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The Journal of Clinical Endocrinology & Metabolism 89(7):3332–3336
Copyright © 2004 by The Endocrine Society
doi: 10.1210/jc.2003-032066
Changes in Serum Receptor Activator of Nuclear Factor␬B Ligand, Osteoprotegerin, and Interleukin-6 Levels in
Patients with Glucocorticoid-Induced Osteoporosis
Treated with Human Parathyroid Hormone (1–34)
ERIC C. BUXTON, WEI YAO,
AND
NANCY E. LANE
Department of Medicine, University of California at San Francisco, San Francisco, California 94143
Changes in biochemical markers of bone turnover following
intermittent injections of human (h)PTH (1–34) suggest that
bone formation is initially favored over bone resorption.
hPTH (1–34) is also known to influence osteoclast maturation
and activity through modulation of osteoblast-derived cytokines, such as receptor activator of nuclear factor-␬B ligand
(RANKL), osteoprotegerin (OPG), IL-6, and IL-6 soluble receptor (IL-6sR). In this experiment, we investigated the
changes in serum levels of soluble RANKL (sRANKL), OPG,
IL-6, and IL-6sR in patients with glucocorticoid-induced osteoporosis treated with hPTH (1–34). Fifty-one postmenopausal women with glucocorticoid-induced osteoporosis were
randomized to receive 12 months of 400 U hPTH (1–34) (⬃40
␮g) daily and standard hormone replacement therapy, or hor-
T
HE TREATMENT OF osteoporosis in postmenopausal
women and men with human (h)PTH (1–34) results in
a significant increase in lumbar spine bone mass, and a reduction in incident vertebral and nonvertebral fracture risk
(1– 4). Daily injections of hPTH (1–34) and PTH (1– 84) are
associated with an initial increase in markers of osteoblast
activity followed closely by an increase in markers of osteoclast activity (5, 6). This increase in bone turnover, as reflected by changes in biochemical markers of bone turnover,
provides insight into the complex way in which PTH increases bone strength. These biochemical markers demonstrate that rapid bone formation occurs first, and over time
bone resorption increases. Earlier work from our research
group demonstrated that after 1 month of daily treatment
with hPTH (1–34), postmenopausal women with glucocorticoid-induced osteoporosis (GIOP) demonstrated increases
in serum osteocalcin (OC) of nearly 200% and in bonespecific alkaline phosphatase (BSAP) of nearly 75% above the
baseline levels. This was followed by a more gradual but
eventually equally significant increase in deoxypyridinoline
cross-links (DPD) excretion (7). These data suggested that
Abbreviations: BSAP, Bone-specific alkaline phosphatase; DPD, deoxypyridinoline cross-links; GIOP, glucocorticoid-induced osteoporosis; hPTH, human PTH; HRT, hormone replacement therapy; IL-6sR,
IL-6 soluble receptor; OC, osteocalcin; OPG, osteoprotegrin; RANK, receptor activator of nuclear factor-␬B; RANKL, RANK ligand; sRANKL,
soluble RANKL.
JCEM is published monthly by The Endocrine Society (http://www.
endo-society.org), the foremost professional society serving the endocrine community.
mone replacement therapy alone. Serum levels of sRANKL,
OPG, IL-6, and IL-6sR were measured at baseline, 1 month,
and every 3 months thereafter for a total of 24 months. hPTH
(1–34) caused a rapid and significant increase in sRANKL
within 1 month, and the levels remained elevated throughout
the duration of therapy. IL-6 and IL-6sR increased significantly within 1 month, but returned to baseline levels more
rapidly. In contrast, OPG was mildly suppressed beginning 6
months after hPTH therapy. These data support the hypothesis that hPTH (1–34) initially stimulates osteoblast maturation and function, which in turn leads to osteoclast activation
and a gradual rebalancing of bone formation and resorption.
(J Clin Endocrinol Metab 89: 3332–3336, 2004)
hPTH (1–34) treatment induced an initial uncoupling of the
bone remodeling process to favor bone formation over bone
resorption and that continued osteoblast activation appeared
to increase osteoclast activity.
