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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)

Department of Medicine, University of California at San Francisco, San Francisco, California 94143

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{at}itsa.ucsf.edu.

	Abstract

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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 µg) daily and standard hormone replacement therapy, or hormone 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.

	Introduction

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THE 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, 2, 3, 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 bone-specific 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 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

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The 51 postmenopausal women, 50–82 yr of age with osteoporosis (T score –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 .

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 µg/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 µg) 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

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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 (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 .

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 12-month 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.

View larger version (32K): [in this window] [in a new window]   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 ).

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 baseline values), and remained elevated until discontinuation of hPTH.

	Discussion

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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 operate 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 time-dependent 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, 13, 14, 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 dose- and 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 PTH-induced 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 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 µg/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.

	Footnotes

 
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.

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.

Received December 2, 2003.

Accepted March 28, 2004.

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