of variation are less than 8%.
Urinary total deoxypyridinoline (DPyr) was measured by ELISA
(Pyrilin ks-D, Metra Biosystems Inc.,
Mountain View, CA) after acid hydrolysis. This assay uses a monoclonal
antibody with less than 1% cross-reactivity with free pyridinoline and
10% cross-reactivity with cross-linked polypeptides (17).
The sensitivity of the assay is 3 nmol/L. Intra- and interassay
coefficients of variation are less than 10%.
Hormones
Serum total 17ßE2 and total T were measured by tritiated RIA after diethylether extraction (18). For T, the limit of detection is 0.06 nmol/L, and the interassay coefficient of variation is 10% for a concentration of 1 nmol/L and 7.8% for 6 nmol/L. For total 17ßE2, the limit of detection is 11 pmol/L, and the interassay coefficient of variation is 9.4% for a concentration of 169 pmol/L and 6.2% for 510 pmol/L. SHBG was measured by immunoradiometric assay (125I SBP Coatria, Bio-Mérieux, Marcy l’Etoile, France) with an interassay coefficient of variation of 4.1% for a concentration of 16 nmol/L and 5.3% for 100 nmol/L. The limit of detection is 0.5 nmol/L. Serum free T was measured by RIA (Coat-A-Count, Behring, Deerfield, IL). The interassay coefficient of variation is 5.5% for a concentration of 0.16 pmol/L and 3.4% for 14.7 pmol/L. The limit of detection is 0.05 pmol/L. As the concentration of free T may be influenced by the serum protein concentration, we calculated the bioavailable T level (bio-T) using the formula: bio-T = free T x (3.6 x 104 L/mol x albumin concentration + 1) (18). The free T index (FTI) was calculated using the formula: total T/SHBG. Serum androstenedione was measured by tritiated RIA after diethylether extraction (19). The interassay coefficient of variation is 6% for a concentration of 1.96 nmol/L and 8.3% for 3.98 nmol/L. Serum bio-17ßE2 was measured using the method described by Tremblay and Dube (20). Briefly, SHBG and the hormones bound to it were precipitated using 50% ammonium sulfate. In the supernatant, bio-17ßE2 was measured using the same RIA as that used for total 17ßE2. The interassay coefficient of variation is 13% for a concentration of 56 pmol/L.
Evaluation of spinal arthritis
Arthritis of the lumbar spine was evaluated on the antero-posterior and lateral radiographs of the lumbar spine performed according to a standardized protocol described recently (9). They were analyzed by a single observer blinded to BMD results. The arthritis score was based on previously published scores (21, 22, 23). As osteophytes more that 3 mm in length were found to significantly influence spine BMD, we used the following grades: no osteophyte, grade 0; osteophyte less than 3 mm, grade 1; osteophyte 3–6 mm, grade 2; osteophyte more than 6 mm,grade 3; no or mild endplate sclerosis, grade 0; marked end-plate sclerosis, grade 1 (osteophytes and endplate sclerosis were evaluated independently on superior and inferior plate of vertebral bodies); no posterior arthritis, grade 0; and marked posterior arthritis, grade 1. The total arthritis score (i.e. 1–27) was evaluated by summing up for lumbar vertebrae from L2 to L4. As aortic calcifications were not found to influence lumbar spine BMD, they were not analyzed (21, 22, 23).
Statistical methods
All calculations were performed using SAS software (SAS Institute, Inc., Cary, NC). Correlations between the variables were evaluated using Pearson’s simple and partial correlation coefficients as well as multiple linear regression. BMDs of different sites of measurement and levels of bone biochemical markers were compared in four groups corresponding to quartiles of the bio-17ßE2 level using the age- and body weight-adjusted analysis of covariance.
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Densitometric, biochemical, and hormonal data of the cohort are
presented in Table 1
. Total T and total
17ßE2 did not decrease significantly with age
and remained stable even in very old men (Table 2). Free T, bio-T, and FTI as well as
bio-17ßE2 concentrations decreased with age.