In vitro and short-term in vivo studies report hPTH (1–34)
increases osteoblast production of receptor activator of nuclear factor-␬B (RANK) ligand (RANKL), IL-6, and IL-6 soluble receptor (IL-6sR). Because osteoclast maturation and
activity are influenced by RANKL and IL-6/IL-6sR, the purpose of this investigation was to determine the serum levels
of soluble RANKL (sRANKL), osteoprotegerin (OPG), IL-6,
and IL-6sR at multiple time points in patients with GIOP
treated with hPTH (1–34) for 1 yr with an additional 1 yr of
follow-up.
Subjects and Methods
The 51 postmenopausal women, 50 – 82 yr of age with osteoporosis (T
score ⱕ ⫺2.5 at the lumbar spine and/or hip) were enrolled in the clinical
study (8). Women were eligible if they were postmenopausal for at least
3 yr, taking Premarin 0.625 mg daily (Wyeth-Ayerst, Princeton, NJ) or
equivalent for more than 1 yr, and on a stable dose of prednisone (mean
dose, 5–20 mg daily or equivalent) for at least 1 yr before enrollment and
were expected to continue glucocorticoid treatment for at least 1 yr.
Patients were excluded if they had secondary osteoporosis other than
from glucocorticoids and an underlying rheumatic disease, significant
renal or hepatic dysfunction, or abnormalities on baseline spine radiographs that precluded accurate measurement by quantitative computed
tomography or dual-energy x-ray absorptiometry. All patients gave
informed consent, and the study was approved by the Committee on
Human Research of the University of California at San Francisco (7, 8).
The research subjects and experimental methods have been described in
detail in Refs. 7 and 8.
3332
Buxton et al. • Patients with Glucocorticoid-Induced Osteoporosis
J Clin Endocrinol Metab, July 2004, 89(7):3332–3336 3333
Treatment protocol
Women satisfying the entry criteria were randomly assigned by a
computer-generated table into one of two possible groups. The active
treatment group consisted of 28 women who were randomized to receive daily hPTH (1–34), 400 U/d (⬃40 ␮g/d), sc for 12 months in
addition to concurrent hormone replacement therapy (HRT). The remaining 23 women received HRT alone. Each woman was also given
calcium carbonate supplements, if needed, to achieve a daily dietary
calcium intake totaling 1500 mg, and 800 IU vitamin D per day in the
form of two multivitamins. Subjects were followed for a total of 24
months (7, 8).
hPTH (1–34) was purchased from Bachem California (Torrance, CA)
as a lyophilized powder, reconstituted with 0.9% benzyl alcohol and
normal saline, and sterilized using Millipore filtration (Millipore Corp.,
Billerica, MA). Patients were taught sc self-injection by the research
nurse at the start of the study. Placebo injections were not used. hPTH
(1–34) at a dose of 400 U (⬃40 ␮g) was given daily for 12 months.
Compliance was estimated by measuring the remaining volume in returned medication vials at each study visit and ranged from 80 –90% of
the daily doses (7, 8).
Biochemical assays
Biochemical markers of sRANKL, OPG, IL-6, and IL-6sR were obtained at baseline, 1 month, and every 3 months for a total of 24 months.
Serum levels of sRANKL and OPG were analyzed in duplicate using
ELISA kits from ALPCO Diagnostics (Windham, NH). Serum levels of
OC and DPD were measured by ELISA (Metra-Biosystems, Mountain
View, CA) and were previously reported (7, 8). Serum levels of IL-6 and
IL-6sR were measured using ELISA kits from R&D Systems (Minneapolis, MN). The manufacturers’ protocols were followed, and all samples
were assayed in duplicate. A standard curve was generated from each
kit, and the absolute concentrations were determined. The coefficient of
variations was less than 8% for sRANKL (range, 1– 690 pg/ml), 6% for
OPG (range, 20 –300 pg/ml), less than 10% for OC (3–36 ng/ml), less
than 7% for DPD (1–24.8 nm/mM creatinine), less than 10% for IL-6
(range, 2.2–260 pg/ml), and 5% for IL-6sR (range, 2.9 –72 ng/ml) in our
laboratory; these values were similar to the manufacturers’ references.
