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The Journal of Clinical Endocrinology & Metabolism Vol. 86, No. 2 511-516
Copyright © 2001 by The Endocrine Society

From the Clinical Research Centers

Effects of Gonadal Steroid Suppression on Skeletal Sensitivity to Parathyroid Hormone in Men1

Benjamin Z. Leder, Matthew R. Smith, Mary Anne Fallon, Mei-Ling T. Lee and Joel S. Finkelstein

Endocrine Unit (B.Z.L., J.S.F.) and Hematology/Oncology Unit (M.R.S., M.A.F.), Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts 02114; and Channing Laboratory (M.-L.T.L.), Brigham & Women’s Hospital, Boston, Massachusetts 02115

Address all correspondence and requests for reprints to: Benjamin Z. Leder, Endocrine Unit, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts 02114. E-mail: bleder{at}partners.org


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Hypogonadism is associated with osteoporosis in men. GnRH- agonist-induced hypogonadism increases bone turnover and bone loss in men, but the mechanism underlying these changes is unknown. To determine whether gonadal steroid deprivation increases the skeletal sensitivity to PTH or blunts the ability of PTH to promote 1,25-dihydroxyvitamin D formation, we infused human PTH-(1–34) at a dose of 0.55 U/kg·h for 24 h, in 11 men (ages, 50–82 yr) with locally advanced, node-positive, or biochemically recurrent prostate cancer but no evidence of bone metastases. PTH infusions were performed before initiation of GnRH agonist therapy (leuprolide acetate, 22.5 mg im, every 3 months) and again after 6 months of confirmed GnRH agonist-induced hypogonadism. Serum osteocalcin (OC), bone- specific alkaline phosphatase (BSAP), N-telopeptide (NTX), whole-blood ionized calcium, and 1,25-dihydroxyvitamin D were measured at baseline and every 6 h during each PTH infusion. Urinary NTX and free deoxypyridinoline (DPD) were assessed on spot morning samples before PTH infusion and on 24-h samples collected during the PTH infusions. Sex steroid levels were lowered to the castrate range in all subjects. Baseline serum NTX levels (drawn before PTH infusion) increased from 9.1 ± 3.7 before leuprolide therapy to 13.9 ± 5.0 nmol bone collagen equivalents (BCE)/L after leuprolide therapy (P = 0.003). Spot urine NTX collected before PTH infusion increased from 28 ± 8 before leuprolide therapy to 49 ± 17 nmol BCE/mmol creatinine after leuprolide therapy (P < 0.001), and urinary DPD increased from 4.7 ± 1.1 to 7.4 ± 1.8 nmol BCE/mmol creatinine (P < 0.001). Baseline serum OC and BSAP levels drawn before each PTH infusion did not change before vs. after leuprolide therapy. Serum NTX levels increased significantly during PTH infusion pre-GnRH agonist therapy (P < 0.001), and the rate of increase was greater after 6 months of GnRH agonist-induced hypogonadism (P < 0.01 for the difference in rates of change before and after GnRH agonist administration). Serum OC and BSAP levels decreased during PTH infusion (P < 0.001 for OC and P = 0.002 for BSAP), but the rates of decrease did not differ before or after leuprolide therapy (P = 0.45 for OC and P = 0.19 for BSAP). Whole-blood ionized calcium levels increased during PTH infusion (P < 0.001), and the rate of increase was greater after GnRH agonist-induced hypogonadism (P = 0.068). Serum 1,25-dihydroxyvitamin D levels increased in response to PTH infusion before leuprolide therapy (P = 0.022), but there was no difference in the rate of increase before or after leuprolide therapy (P = 0.66). The incremental increase in urinary NTX excretion, but not DPD, during PTH infusion was greater after 6 months of leuprolide therapy (P = 0.029 for NTX, P = 0.578 for DPD). We conclude that suppression of sex steroids in elderly men increases the skeletal responsiveness to the bone resorbing effects of PTH infusion but does not affect the response of bone formation markers or 1,25-dihydroxyvitamin D to PTH. Changes in skeletal sensitivity to PTH may play an important role in the pathogenesis of hypogonadal bone loss in men.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
HYPOGONADISM IS ASSOCIATED with osteoporosis in both men and women, though the precise mechanisms involved are incompletely understood. In women, the induction of sex-steroid deprivation by the administration of GnRH agonists leads to high turnover bone loss (1, 2, 3, 4). Similar findings have also been reported in men receiving GnRH agonists (5, 6). Men with recurrent or metastatic prostate cancer are now routinely treated with GnRH agonists, often for prolonged periods of time. Furthermore, the use of GnRH agonists in men with prostate cancer is associated with a higher risk of fracture (7, 8). The administration of GnRH agonists to men causes deficiency of both androgen and estrogen. These hormonal deficiencies may induce bone loss by directly affecting locally produced cytokines or other factors (9, 10). GnRH agonist-induced hypogonadism may also promote bone loss by altering the production or tissue sensitivity to calcium regulatory hormones, such as PTH. In women, some studies, but not all, suggest that estrogen deficiency increases skeletal sensitivity to the bone resorbing action of PTH and thereby promotes hypogonadal bone loss (11, 12, 13). Additionally, there is conflicting evidence concerning estrogen’s effects on PTH-mediated production of 1,25-dihydroxyvitamin D (14, 15, 16, 17).

