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Original Studies |
Departments of Medicine, Pediatrics, Biochemistry and Physiology, Loma Linda University and Musculoskeletal Disease Center, J. L. P. Memorial Veterans Administration Medical Center (C.L., D.J.B., S.M.); and the Department of Pediatrics, Loma Linda University (E.L.-W.), Loma Linda, California 92357; and the Department of Endocrinology, University of Madras (N.S.), Taramani, Madras 600 113, India
Address all correspondence and requests for reprints to: Dr. Subburaman Mohan, Research Service (151), J. L. P. Memorial Veterans Administration Medical Center, 11201 Benton Street, Loma Linda, California 92357. E-mail: hyperlink mailto:mohans{at}llvamc.va.gov
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Abstract |
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 Top Abstract IntroductionSubjects and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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The dramatic accumulation of bone mass during puberty is caused by changes in both modeling and remodeling that occur simultaneously during this period of life. In addition, there is some suggestion that both enhanced bone formation and decreased bone resorption contribute to the increment in bone density that occurs during puberty. With respect to bone resorption, recent studies by Slemenda et al. (9) and our group (10) have provided evidence that reduced rates of skeletal modeling during periods of growth could contribute to the bone density increase seen during puberty. However, the mechanisms that contribute to reduced remodeling during puberty remain poorly understood. In this study we evaluated the role of serum cytokines in mediating the changes in bone resorption that occur during puberty based on accumulated evidence that cytokines are important regulators of bone resorption in vitro and in vivo and that sex steroids (which increase during puberty) inhibit the production of one or more cytokines (11, 12, 13).
Turning to the potential role of bone formation in the acquisition of peak bone density, it has been suggested that molecules that might signal such an increase in bone formation would include the GH-insulin-like growth factor (IGF) axis. This concept is based on the well known finding that GH production is increased during sexual development and that the effects of GH on skeletal growth are largely mediated via IGF-I (14, 15, 16). The findings that bone formation is impaired severely in GH-deficient and IGF knockout mice and that exogenous administration of IGFs stimulates bone formation parameters in both animals and humans (17, 18, 19) further stress the important role for the IGF system in regulating bone formation. It is also known that the actions of IGFs in bone are regulated by complex interplay between inhibitory and stimulatory IGF-binding proteins (IGFBPs) and their corresponding proteases (20, 21).
The purposes of this study were 2-fold. Firstly, we evaluated whether the skeletal accretion that occurs during puberty is due to increased bone formation and/or decreased bone resorption by determining the relationship between biochemical indexes of bone turnover vs. 1) bone mineral content (BMC) adjusted for body mass index (BMI), and 2) metacarpal bone indexes. Secondly, we evaluated the role of cytokines and IGF system components in mediating the skeletal changes that occur during puberty by determining the relationship between serum levels of cytokines and stimulatory IGF system components vs. 1) bone formation and resorption parameters, 2) BMC adjusted for BMI, and 3) metacarpal bone indexes.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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This study was approved by the institutional review board of our
institution. Eighty-one Caucasian girls (age range, 9.4–14.8 yr old)
were recruited from the community. Each girl and parent signed an
informed consent form. Sixteen girls were not eligible [bone age
different than chronological age (n = 2), or did not complete the
blood draw or the 24-h urine collection (n = 14)]. All remaining
65 girls (age range, 9.4–14.4 yr old) were in good health, free of
medical problems, and not taking any medications and had a bone age, as
determined by hand x-ray, within 1 yr of the chronological age. The
girls were grouped according to sexual development into Tanner stage
(TS) II (n = 19), TS III (n = 24), or TS IV (n = 22).
Height and weight were measured using a stadiometer and a calibrated
scale, respectively. Demographic data for the entire group and for each
TS of sexual development are detailed in Table 1
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Standardized right hand x-rays were obtained to determine bone age, according to the standardized atlas of Greulich and Pyle (22). Skeletal changes during puberty were followed by measurement of metacarpal changes established by the pioneering work of Garn et al. (23). In addition, the x-rays were used to measure, using a caliper, the following metacarpal indexes at the middle of the second metacarpal: metacarpal length, total metacarpal thickness (tt), and cortical thickness (ct). Marrow width (mw) was determined by the formula: mw = tt - 2 x ct. Metacarpal indexes were obtained in duplicate by two different observers. The coefficient of variation for metacarpal measurements was less than 2%.