Statistical analysis
Baseline differences between the groups were tested for significance
with Student’s t test for normally distributed variables. Differences
between and within the hPTH plus HRT and the HRT-only groups
during the course of the treatment were analyzed by repeated measurement ANOVA with a grouping factor. The repeated measure was
time, and treatment was used as the grouping factor. Post hoc analysis
was performed using Tukey’s method.
Results
Baseline characteristics of the 51 study subjects are shown
in Table 1. There were no significant differences between the
groups in terms of mean age, years after menopause, years
taking glucocorticoids or HRT, mean glucocorticoid dose, or
lumbar spine or hip bone mineral density measurements.
The mean daily dose of prednisone (or equivalent) was 8
mg/d in the PTH group and 9.4 mg/d in the HRT only group
TABLE 1. Baseline characteristics of the study subjects (mean ⫾
(P ⫽ not significant; Table 1). The underlying disorders for
which glucocorticoid treatment was used included rheumatoid arthritis (15 of 28 PTH group vs. 10 of 23 HRT only),
systemic lupus erythematosus (3 of 28 vs. 5 of 23), vasculitis
(4 of 28 vs. 2 of 23), polymyalgia rheumatica (3 of 28 vs. 1 of
23), asthma (2 of 28 vs. 5 of 23), and kidney transplant (1 of
28 vs. 0 of 23). Additional details are published in Refs. 7
and 8.
Biochemical markers
Table 2 and Fig. 1 demonstrate the levels of biochemical
markers of bone turnover at baseline, at multiple time points
during the 12-month treatment period, and during the 12month follow-up period. In the control group, no significant
changes were observed in sRANKL, OPG, IL-6, or IL-6sR
levels at any point during the 24-month observational study.
In the hPTH group, OC and BSAP reached near maximum
values after 1 month of therapy. The levels remained significantly elevated throughout the duration of hPTH therapy,
with maximum levels achieved between 6 and 9 months. The
median increase was 164% for OC and 113% for BSAP (data
not shown) (7, 8). Additionally, there was a relatively rapid
increase in serum sRANKL within 2 months, with a peak of
more than 250% above baseline levels at 3 months (5.1 ⫾ 3.0
vs. 1.3 ⫾ 1.9, P ⬍ 0.05). Serum sRANKL remained at least
150% above baseline levels for the next 9 months, although
levels began to decline after 6 months of therapy, gradually
returned to baseline values, and were no longer significantly
different from the baseline levels by 3 months after discontinuation of hPTH therapy. The increases in serum sRANKL,
OC, and BSAP were both earlier and greater than the elevation of DPD, a surrogate marker for bone resorption. DPD
increased more gradually, with levels 70% above baseline
after 1 month of hPTH treatment and an eventual peak at 9
months of therapy.
In contrast, serum OPG levels were unchanged for the first
3 months, decreased 23% at 6 months, and decreased approximately 45% at 12 months. After discontinuation of
hPTH therapy, OPG returned to baseline values.
Serum IL-6 levels increased rapidly and transiently,
peaked at more than 130% above baseline at 3 months (14.4 ⫾
7.0 vs. 6.1 ⫾ 2.5, P ⬍ 0.05 from baseline values; 14.4 ⫾ 7.0 vs.
5.0 ⫾ 4.4, P ⬍ 0.05 from control group), and then returned
to baseline by 9 months. The 3-month increase of IL-6 paralleled the increases observed in DPD. Serum IL-6sR also
increased significantly early during the course of therapy,
peaked at 1 month (41.3 ⫾ 13.9 vs. 31.4 ⫾ 11.1, P ⬍ 0.05 for
SD)
Demographics
HRT (n ⫽ 23)
PTH ⫹ HRT (n ⫽ 28)
P
Age (yr)
Postmenopause (yr)
Years on HRT (yr)
Years on steroid (yr)
Prednisone dose or equivalent (mg/d)
L1 BMD (g/cm2)
Total hip BMD (g/cm2)
59.9 ⫾ 10.2
16.3 ⫾ 11.2
11.4 ⫾ 10.3
9.4 ⫾ 4.5
8.0 ⫾ 3.8
0.8 ⫾ 0.1
0.7 ⫾ 0.1
65.1 ⫾ 9.6
19.3 ⫾ 8.9
16.6 ⫾ 11.1
8.0 ⫾ 3.7
9.4 ⫾ 4.5
0.8 ⫾ 0.1
0.7 ⫾ 0.1
NS
NS
NS
NS
NS
NS
NS
Baseline demographic data have been published previously in Refs. 7 and 8. BMD, Bone mineral density; NS, not significant.