Androstenedione decreased with age, whereas the serum concentration of
SHBG increased with age. Total, free, and bio-T decreased with
increasing body weight. SHBG decreased, whereas
bio-17ßE2 increased slightly with increasing
body weight. Total 17ßE2, androstenedione, and
FTI were not correlated with body weight.
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The BMD of all sites of measurement was correlated significantly
with the concentrations of total 17ßE2 and
bio-17ßE2. FTI was correlated positively with
the BMD of the forearm, and there was a weak negative correlation
between SHBG and BMD of hip, forearm, and whole body bone mineral
content (BMC; Table 3). Other simple
correlations were nonsignificant. However, at all sites, BMD decreased
with age [for lumbar spine, in the men without osteoarthritis (OA):
r = -0.15–0.32; P = 0.0001] and increased with
body weight (r = 0.22–0.65; P = 0.0001). Thus,
all correlations between the hormones and BMD were adjusted for age and
body weight. The BMD of the hip was correlated positively with
17ßE2 and bio-17ßE2,
but not with total, bio-, or free T; FTI; androstenedione; or SHBG
(Table 4). Whole body BMC and BMD were
correlated significantly with 17ßE2 and
bio-17ßE2 and, more weakly, with free and
bio-T. The BMDs of the distal forearm and ultradistal radius were
correlated positively with 17ßE2 and
bio-17ßE2, but not with total, bio-, and free
T; FTI; androstenedione; or SHBG. In men without severe OA, lumbar
spine BMD was positively correlated with 17ßE2
and bio-17ßE2, but not with other biochemical
parameters. After adjustment for age and body weight, total hip and
distal forearm BMD as well as whole body BMC were lower in men with the
lowest bio-17ßE2 level (first quartile) than in
men in the three upper quartiles (Q2–Q4; Fig. 1). The quartile values of
bio-17ßE2 were as follows: Q1, 53 pmol/L; Q2,
63 pmol/L; and Q3, 75 pmol/L.
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Among the biochemical markers of bone turnover, only DPyr
increased with age (r = 0.21; P = 0.0001). OC as
well as urinary and serum ßCTX were correlated negatively with body
weight (r = -0.11 and P < 0.01, r = -0.16
and P = 0.0001, and r = -0.12 and
P < 0.01, respectively). The steroid hormones
disclosed variable correlations with age and body weight (Table 2
).
Thus, all statistical models were adjusted for age and body weight. The
levels of biochemical markers (except BAP) were correlated negatively
(r = -0.11–0.17; P < 0.01–0.0001) with the
bio-17ßE2 level after adjustment for age and
body weight (Table 5).
Some bone markers disclosed a weak, but significant, inverse
correlation with 17ßE2 or FTI and a positive
correlation with SHBG, but not with androstenedione and total, free, or
bio-T. In the multiple regression, bio-17ßE2
contributed slightly, but significantly, to the explanation for the
variability in biochemical bone marker levels (Table 6). For
example, age and body weight explained 2.8% of the variability in
urinary ßCTX, and addition of bio-17ßE2 to
the model increased the percentage of the explained variability to
5.7%.
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) and for the markers of bone
resorption (Fig. 3), the average levels
were the highest in the men with the lowest concentration of
bio-17ßE2 (Q1). Differences between the average
levels of markers of bone turnover were smaller or nonsignificant in
men in the three upper quartiles (Q2–Q4) for
bio-17ßE2 concentration.
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To evaluate the association among bio-17ßE2 level, bone turnover, and BMD, we compared average BMD and levels of bone markers in men with the lowest concentration of bio-17ßE2 (first quartile) to values in men with the highest concentrations of bio-17ßE2 (fourth quartile). In those in the lowest bio-17ßE2 quartile, the average BMDs of total hip, lumbar spine (without OA), distal forearm, and ultradistal radius were lower than those in men in the highest quartile by 7.7%, 7.5%, 6.6%, and 8.7%, respectively. This difference corresponds to 0.65, 0.45, 0.60, and 0.64 SD.