BMD and BMC measurements
Lumbar BMD and BMC measurements were performed at the L1–L4 region using a QDR 1000 (Hologic, Inc., Waltham, MA). Because of differences in bone sizes between girls at different TS, we also adjusted BMC measurements for BMI and calculated bone mineral apparent density (BMAD) according to the method of Katzman et al. (24).
Serum and urine samples
Blood samples were obtained by arm venipuncture between 0800–0900 h. After clotting and centrifugation, serum was separated and aliquoted into 250-µL samples. Serum samples were stored at -70 C until assay time. To reduce interassay variation, all samples were run in the same assay. Twenty-four-hour urine collections were obtained on a hydroxyproline-free diet. Urine volumes were measured, and aliquots of urine were frozen at -20 C until assay time.
Bone turnover assays
Bone formation was assessed by serum skeletal alkaline phosphatase (ALP) and serum osteocalcin as described previously (25, 26). Bone resorption was assessed by urinary hydroxyproline (OH-Prol), pyridinoline (Pyr), and deoxypyridinoline (Dpyr) measurements (25, 26). Urinary creatinine was measured by standard methods.
IGF system components
Serum levels of IGF-I and IGF-II were measured after complete removal of IGFBPs by the rapid acid gel filtration protocol as previously described (27). IGF-I and IGF-II levels were measured by RIA using recombinant human IGF-I and IGF-II standard and tracer. The intra- and interassay coefficients of variation were less than 10% for both of these assays. The cross-reactivity of IGF-II in the IGF-I assay was less than 0.1%, whereas the cross-reactivity of IGF-I in the IGF-II assay was less than 0.5%. IGFBP-3 levels in the serum were measured by RIA using rabbit polyclonal antiserum and recombinant IGFBP-3 as standard and tracer, respectively (28). IGFBP-5 levels were measured using polyclonal guinea pig antiserum and recombinant IGFBP-5 as standard and tracer, respectively (29). Other IGFBPs did not show significant cross-reactivity in either of these two assays. The intra- and interassay coefficients of variation for IGFBP-3 and IGFBP-5 measurements were less than 10%.
Sex steroid hormones
The serum estradiol level was measured by RIA (ICN Biomedicals, Inc. Costa Mesa, CA). Serum free testosterone was determined by coated tube RIA (Diagnostics Systems Laboratories, Inc., Webster, TX). The intraassay coefficient of variation was less than 5% for both assays. Lower limits of detection for serum estradiol and serum free testosterone were 10 and 0.05 pg/mL, respectively.
Cytokines
Serum levels of interleukin-1ß (IL-1ß), IL-6, IL-11,
macrophage colony-stimulating factor, and tumor necrosis factor-
were measured by enzyme-linked immunosorbent assay (R&D Systems,
Minneapolis, MN).
Statistics
Regression analyses, multiple step regression analyses, t test, and one-way ANOVA were performed using Systat 5.03 for Windows (Systat, Inc., Evanston, IL). Results are given as the mean ± SEM. P < 0.05 was considered significant.
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Skeletal changes were evaluated by changes in lumbar BMD and
lumbar BMC content as well as by changes in metacarpal bone indexes in
girls at TS II, III, and IV. Lumbar BMD and BMC increased by 19%
(P < 0.001) and 45% (P < 0.001),
respectively, between TS II and III and by 18% (P <
0.001) and 28% (P < 0.001) between TS III and IV
(Table 2). Between TS II and IV, BMD
was increased by 40%, and BMC was increased by 87%. The increase in
BMC could not be attributed to the increase in body size alone, as BMC
was adjusted for BMI, and BMAD also increased significantly between TS
II and IV (Table 2). Metacarpal length increased significantly between
TS II and III, but not between TS III and IV (Fig. 1). In contrast, metacarpal width
increased significantly between TS II and III as well as between TS III
and IV. Marrow width, on the other hand, decreased significantly in TS
IV girls compared to that in TS III girls (Fig. 1).
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Serum levels of skeletal ALP and osteocalcin showed no significant
changes between TS II and III. Serum levels of skeletal ALP were
significantly reduced (27%) in TS IV girls compared to those in TS II
and III girls. The serum osteocalcin level was also 18% less in TS IV
girls than in TS II girls; however, this difference did not reach
statistical significance (Table 3).
Urinary levels of bone resorption markers (OH-Prol, Pyr, and Dpyr) were
significantly less in TS IV girls than in TS II and III girls, but were
not different between TS II and III girls, presumably due to the small
sample size (Table 3). OH-Prol and Pyr markers were modestly correlated
(r = 0.40; P < 0.05), whereas Pyr and Dpyr
urinary markers were highly correlated (r = 0.92;
P < 0.001). Urinary creatinine levels (24 h) were not
significantly different in girls between TS (data not shown).