3334
J Clin Endocrinol Metab, July 2004, 89(7):3332–3336
TABLE 2. Biochemical markers (mean ⫾
Biochemical markers
HRT ⫹ PTH
sRANKL (pg/ml)
OPG (pg/ml)
IL-6 (pg/ml)
IL-6sR (ng/ml)
HRT
sRANKL (pg/ml)
OPG (pg/ml)
IL-6 (pg/ml)
IL-6sR (ng/ml)
SD)
Buxton et al. • Patients with Glucocorticoid-Induced Osteoporosis
at various time points
0 month
1 month
3 months
6 months
12 months
24 months
26 ⫾ 38
122 ⫾ 34
6.1 ⫾ 2.5
31.4 ⫾ 11.1
32 ⫾ 26a
114 ⫾ 54
10.5 ⫾ 6.5b
41.3 ⫾ 13.9cp
98 ⫾ 60dk
128 ⫾ 58
14.4 ⫾ 7.0eo
38.6 ⫾ 17.2q
92 ⫾ 50l
74 ⫾ 54
5.5 ⫾ 3.1
35.0 ⫾ 11.6f
72 ⫾ 36m
44 ⫾ 10n
6.7 ⫾ 4.3
39.2 ⫾ 14.7
18 ⫾ 12
122 ⫾ 64
5.5 ⫾ 5.4
22.8 ⫾ 8.8
74 ⫾ 46
106 ⫾ 62
6.2 ⫾ 2.8
31.2 ⫾ 9.8
12 ⫾ 6g
106 ⫾ 74
5.0 ⫾ 2.2
30.6 ⫾ 7.9
76 ⫾ 42
86 ⫾ 42
5.0 ⫾ 4.4
31.1 ⫾ 10.7
44 ⫾ 24g
76 ⫾ 54i
5.2 ⫾ 3.5
25.4 ⫾ 14.2
40 ⫾ 38h
36 ⫾ 24j
6.0 ⫾ 3.4
33.6 ⫾ 9.3
40 ⫾ 60
72 ⫾ 44
5.9 ⫾ 2.7
22.1 ⫾ 12.4
a
P ⬍ 0.05 from HRT for sRANKL at 1 month; b P ⬍ 0.05 from HRT for IL-6 at 1 month; c P ⬍ 0.05 from HRT for IL-6sR at 1 month; d P ⬍
0.05 from HRT for sRANKL at 3 months; e P ⬍ 0.05 from HRT for IL-6 at 3 months; f P ⬍ 0.05 from HRT for IL-6sR at 6 months; g P ⬍ 0.05
from 0 months for sRANKL within HRT group at 6 months; h P ⬍ 0.05 from 0 months for sRANKL within HRT group at 12 months; i P ⬍ 0.05
from 0 months for OPG within HRT group at 6 months; j P ⬍ 0.05 from 0 months for OPG within HRT group at 12 months; k P ⬍ 0.05 from
0 months for sRANKL within HRT ⫹ PTH group at 3 months; l P ⬍ 0.05 from 0 months for sRANKL within HRT ⫹ PTH group at 6 months;
m
P ⬍ 0.05 from 0 months for sRANKL within HRT ⫹ PTH group at 12 months; n P ⬍ 0.05 from 0 months for OPG within HRT ⫹ PTH group
at 12 months; o P ⬍ 0.05 from 0 months for IL-6 within HRT ⫹ PTH group at 3 months; p P ⬍ 0.05 from 0 months for IL-6sR within HRT ⫹
PTH group at 1 month; q P ⬍ 0.05 from 0 months for IL-6sR within HRT ⫹ PTH group at 3 months. To convert sRANKL or OPG to pmol/liter,
multiply by 0.5. To convert IL-6 to IU/ml, multiply by 0.131. To our knowledge, there is no conversion to SI units currently available for IL-6sR.