Men in the lowest quartile for bio-17ßE2 had 11–18% higher average concentrations of markers of bone formation than men with the highest bio-17ßE2 level, which corresponded to 0.4–0.6 SD. The average serum and urinary ßCTX levels were higher by 25–35% (0.6–0.7 SD) in men with the lowest bio-17ßE2 levels compared with those in the highest quartile. Urinary levels of total DPyr were also higher in men in the lowest quartile for bio-17ßE2 compared with those of men in the highest quartile (16% or 0.5 SD).
In men in both the lowest quartile of bio-17ßE2
and the highest quartile of urinary DPyr or ßCTX, the average BMDs of
total hip and distal forearm were 8% and 10% lower, respectively,
than those in men in both the highest quartile of
bio-17ßE2 and the lowest quartile of bone
resorption marker. In men in both the lowest quartile of FTI and the
highest quartile of urinary DPyr or ßCTX, the average BMDs of total
hip and forearm were 6% and 7% lower, respectively, compared with
those in men in the highest quartile of FTI and the lowest quartile of
the marker of bone resorption (Fig. 4).
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Discussion |
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During recent years, the role of 17ßE2 in bone
metabolism in men has been suggested in several studies. In early
pubertal boys, an increase in 17ßE2 coincides
with the peak growth velocity during the pubertal growth spurt
(24). Case reports of young osteopenic and still growing
men presenting mutations of estrogen receptor or aromatase genes showed
that 17ßE2 is necessary for the acquisition of
peak BMD and the consolidation of growth cartilage
(25, 26, 27). Treatment with 17ßE2,
but not with T, in two men with the aromatase gene mutation resulted in
an increase in BMD, consolidation of growth cartilage, and cessation of
growth (27, 28), whereas treatment with
17ßE2 or T was ineffective in a man who had no
functional estrogen receptor due to a premature stop codon in the
estrogen receptor gene (25). Two young men with Noonan’s
syndrome described recently had undetectable
17ßE2 levels and severe osteoporosis, although
their T, free T, and dihydrotestosterone levels were normal
(29). Preliminary results presented by Braidman et
al. suggest a very low cellular level of estrogen receptor in
young men with idiopathic osteoporosis (30). Similarly, in
osteoporotic men, the concentration of 17ßE2,
but not that of T or dihydroepiandrosterone, was lower than that in
age-matched healthy men (31). In T-treated osteoporotic
men, the increase in BMD was correlated with the increase in
17ßE2, but not with that in T
(32). Treatment with 17ßE2
decreased the levels of bone turnover markers in healthy elderly men
and in patients who had been orchidectomized due to prostatic cancer
(33, 34). Treatment with 17ßE2
prevented bone loss in elderly men who had been orchidectomized due to
prostatic cancer and in male-female transsexuals and increased BMD in
patients with the androgen insensitivity syndrome
(35, 36, 37).
In our cohort, FTI as well as concentrations of free and of bio-T and bio-17ßE2 decreased with age, whereas those of total T and 17ßE2 remained stable, which confirms previous data (38, 39, 40). The decrease in the biologically active fraction of 17ßE2 may result from an increase in SHBG and a decrease in circulating free T, which is a substrate for peripheral aromatization.