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Bone formation markers did not correlate with BMD, BMC, BMAD, or
BMC adjusted for BMI. In contrast, bone resorption markers adjusted for
creatinine showed a significant negative correlation to BMD, BMC/BMI,
as well as BMAD for all subjects combined and for girls in TS III and
IV, when changes in bone resorption take place (Table 4). Furthermore, those subjects in the
top tertile of BMC had significantly lower OH-Prol, Pyr, and Dpyr
(P < 0.05) compared to those in the lower tertile
(data not shown). Using bone resorption values unadjusted for
creatinine reduced the significance of the correlations between BMD and
bone resorption markers.
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Neither osteocalcin nor skeletal ALP were correlated with
metacarpal indexes, except during TS II, when cortical and total
thickness were positively correlated with osteocalcin (r = 0.64
and 0.74, respectively; P < 0.01). On the other hand,
bone resorption was negatively associated with cortical thickness
(r = -0.40, -0.50, and -0.49, respectively, for OH-Prol, Pyr,
and Dpyr; all P < 0.01) and positively associated with
marrow width (r = 0.34, 0.29, and 0.29 for OH-Prol, Pyr, and Dpyr,
respectively; all P < 0.05) in the combined data from
all three TS. Table 4
shows the correlations between bone resorption
markers and skeletal changes in the pooled data from TS III and IV
girls during the phase when active resorption was taking place.
Relationship between sexual development and IGF system components
Serum levels of IGF-I and IGF-II were 50% and 14% higher,
respectively, in TS III girls than in TS II girls (P <
0.001). Serum levels of IGFBP-3 and IGFBP-5 were also significantly
higher in TS III girls than in TS II girls (Fig. 2). None of the stimulatory IGF system
components was significantly different between TS III and TS IV girls.
Between TS II and IV of sexual development, age was positively
associated with IGF-I, IGFBP-3, and IGFBP-5 (r = 0.50, 0.32, and
0.40, respectively; all P < 0.01), but not IGF-II
(r = -0.07; P = NS).
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Table 5 shows the correlation
between serum IGF system components and BMC adjusted for BMI in TS II,
III, and IV girls. In the pooled data from TS II and III girls, serum
levels of IGF-I, IGFBP-3, and IGFBP-5, but not IGF-II, showed a
significant positive correlation to BMC adjusted for BMI. In general,
serum levels of IGF system components showed a significant positive
correlation to BMC adjusted for BMI in TS II and III girls, but not in
TS IV girls. Similar correlations were obtained between serum levels of
IGF-I, IGFBP-3, and IGFBP-5 vs. BMD, BMC, or BMAD (data not
shown).
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For all subjects combined, IGF-I, IGFBP-3, and IGFBP-5 were
significantly correlated to cortical thickness (r = 0.60, 0.45,
and 0.52, respectively; all P < 0.001), total
thickness (r = 0.66, 0.55, and 0.56, respectively; all
P < 0.001), and metacarpal length (r = 0.39,
0.36, and 0.34, respectively; all P < 0.01), but not
with marrow width (r = -0.10,0.02 and -0.11, respectively;
P = NS). IGF-II did not correlate with any metacarpal
index value. Within each TS of sexual development, only cortical
and total metacarpal thickness correlated significantly with IGF-I,
IGFBP-3, and IGFBP-5. Those associations were strongest during TS II
and were lost with advancing sexual development (Fig. 3 and Table 6). Serum levels of IGF-I, IGFBP-3, and
IGFBP-5 showed significant positive correlations to metacarpal bone
length in TS II, but not in TS IV, girls (data not shown). The
correlations between serum levels of IGF-I vs. metacarpal
bone length and width in TS II girls are plotted in Fig. 3.
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Serum levels of IGF-I showed a significant positive correlation to
serum osteocalcin levels (r = 0.76; P < 0.001;
Fig. 3) in TS II, but not in TS IV (r = -0.02), girls. Similarly,
serum levels of IGFBP-3 (r = 0.67; P < 0.01) and
IGFBP-5 (r = 0.40; P < 0.01) showed a significant
positive correlations to serum osteocalcin levels in TS II, but not in
TS IV, girls. None of the serum IGF system components measured showed a
significant correlation with bone resorption markers in the pooled data
or in individual TS.