FIG. 1. Percentage of changes in the biochemical markers of bone
turnover in postmenopausal women treated with HRT ⫹ hPTH (1–34)
or HRT alone for 12 months with 12 months of follow-up. Note that
DPD and OC results were reported previously (7, 8).
baseline values), and remained elevated until discontinuation of hPTH.
Discussion
This study demonstrates that very soon after the initiation
of low-dose daily injections of hPTH (1–34), there is an increase in biochemical markers of bone turnover. The markers
of osteoblast activation and function (sRANKL, OC, BSAP)
peaked earlier and to a greater degree than a marker of
osteoclast activity (DPD). We reported earlier that osteoblast
activity, as measured by serum OC and BSAP levels, increased to near maximum at 1 month and peaked at nearly
200% above baseline levels between 6 and 9 months (7, 8). We
now report that other osteoblast-derived cytokines involved
in the bone remodeling process, including sRANKL, IL-6,
and IL-6sR, increase in response to hPTH (1–34) therapy.
Serum sRANKL increased significantly within 1 month of
initiation of hPTH therapy, peaked at more than 250% above
baseline levels at 3 months, and remained significantly elevated for the duration of hPTH therapy. IL-6 and IL-6sR also
increased shortly after the initiation of hPTH. IL-6 peaked at
130% above baseline values at 3 months, and IL-6sR increased more modestly with a peak at 1 month. OPG, a
known inhibitor of osteoclastogenesis, was mildly suppressed beginning 6 months after hPTH therapy and returned to baseline levels after discontinuation. An indicator
of osteoclast function, DPD, increased more gradually and to
a lesser extent than most osteoblast-derived cytokines. These
data support the hypothesis that hPTH (1–34) rapidly and
powerfully stimulates osteoblast maturation and function.
PTH induced an up-regulation of osteoblast cytokines such
as sRANKL, IL-6, IL-6sR, and a suppression of OPG. These
actions ultimately led to osteoclast activation and a gradual
rebalancing of bone formation and resorption.
PTH controls bone formation and resorption primarily
through modulation of the OPG/RANKL/RANK system (9).
In response to PTH, immature cells in the osteoblast lineage
increase expression of the membrane-bound cytokine
RANKL and produce and release multiple cytokines, including IL-6, IL-6sR, and macrophage colony-stimulating factor.
RANKL may then bind to its true receptor RANK, which is
expressed on osteoclastic precursors and mature osteoclasts.
The association of RANKL with RANK in the presence of
cytokine permissive factors promotes osteoclastogenesis.
OPG, also produced by osteoblast precursors, serves as a
soluble decoy receptor for RANKL. The binding of OPG to
RANKL prevents the association of RANKL with RANK and
therefore inhibits osteoclastogenesis. PTH functions to suppress OPG production and secretion. Therefore, our data
support the paradigm in which PTH initially activates osteoblasts, which produce and release substances that gradually lead to osteoclast maturation and function. It is likely
that multiple osteoclast activation pathways exist, and the
OPG/RANKL/RANK system and IL-6/IL-6sR systems op-
Buxton et al. • Patients with Glucocorticoid-Induced Osteoporosis
erate independently. The relative contribution of each individual pathway to osteoclastogenesis is unknown.
Our observations are supported by both in vitro and in vivo
studies. After exposure to hPTH (1–34), cultured murine
bone marrow cells, calvaria, and osteoblasts increased
RANKL mRNA expression and decreased OPG mRNA expression (10). Importantly, these changes preceded hPTH
(1–34) augmentation of osteoclast-like cell formation by several hours. Similarly, Ma et al. (11) reported that continuous
administration of hPTH (1–38) resulted in a dose- and timedependent increase in RANKL mRNA as well as decreased
OPG mRNA and protein in osteoblasts. These changes preceded the peak increase in bone resorption. Multiple other
investigators have confirmed these observations (12–15).