The effects of androgen and estrogen deprivation on skeletal sensitivity to PTH or 1,25-dihydroxyvitamin D metabolism have not been studied in men. Additionally, most previous studies of the effects of sex steroids on calcium regulatory hormones have involved exogenous hormone administration; and thus, the physiological relevance is difficult to ascertain. To assess the effects of gonadal steroids on skeletal sensitivity to PTH, as well as the effects of gonadal steroids on vitamin D metabolism in men, we infused human PTH [(h)PTH-(1–34)] for 24 h in 11 eugonadal men with nonmetastatic prostate cancer immediately before and 6 months after induction of sex-steroid deprivation with a long-acting potent GnRH agonist.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Study subjects

Eleven men between the ages of 50 and 82 with locally advanced, lymph node-positive, or biochemically recurrent (rising prostate- specific antigen) prostate cancer (but no evidence of bone metastases) were studied. No subject had received prior androgen deprivation therapy or had ever been treated with a bisphosphonate. All men had normal serum testosterone, calcium, albumin, phosphorous, magnesium, aspartate aminotransferase, and bilirubin levels; a serum creatinine less than 2.0 mg/dL; and a 99Tc bone scan showing no evidence of metastatic disease. Additionally, men with disorders affecting bone metabolism (including hypogonadism, vitamin D deficiency, Paget’s disease, hyperthyroidism, hyperparathyroidism, Cushing’s disease, hyperprolactinemia, chronic renal disease, or chronic liver disease) or taking medications known to affect bone metabolism (including glucocorticoids, anticonvulsants, or suppressive doses of thyroxin) were excluded.

The study was approved by the Dana Farber Partners Cancer Care Internal Review Board, and all subjects gave written informed consent.

Protocol

The study subjects were recruited from the control group of men participating in a randomized controlled trial of pamidronate for the prevention of GnRH agonist-induced bone loss. All men were admitted to the General Clinical Research Center at the Massachusetts General Hospital, for 24-h periods, before treatment with leuprolide acetate (Lupron Depot, TAP Pharmaceuticals, Inc., Deerfield, IL) at a dose of 22.5 mg im every 3 months, and after 6 months of leuprolide therapy. During each admission, subjects received a 24-h iv infusion of hPTH-(1–34) (Bachem Inc., Torrance, CA) at a dose of 0.55 U/kg·h. Whole-blood ionic calcium levels were measured every 6 h during the infusion, and infusions were discontinued if the ionized calcium exceeded 1.50 mmol/L. Serum 1,25-dihydroxyvitamin D, osteocalcin (OC), bone- specific alkaline phosphatase (BSAP), and N-telopeptide (NTX) were also measured every 6 h during the PTH infusion. Urinary NTX- and deoxypyridinoline (DPD)-to-creatinine ratios were measured on spot baseline samples collected immediately before the PTH infusion and on 24-h samples collected during the hPTH infusion. To confirm gonadal suppression, serum testosterone and estradiol levels were measured before leuprolide therapy and at the 6-month visit.