In previous studies performed in elderly men, 17ßE2 and bio-17ßE2 concentrations were correlated with BMD independently of age, body weight, or other variables, in contrast to T, free T, bio-T, dehydroepiandrosterone, dehydroepiandrosterone sulfate, androstenedione, or SHBG, which were weakly or nonsignificantly correlated with BMD (5, 6, 7, 41). Our results also suggest that 17ßE2 is the most potent determinant of BMD among sexual steroids in men. However, its correlations with BMD are weak, and the difference between the average BMD in men with concentrations of bio-17ßE2 in the lowest quartile and those with concentrations in the highest quartile is about 0.5–0.6 SD. This difference is mainly due to a lower BMD in men with the lowest levels (first quartile) of bio-17ßE2. Greendale et al. (5) used a linear model of relation between bio-17ßE2 level and BMD. They showed that an increase in bio-17ßE2 by 1 SD resulted in a average increase in BMD by 0.13–0.18 SD in men, which was comparable to that observed in postmenopausal women (0.1–0.2 SD). By extrapolation of data from other studies, the risk of fracture in the men with the lowest 17ßE2 level is 50–100% higher than that in the men with the highest concentration of 17ßE2 (42). Age- and body weight-adjusted correlations of BMD with 17ßE2 and bio-17ßE2 were similar, in contrast to the study by Khosla, who found stronger simple correlations of BMD with bio-17ßE2 compared with 17ßE2 (6). Body weight is correlated positively with BMD and negatively with SHBG. Thus, an increase in body weight could have resulted in an increase in the bio-17ßE2, as suggested by our study, and could have falsely augmented the simple correlations between BMD and bio-17ßE2.
Our study is concentrated on the correlation between the bio-17ßE2 level and biochemical markers of bone turnover. Levels of biochemical bone markers were negatively correlated with bio-17ßE2, but not with 17ßE2, after adjustment for age and body weight. This seems logical, because the bone biochemical markers reflect the present metabolic status of the skeleton, which depends on the present concentration of the biologically active fraction of the hormone. In the men in the lowest quartile for bio-17ßE2, the levels of ßCTX are 25–35% higher, whereas the bone formation markers are only 15% higher compared with those in men in the upper quartile for bio-17ßE2. This pattern suggests that low bio-17ßE2 levels are associated with increased bone resorption, which is only partly matched by increased bone formation. This uncoupling may result in bone loss. These results are in agreement with data showing an age-related increase in bone marker levels and their negative correlation with BMD in elderly men, suggesting that the age-related bone loss in men may be associated with an increased bone turnover (6, 43). BMD is lower and bone turnover is increased mainly in men in the lowest quartile for bio-17ßE2, suggesting a threshold for bio-17ßE2 under which bone turnover increases, leading to bone loss.
The weak correlations between bio-17ßE2 and 17ßE2 levels, on the one hand, and BMD or bone biochemical markers, on the other, may be due to several reasons. 17ßE2 may have a small impact on bone metabolism and BMD. Correlation coefficients may be falsely diminished due to measurement errors. Serum 17ßE2 levels may not reflect hormonal level in peripheral tissues. Bone cells contain not only estrogen receptors (44, 45), but also enzymes of sex steroid pathways, such as aromatase and 17ß-hydroxysteroid dehydrogenase (46, 47, 48, 49, 50). Aromatase activity and messenger ribonucleic acid were found in human osteosarcoma cell lines and in primary human osteoblasts. Expression of messenger ribonucleic acid of three types of 17ß-hydroxysteroid dehydrogenase (I, II, and IV) was also identified in human osteosarcoma cell lines. These findings suggest that human osteoblastic cells may synthesize estrogens from androgens and interconvert 17-keto- and 17ß-hydroxy forms of sexual steroids. The physiological importance of the local metabolism of sex steroids in bone remains to be established. It will be also useful for a better understanding of our data. For example, FTI disclosed a significant positive correlation with some biochemical bone markers but not with BMD, in contrast to the recent data presented by Scopacasa et al. (51). However, FTI is strongly correlated with bio-17ßE2, because 17ßE2 decreases the level of SHBG. Moreover, FTI corresponds to the biologically available fraction of T that may enter the cell. As T may undergo aromatization in the bone cells, the positive correlation of FTI with biochemical bone markers does not necessarily mean that T is the active hormone at the level of bone.
Using a panel of sensitive bone markers in a cohort of elderly men, we showed that the low level of bio-17ßE2 is associated with accelerated bone turnover. We confirm the positive correlation of 17ßE2 level with BMD and suggest that the age-related decrease in bio-17ßE2 contributes to bone loss in elderly men by increasing bone turnover.
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Footnotes |
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Received July 11, 2000.
Revised September 26, 2000.
Accepted October 2, 2000.
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References |
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protein
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