Concurrent use of glucocorticoids may also have influenced changes in the expression of sRANKL and OPG. Hydrocortisone was found to decrease OPG mRNA in a doseand time-dependent manner in vitro (16). Patients with
chronic glomerulonephritis who were treated with glucocorticoids had lower serum OPG levels compared with pretreatment baseline (17). Additionally, dexamethasone was
reported to decrease human osteoblast OPG mRNA levels
and stimulate OPG-ligand mRNA levels, suggesting a possible mechanism through which glucocorticoids promote osteoclastogenesis (18). Similarly, in our experiment we observed a decrease in serum OPG in the hPTH treatment
group compared with the control group, which suggests that
hPTH was the causative factor.
Observed changes in markers of bone remodeling following hPTH exposure in patients with postmenopausal and
GIOP support the findings of early osteoblast stimulation.
Lindsay et al. (2) reported significant increases in OC within
1 month after hPTH (1–34) therapy. The bone resorption
marker urinary n-telopeptide increased more slowly and
peaked after 6 months. Rittmaster et al. (5) also observed early
increases in both OC and BSAP after 12 months of hPTH,
whereas the urinary n-telopeptide levels trended slightly
higher at 12 months. Our research group (7) previously demonstrated that the use of hPTH (1–34) in GIOP resulted in
greater and more rapid increases in OC compared with DPD.
These findings suggest that osteoblast activation and bone
formation precede osteoclastic bone resorption.
Although the OPG/RANKL/RANK pathway is critical to
the action of hPTH, other pathways exist. The IL-6/IL-6sR
cytokine system stimulates bone remodeling through a signaling cascade involving a glycoprotein-130 receptor (19).
This cytokine system is thought to play a role in both PTHinduced bone resorption and in bone loss due to estrogen
deficiency. In vitro and in vivo models have demonstrated
that PTH induces IL-6 and IL-6sR production by liver cells
(20) and increases IL-6 mRNA and circulating IL-6 levels in
vivo and in mouse osteoblastic cells (21, 22). IL-6 knockout
mice were found to have diminished resorptive responses to
hPTH, and antibodies to the IL-6sR were capable of inhibiting PTH-induced bone resorption (23). In patients with
primary hyperparathyroidism, IL-6 and IL-6sR levels were
markedly elevated and found to correlate strongly with biochemical markers of bone resorption (24). Our present experiment supports the conclusions that PTH does indeed
increase serum levels of IL-6 in a transient fashion and likely
J Clin Endocrinol Metab, July 2004, 89(7):3332–3336 3335
contributes to osteoclast generation and bone resorption.
Finally, estrogen does appear to modulate the deleterious
effects of IL-6/IL-6sR on bone. Estrogen-deficient women
have elevated IL-6sR levels and have a more exaggerated
elevation of IL-6 and IL-6sR in response to PTH than estrogen-replete women (25, 26).
Although our findings are interesting, they must be interpreted with caution. First, we only studied postmenopausal women chronically treated with HRT and glucocorticoids. It is possible that long-term therapy with either HRT
or glucocorticoids before hPTH might influence the pattern
of changes in serum markers after initiation of hPTH. However, as discussed earlier, the changes observed were similar
to those reported in other studies in patients with postmenopausal osteoporosis not treated with glucocorticoids. Second,
we treated our study subjects with 400 U hPTH (1–34) daily.
This dose is higher than the approved daily dose of recombinant hPTH (1–34) of 20 ␮g/d, so our results may differ from
those of the currently approved recombinant hPTH (1–34)
product. Third, our serum samples were collected over 5 yr
before analysis, and all samples had been thawed and refrozen at least two times.
In summary, we found that daily hPTH (1–34) injections
increase serum sRANKL, IL-6, and IL-6sR and modestly
decrease OPG production by osteoblasts. Alterations in the
levels of these osteoblast-derived factors occurred before
osteoclast activation and function, as measured by DPD.
Furthermore, the increases of sRANKL, IL-6, OC, and BSAP
were both more rapid and more pronounced than that observed with the marker of osteoclast function (DPD). These
results support the hypothesis that daily injections of hPTH
(1–34) increase osteoclast activity by stimulating osteoblast
modulation of the OPG/RANKL/RANK and IL-6/IL-6sR
pathways. Additional studies are now underway to determine whether changes in RANKL/OPG levels are correlated
with or predict bone mineral density changes with hPTH
(1–34) treatment.
Acknowledgments
Received December 2, 2003. Accepted March 28, 2004.