Measurements

Serum 1,25-dihydroxyvitamin D was measured using a radioreceptor assay (Nichols Institute Diagnostics, San Juan Capistrano, CA) with a sensitivity of 5 pg/mL and intra- and interassay coefficients of variation of 11% and 16%, respectively. Serum 25-hydroxyvitamin D was measured using a double-antibody RIA (DiaSorin, Inc., Stillwater, MN) with a sensitivity of 1.5 ng/mL and intra- and interassay coefficients of variation of 9–13% and 8–11%, respectively. Whole-blood ionized calcium was measured in lithium heparin syringes using a NOVA calcium electrode. Serum testosterone was measured by RIA using a commercial kit (Diagnostic Products, Los Angeles, CA) with an intraassay coefficient of variation of approximately 5% for values within the normal range and 18% for values in the castrate range, and an interassay coefficient of variation of 7–12%. Serum estradiol was measured using an RIA (Nichols Institute Diagnostics) with a sensitivity of 3 pg/mL and intra- and interassay coefficients of variation of 10% and 14%, respectively.

Serum OC was measured using a double-antibody immunoradiometric assay (Nichols Institute Diagnostics) with a sensitivity of 0.5 ng/mL and intra- and interassay coefficients of variation of 2–4% and 3–6%, respectively. Serum BSAP was measured using an enzyme-linked immunoassay (Metra Biosystems, Mountain View, CA) with a sensitivity of 1.1 nmol/L and intra- and interassay coefficients of variation of 3–4% and 4–7%, respectively. Serum NTX was measured using a competitive inhibition enzyme immunoassay (Osteomark, Ostex International, Inc., Seattle, WA) with a sensitivity of 1 nmol/L bone collagen equivalents (BCE) and intra- and interassay coefficients of variation of 6% and 9%, respectively. Urinary NTX was measured using a competitive inhibition enzyme immunoassay (Osteomark, Ostex International, Inc.) with a range of 1–300 nmol/L BCE and intra- and interassay coefficients of variation of 5–9% and 10–12%, respectively. Urinary DPD was measured using a competitive enzyme-linked immunoassay (Metra Biosystems) with a range of 3–300 nmol/L BCE and intra- and the interassay coefficients of variation of 5–9% and 4–8%, respectively. All samples for serum 1,25-dihydroxyvitamin D, OC, BSAP, and NTX, and urinary NTX and DPD for a given individual were analyzed in the same assay.

Lean body mass was measured by dual-energy x-ray absorptiometry using a QDR 4500 (Hologic, Inc., Waltham, MA).

Statistical analyses

Baseline hormone levels, urinary creatinine, and bone turnover markers before and after leuprolide treatment were compared using paired t tests.

Changes in serum markers of bone turnover, 1,25-dihydroxyvitamin D, and whole-blood ionic calcium levels in response to PTH infusion before and after GnRH analog-induced hypogonadism were compared using a mixed-effects model (analysis of covariance). This model estimates a separate slope and intercept for each patient and compares the slopes before and after GnRH agonist therapy. Because the PTH infusions were stopped after 18 h in 4 of the 11 subjects (whose ionic calcium level exceeded 1.50 mmol/L), the 24-h time point was excluded from the analysis of the serum data of all subjects.