Relationship between serum levels of cytokines and bone density vs. urinary bone resorption markers
Because BMC and BMC/BMI were negatively correlated with bone
resorption (r = -0.86; P < 0.001) and because
cytokines have been shown to be important regulators of osteoclastic
bone resorption, we tested the hypothesis that the inhibition of bone
resorption during sexual development was mediated by changes in serum
cytokine levels. Of the serum levels of various cytokines tested
(IL-1ß, IL-6, IL-11, macrophage colony-stimulating factor, and tumor
necrosis factor-), only serum levels of IL-6 decreased during late
puberty and were negatively correlated to BMC/BMI during TS III and IV
(r = 0.45; P = 0.02 and r = 0.37;
P < 0.05, respectively).
Relationship between metacarpal indexes and sexual hormones
Because sex steroid hormones have been shown to play a major role
in the regulation of bone turnover, we determined the relationship
between metacarpal indexes and sex steroid hormone levels. As expected,
both serum free testosterone and serum estradiol increased between TS
II and IV (Table 7). Estradiol was not
correlated to any metacarpal index. On the other hand, serum free
testosterone was positively correlated to cortical thickness (r =
0.37; P < 0.05) and to total thickness (r = 0.33;
P < 0.05).
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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The rapid accretion of bone during the period of sexual maturation is associated with changes in both longitudinal bone growth as well as cortical thickness. Our findings demonstrate that increases in metacarpal bone length ceased to occur after TS III, whereas the increase in cortical thickness continued to occur beyond TS III. These data suggest that different mechanisms may regulate increases in longitudinal bone growth vs. cortical thickness, both of which occur during the puberty-induced growth spurt and both of which potentially relate to fracture risk later in life. In terms of potential signaling molecules that contribute to the rapid increase in longitudinal bone growth, the GH-IGF axis is a potential candidate based on a number of observations (14, 15, 17, 18, 19, 32, 33, 34). The positive association between increasing serum levels of IGF stimulatory system components and metacarpal bone length as well as serum IGF-I and osteocalcin levels in TS II girls, but not in TS IV girls, is consistent with the idea that up-regulation of IGF-I and its stimulatory binding proteins could in part contribute to the longitudinal bone growth that occurs during puberty.
In addition to the longitudinal growth spurt associated with puberty,
we have confirmed the work of others that cortical thickness also
increases during sexual development. In this regard, the increase in
cortical width during puberty may relate to an increase in periosteal
bone formation, a decrease in endosteal bone resorption, or both. The
finding of our study that the cortical thickness of metacarpal bone
increases significantly between TS II and III without a corresponding
decrease in either marrow width or the rate of bone resorption is
consistent with the idea that an increase in periosteal bone formation
could in part contribute to the observed differences in cortical
thickness during early pubertal changes. The finding that serum
osteocalcin levels showed a significant positive correlation with
cortical thickness in TS II girls (r = 0.66; P <
0.001) is consistent with the above hypothesis. The increase in
periosteal bone formation may be mediated in part by the rapid increase
in the production of stimulatory IGF system components that occur
during the same time period based on the findings in this study (Fig. 4) as well as other studies (35, 36, 37, 38). If
the IGF-induced increase in bone formation contributes in part to the
changes in cortical width that occur between TS II and III, we would
anticipate higher serum levels of bone formation markers in girls at TS
III than in those at TS II. However, the mean serum osteocalcin and ALP
(skeletal isoenzyme) levels were essentially unchanged between TS II
and III girls in our study. The likely explanation for this apparent
discrepancy is that complex changes (i.e. longitudinal
growth, periosteal expansion, modeling-dependent remodeling, and sex
hormone-dependent reduction in remodeling of trabecular bone) are
occurring in the skeleton during puberty and that contemporary bone
turnover markers cannot discern the various processes occurring at the
same time.
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). The reasons that support the above conclusion are as follows.
First, marrow width was significantly decreased in TS IV girls compared
to that in TS III girls and was associated with corresponding decreases
in bone resorption markers. Second, the bone resorption markers showed
a significant negative correlation with cortical width and a positive
correlation with marrow width in TS IV, but not TS II girls. Third,
bone resorption markers when corrected for creatinine showed
significant negative correlations with bone density measurements in TS
III and IV girls, and those girls in the top tertile of BMD exhibited
significantly lower bone resorption markers than those in the lower
tertile of BMD. However, the correlation between bone density and bone
resorption markers failed to maintain significance when bone resorption
values were not corrected for creatinine. This apparent discrepancy
reminds us of the known limitation of bone resorption markers to
predict bone density changes. However, a number of studies have
implicated an important role for reduced remodeling in increasing bone
gain during puberty. For example, Slemenda et al. (9) have
recently shown that black children accumulated 10% greater bone mass
than white children and had significantly reduced bone turnover, as
measured by serum levels of osteocalcin and tartrate-resistant acid
phosphatase, compared to white children during pubertal growth.