Address all correspondence and requests for reprints to: Dr. Nancy
Lane, Division of Rheumatology, Box 0868, University of California at
San Francisco, San Francisco, California 94143. E-mail: nelane@itsa.
ucsf.edu.
This work was supported by National Institutes of Health Grants
AR048841-01 and DK46661-07, the Rosalind Russell Arthritis Research
Center, and by a Research Enhancement Award from the Department
of Veterans Affairs.
References
1. Neer RM, Arnaud CD, Zanchetta JR, Prince R, Gaich GA, Reginster JY,
Hodsman AB, Eriksen EF, Ish-Shalom S, Genant HK, Wang O, Mitlak BH
2001 Effect of parathyroid hormone (1–34) on fractures and bone mineral
density in postmenopausal women with osteoporosis. N Engl J Med 344:1434 –
1441
2. Lindsay R, Nieves J, Formica C, Henneman E, Woelfert L, Shen V, Dempster
D, Cosman F 1997 Randomised controlled study of effect of parathyroid
hormone on vertebral-bone mass and fracture incidence among postmenopausal women on oestrogen with osteoporosis. Lancet 350:550 –555
3. Black DM, Greenspan SL, Ensrud KE, Palermo L, McGowan JA, Lane TL,
Garnero P, Bouxsein ML, Biliezikian J, Rosen CJ 2003 The effects of parathyroid hormone and alendronate alone or in combination in postmenopausal
osteoporosis. N Engl J Med 349:1207–1215
4. Finkelstein JS, Hayes A, Hunzelman JL, Wyland JJ, Lee H, Neer RM 2003 The
3336
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
J Clin Endocrinol Metab, July 2004, 89(7):3332–3336
effects of parathyroid hormone, alendronate, or both in men with osteoporosis.
N Engl J Med 349:1216 –1226
Rittmaster RS, Bolognese M, Ettinger MP, Hanley DA, Hodsman AB, Kendler DL, Rosen CJ 2000 Enhancement of bone mass in osteoporotic women
with parathyroid hormone followed by alendronate. J Clin Endocrinol Metab
344:1434 –1441
Hodsman AB, Fraher LJ, Watson PH, Ostbye T, Stitt LW, Adachi JD, Taves
DH, Drost D 1997 A randomized controlled trial to compare the efficacy of
cyclical parathyroid hormone versus cyclical parathyroid hormone and sequential calcitonin to improve bone mass in postmenopausal women with
osteoporosis. J Clin Endocrinol Metab 82:620 – 628
Lane NE, Sanchez S, Genant HK, Jenkins DK, Arnaud CD 2000 Short term
increases in bone turnover markers predict parathyroid hormone-induced
spinal bone mineral density gains in postmenopausal women with glucocorticoid-induced osteoporosis. Osteoporos Int 11:434 – 442
Lane NE, Sanchez S, Modin GW, Genant HK, Pierini E, Arnaud CD 1998
Parathyroid hormone treatment can reverse corticosteroid-induced osteoporosis. Results of a randomized controlled clinical trial. J Clin Invest 102:1627–
1633
Khosla S 2001 Minireview: the OPG/RANKL/RANK system. Endocrinology
142:5050 –5055
Lee SK, Lorenzo JA 1999 Parathyroid hormone stimulates TRANCE and
inhibits osteoprotegerin messenger ribonucleic acid expression in murine bone
marrow cultures: correlation with osteoclast-like cell formation. Endocrinology 140:3552–3561
Ma YL, Cain RL, Halladay DL, Yang X, Zeng Q, Miles RR, Chandrasekhar
S, Martin TJ, Onyia JE 2001 Catabolic effects of continuous human PTH (1–38)
in vivo is associated with sustained stimulation of RANKL and inhibition of
osteoprotegerin and gene-associated bone formation. Endocrinology 142:4047–
4054
Locklin RM, Khosla S, Turner RT, Riggs BL 2003 Mediators of the biphasic
responses of bone to intermittent and continuously administered parathyroid
hormone. J Cell Biochem 89:180 –190
Horwood NJ, Elliott J, Martin TJ, Gillespie MT 1998 Osteotropic agents
regulate the expression of osteoclast differentiation factor and osteoprotegerin
in osteoblastic stromal cells. Endocrinology 139:4743– 4746
Onyia JE, Miles RR, Yang X, Halladay DL, Hale J, Glasebrook A, McClure
D, Seno G, Churgay L, Chandrasekhar S, Martin TJ 2000 In vivo demonstration that human parathyroid hormone 1–38 inhibits the expression of
osteoprotegerin in bone with the kinetics of an immediate early gene. J Bone
Miner Res 15:863– 871
Fu Q, Jilka RL, Manolagas SC, O’Brien CA 2002 Parathyroid hormone stimulates receptor activator of NF-␬B ligand and inhibits osteoprotegerin expres-
Buxton et al. • Patients with Glucocorticoid-Induced Osteoporosis
16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
26.