The changes in urine markers of bone turnover in response to PTH infusion were compared by analysis of covariance using baseline levels of each marker as a covariate to control for changes caused by GnRH agonist therapy alone before PTH infusion. This model compares the slope of the relationship between the baseline and 24-h urine samples in all 11 subjects before and after GnRH analog-induced hypogonadism.

Data shown in figures are expressed as the mean ± SEM. All P values are two-sided, and P values of less than 0.05 are considered statistically significant.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Table 1Go shows the mean whole-blood ionic calcium, urine creatinine, serum PTH, 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D, testosterone, and estradiol levels determined just before the 0- and 6-month iv PTH infusions. The baseline clinical characteristics are also shown. As expected, serum testosterone and estradiol levels fell into the castrate range after 6 months of leuprolide therapy. Serum PTH, 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D levels, whole-blood ionized calcium levels, and urinary creatinine excretion did not change significantly after 6 months of leuprolide therapy. Additionally, there was no significant difference in the subject’s mean weight or lean body mass before vs. after 6 months of GnRH analog therapy (79 ± 11 vs. 79 ± 13 kg, P = 0.71 for weight; 55 ± 7 kg vs. 54 ± 8 kg, P = 0.06 for lean body mass).


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  		Table 1. Clinical characteristics before and after GnRH agonist therapy

 
Baseline serum markers of bone formation (drawn before PTH infusion) did not significantly change after 6 months of leuprolide therapy, though there was a trend toward an increase in serum OC levels (P = 0.11) (Table 2Go). Markers of bone resorption drawn before PTH infusion (serum NTX, urine NTX/creatinine, and urine DPD/creatinine) increased significantly after 6 months of GnRH agonist-induced hypogonadism (Table 2Go).


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  		Table 2. Baseline biochemical markers of bone turnover

 
Figure 1Go shows the response of serum bone formation markers to PTH infusion. Before GnRH agonist therapy, serum OC levels decreased during PTH infusion (P < 0.001). The rate of decrease, however, did not differ before or after leuprolide therapy (P = 0.45). Similarly, serum BSAP levels decreased during PTH infusion before GnRH agonist administration (P = 0.002), but the rate of decrease did not differ before or after leuprolide therapy (P = 0.19).



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  		Figure 1. Mean ± SE serum OC and BSAP levels during hPTH-(1–34) infusion before (circles) and 6 months after (squares) GnRH agonist-induced gonadal steroid suppression. P values refer to the difference in rates of change before and after GnRH agonist administration. NS, Not significant.

 
Serum NTX levels increased significantly during PTH infusion before GnRH agonist therapy (P < 0.001) (Fig. 2Go). Moreover, the rate of increase of serum NTX during PTH infusion was greater after 6 months of GnRH agonist- induced hypogonadism (P < 0.01). Similarly, whole-blood ionized calcium concentrations increased during PTH infusion (P < 0.001), and the rate of increase seemed to be greater after GnRH agonist-induced hypogonadism, though this change did not reach statistical significance (P = 0.068) (Fig. 3Go). Serum 1,25-dihydroxyvitamin D levels increased in response to PTH infusion preleuprolide therapy (P = 0.022), but there was no difference in the rate of increase before or after leuprolide therapy (P = 0.66) (Fig. 4Go).



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  		Figure 2. Mean ± SE serum NTX levels during hPTH-(1–34) infusion before (circles) and 6 months after (squares) GnRH agonist-induced gonadal steroid suppression. The P value refers to the difference in rates of change before and after GnRH agonist administration.

 


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  		Figure 3. Mean ± SE whole-blood ionized calcium levels during hPTH-(1–34) infusion before (circles) and 6 months after (squares) GnRH agonist-induced gonadal steroid suppression. The P value refers to the difference in rates of change before and after GnRH agonist administration.

 


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  		Figure 4. Mean ± SE serum 1,25-dihydroxyvitamin D levels during hPTH-(1–34) infusion before (circles) and 6 months after (squares) GnRH agonist-induced gonadal steroid suppression. The P value refers to the difference in rates of change before and after GnRH agonist administration.