Although these data provide strong evidence that reduced rates of bone
turnover play a major role in accretion of bone mass during puberty in
both blacks and whites, determining the extent to which reduced rates
of skeletal remodeling contribute to bone gain during this phase
requires further longitudinal studies. The molecular cues that signal down-regulation of skeletal remodeling during the period of sexual maturation can only be speculated upon at this time. Our findings together with other published observations provide evidence for a role for IL-6 in mediating the reduced bone resorption seen during puberty (13, 39). A number of studies have shown that IL-6 is an important regulator of osteoclast cell recruitment and activity (11, 12, 13, 40). In addition, it has been shown that treatment of osteoblasts with sex hormones inhibits the production of IL-6 (13, 41). Consistent with these data, we have found that serum levels of IL-6 were significantly reduced in TS IV girls compared to those in TS II girls. Furthermore, serum levels of IL-6 correlated negatively to BMC adjusted for BMI in TS III (r = -0.45; P < 0.02) and TS IV (r = -0.37; P < 0.05) girls, and those girls with serum IL-6 levels in the upper tertile had significantly lower BMC than those with levels in the lower tertile. These changes, which are just mirror images of those occurring during the menopause, support the role of IL-6 in mediating rapid changes in bone density (39, 42). Because serum levels do not reflect what is happening at the local level, we cannot rule out the possibility that other cytokines besides IL-6 may be involved in mediating decreased bone resorption during puberty. Further studies are warranted to detail the role of sex hormone-induced inhibition of production of IL-6 and other cytokines in mediating reduced remodeling during puberty.
Our study demonstrates for the first time that in addition to the previously reported increases in serum levels of IGF-I and IGFBP-3 (16, 43), serum levels of stimulatory IGFBP-5 increase significantly in TS III girls compared to TS II girls. Although the significance of the increase in serum levels of IGFBP-5 during puberty is not established, it is known that this binding protein has several unique features, including potentiation of IGF-induced osteoblast cell proliferation via both IGF-dependent and IGF-independent mechanisms (44, 45). In regard to the potential mechanisms, which cause a rapid increase in serum stimulatory IGF system components during puberty, interactions between GH and sex steroids have been proposed to play an important role (7, 14, 15). The findings that GH treatment of GH-deficient subjects causes a rapid increase in circulating IGFBP-5 levels and that GH treatment increases IGFBP-5 expression in rat osteoblasts (46) implicate the increase in GH as being responsible for the increase in IGFBP-5 production. However, the direct effect of sex steroids on IGFBP-5 expression also cannot be ruled out, as sex steroids modulate production of IGF system components in vitro (47, 48). Together these data support the hypothesis that GH and sex steroids and their interaction may play a crucial role in regulating the production of IGF-I and its stimulatory IGFBPs during puberty.
We anticipated serum levels of estradiol to show significant correlation with metacarpal bone indexes during puberty based on a number of findings, including the following: 1) bone mass is significantly increased as a result of estrogen therapy in a man with aromatase deficiency (49); 2) serum bioavailable estrogen levels predict BMD in both men and women (50); and 3) animals lacking functional estrogen receptor exhibit significant skeletal phenotypic changes (51). Although serum levels of estradiol were higher in TS IV girls compared to TS II girls, metacarpal indexes did not show significant correlation with serum levels of estradiol in this study. Because serum levels of estradiol were measured at a single time point in this study, this may have compromised our ability to detect significant correlation between serum levels of estradiol and metacarpal indexes.
In summary, the rapid increase in skeletal mass that occurs during
puberty is caused by increases in both longitudinal growth as well as
cortical thickness. The increase in cortical thickness may be mediated
via both periosteal envelope expansion as well as reduction in marrow
width. Our data are consistent with a model (Fig. 4) in which a sex
steroid hormone-induced increase in the GH-IGF axis leads to an
increase in longitudinal growth and periosteal expansion, whereas the
sex steroid hormone-induced reduction in bone turnover (via IL-6 and
other cytokines) leads to an increase in cortical thickness via
decreased marrow width. Further studies are needed to examine the
extent to which changes in the GH-IGF axis and IL-6 contribute to
skeletal changes that occur during puberty and the molecular signals
that regulate these growth factors.
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Acknowledgments |
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Footnotes |
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Received January 6, 1999.
Revised April 21, 1999.
Accepted May 10, 1999.
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References |
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