sion via protein kinase A activation of cAMP-response element-binding protein. J Biol Chem 277:48868 – 48875
Vidal NO, Brandstrom H, Jonsson KB, Ohlsson C 1998 Osteoprotegerin
mRNA is expressed in primary human osteoblast-like cells: down-regulation
by glucocorticoids. J Endocrinol 159:191–195
Sasaki N, Kusano E, Ando Y, Nemoto J, Iimura O, Ito C, Takeda S, Yano K,
Tsuda E, Asano Y 2002 Changes in osteoprotegerin and markers of bone
metabolism during glucocorticoid treatment in patients with chronic glomerulonephritis. Bone 30:853– 858
Hofbauer LC, Gori F, Riggs BL, Lacey DL, Dunstan CR, Spelsberg TC,
Khosla S 1999 Stimulation of osteoprotegerin production by glucocorticoids
in human osteoblastic lineage cells: potential paracrine mechanisms of
glucocorticoids-induced osteoporosis. Endocrinology 140:4377– 4381
Kudo O, Sabokbar A, Pocock A, Itonaga I, Fujikawa Y, Athanasou NA 2003
Interleukin-6 and interleukin-11 support human osteoclast formation by a
RANKL-independent mechanism. Bone 32:1–7
Mitnick MA, Grey A, Masiukiewicz U, Bartkiewicz M, Rios-Velez L, Friedman S, Xu L, Horowitz MC, Insogna K 2001 Parathyroid hormone induces
hepatic production of bioactive interleukin-6 and its soluble receptor. Am J
Physiol Endocrinol Metab 280:E405–E412
Pollock JH, Blaha MJ, Lavish SA, Stevenson S, Greenfield EM 1996 In vivo
demonstration that parathyroid hormone and parathyroid hormone-related
protein stimulate expression by osteoblasts of iterleukin-6 and leukemia inhibitory factor. J Bone Miner Res 11:754 –759
Li NH, Ouchi Y, Okamoto Y, Masuyama A, Kaneki M, Futami A, Hosoi T,
Nakamura T, Orimo H 1991 Effect of parathyroid hormone on release of
interleukin 1 and interleukin 6 from cultured mouse osteoblastic cells. Biochem
Biophys Res Commun 179:236 –242
Greenfield EM, Shaw SM, Goraik SA, Banks MA 1995 Adenyl cyclase and
interleukin-6 are downstream effectors of parathyroid hormone resulting in
stimulation of bone resorption. J Clin Invest 96:1238 –1244
Grey A, Mitnick MA, Shapses S, Ellison A, Gundberg C, Insogna K 1996
Circulating levels of interleukin-6 and tumor necrosis factor-␣ are elevated in
primary hyperparathyroidism and correlate with markers of bone resorption–a clinical research center study. J Clin Endocrinol Metab 81:3450 –3454
Nakchbandi IA, Mitnick MA, Lang R, Gundberg C, Kinder B, Insogna K
2002 Circulating levels of interleukin-6 soluble receptor predict rates of bone
loss in patients with primary hyperparathyroidism. J Clin Endocrinol Metab
87:4946 – 4951
Masiukiewicz US, Mitnick M, Gulanski BI, Insogna KL 2002 Evidence that
the IL-6/IL-6 soluble receptor cytokine system plays a role in the increased
sensitivity to PTH in estrogen-deficient women. J Clin Endocrinol Metab
87:2892–2898
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