 
Figure 5Go shows the urinary NTX levels both before and after 6 months of GnRH agonist-induced hypogonadism. The incremental increase in urinary NTX excretion during PTH infusion was greater after 6 months of hypogonadism, even after correcting for the increase in baseline urinary NTX excretion that occurs with GnRH analog therapy alone (P = 0.029). Twenty-four-hour urinary DPD excretion, measured during PTH infusion, was not greater than the baseline spot sample drawn immediately before PTH infusion, either before or after GnRH agonist therapy. Before GnRH agonist therapy, spot urinary DPD excretion was 4.7 + 1.1 (nmol BCE/mmol Cr), and 24-h excretion during PTH infusion was 4.5 + 0.7 (nmol BCE/mmol Cr). After GnRH agonist therapy, spot urinary DPD excretion was 7.4 + 1.8 (nmol BCE/mmol Cr), and 24-h excretion during PTH infusion was 6.1 + 1.1 (nmol BCE/mmol Cr). There was no difference in PTH-induced changes in excretion of DPD before vs. after GnRH agonist-induced hypogonadism (P = 0.576).



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  		Figure 5. Mean ± SE urinary NTX excretion, measured just before PTH infusion (black bars) and during 24-h hPTH-(1–34) infusion (gray bars) before and after 6 months of GnRH agonist administration. The P value refers to the incremental increase in urinary NTX excretion during PTH infusion before vs. after 6 months of GnRH agonist-induced hypogonadism.

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
In this study, we found that sex steroid deprivation increases skeletal sensitivity to the bone resorbing properties of PTH in elderly male subjects with prostate cancer. Hypogonadism is associated with osteoporosis in men, and testosterone replacement increases bone mass in hypogonadal men (18, 19, 20). Although acute hypogonadism is generally associated with increased bone turnover, bone turnover may be normal or reduced in men with long-standing hypogonadism (21). Specifically, the use of GnRH analogs in both men and women has been associated with high turnover bone loss (1, 4, 5, 22, 23). Previous studies in women have also explored the role of sex steroids in altering the skeletal responsiveness to PTH. PTH-stimulated hydroxyproline excretion is greater in postmenopausal women, compared with premenopausal women (12). Similarly, urinary bone turnover markers increase more in response to PTH in postmenopausal osteoporotic women, compared with postmenopausal osteoporotic women receiving oral or transdermal estrogen replacement (11). In contrast, in young women with endometriosis, whole-blood ionic calcium increases similarly in response to PTH infusion before vs. after GnRH analog therapy (15). Because biochemical markers of bone turnover were not measured in this study, however, differences in the skeletal sensitivity to PTH in women treated with a GnRH agonist may have been missed. Taken together, it seems that sex steroids may be protective against the bone resorbing properties of PTH in both sexes, though the underlying cellular mechanisms remain unknown.

There are several possible mechanisms that could explain how sex steroid deprivation increases the skeletal sensitivity to bone resorbing properties of PTH in men. The differential effect of acute PTH infusion on hypogonadal and eugonadal men observed in this study could be explained by either an increase in the sensitivity of the individual osteoclasts to PTH in the sex-steroid-deprived state or by a simple increase in osteoclast number, or both. An increase in osteoclast number could, in turn, be caused by either an increase in the rate of osteoclastogenesis or by a reduction in the rate of osteoclast apoptosis.

Many recent studies exploring the cellular mechanisms of osteoclastogenesis and osteoclast activity have focused on the effects of locally produced bone resorbing cytokines. Androgen deprivation increases osteoclastogenesis in animals via a mechanism involving IL-6, a potent mediator of osteoclastogenesis and bone resorption (24). IL-6 may also be a key mediator of PTH’s effects on bone resorption. IL-6 is produced by osteoblast-like cells in vitro in response to PTH (25, 26, 27). PTH infusion also increases IL-6 in vivo, and these increases correlate with corresponding increases in bone turnover markers (28). Moreover, neutralizing antibodies to IL-6 block the effect of PTH on bone turnover (28). It has recently been reported that estrogen withdrawal augments PTH-induced IL-6 production in osteosarcoma cell lines and that ovariectomized mice demonstrated an exaggerated increase in IL-6 after PTH administration (29). Because our subjects were both androgen and estrogen deficient, it is possible that the increases in skeletal sensitivity to PTH were mediated, at least in part, by the estrogen deprivation. Taken together, these findings suggest that locally produced bone resorbing cytokines may mediate the effects of acute PTH administration on bone and that gonadal steroids may modify these responses.

The effects of gonadal steroids on the expression of NF-kappaB ligand (RANKL) and osteoprotegerin (OPG) may also mediate changes in skeletal sensitivity to PTH. RANKL increases both osteoclast differentiation and activation and decreases osteoclast apoptosis, whereas OPG inhibits these effects (30). PTH increases RANKL messenger RNA expression and inhibits OPG expression (31). The effect of androgens on RANKL and OPG is presently unknown, but estrogens stimulate OPG gene expression in osteoblasts (32). Thus, both PTH and sex steroid deprivation may increase bone resorption through common mechanisms; and, in the setting of sex steroid deprivation, the effects of PTH may be amplified.

We also found that PTH infusion decreases biochemical markers of bone formation, but there was no difference in this effect after GnRH agonist-induced hypogonadism. The acute effect of PTH infusion to decrease markers of bone formation in men is similar to its acute effects in women (12, 33) and contrasts with the effect of long-term daily intermittent PTH administration to increase biochemical markers of bone formation (34). Because there was no differential effect on either OC or BSAP in the subjects before or after GnRH analog-induced hypogonadism, it is difficult to interpret the physiologic significance, if any, of this reduction in men.

Whereas PTH increased serum NTX levels and urinary NTX excretion, urinary DPD levels were not greater in the 24-h samples during PTH infusion vs. the spot urine samples at either time point. Additionally, there was no effect of GnRH agonist-induced hypogonadism on the urinary DPD response to PTH. It is not clear why these markers show discordant results. Interestingly, a recent study in women, comparing skeletal sensitivity to PTH in postmenopausal women receiving placebo, tamoxifen, raloxifene, or conjugated estrogens, showed differential responses in NTX but not pyridinoline (35).

Sex steroid deprivation had no effect on the ability of the kidney to increase 1,25-dihydroxyvitamin D formation in response to PTH. Previous studies of the effect of sex steroids on PTH-induced 1,25-hydroxyvitamin D formation performed in women have produced conflicting results (14, 16, 17). In the only study that compared eugonadal women before and after the induction of hypogonadism, sex steroid deprivation did not alter the ability of PTH to increase 1,25-dihydroxyvitamin D formation (15). Taken together, it seems that the effects of sex steroid deprivation on PTH-induced promotion of 1,25-vitamin D formation are unlikely to play an important role in acute hypogonadal bone loss in men or women.

Certain limitations of our study deserve mention. Because our study involved the exogenous administration of PTH in pharmacological doses, the physiologic significance of this model is unknown. It is possible that the hypogonadism-induced increased sensitivity of the skeleton to PTH is, under physiologic conditions, counteracted by a reduction in PTH levels, though a reduction in PTH was not observed in our subjects after 6 months of hypogonadism. Additionally, because the study size was relatively small, there may have been subtle differences in the bone formation marker response to PTH or the 1,25-dihydroxyvityamin D response to PTH that escaped detection. Finally, total 1,25-dihydroxy-vitamin D levels are dependent on levels of vitamin D binding protein (DBP), and DBP may be influenced by sex steroid levels. It has previously been demonstrated, however, that, in men with prostate cancer, castration has no effect on DBP levels (36). Thus, it is unlikely that the total serum1,25- dihydroxyvitamin D levels in our study were affected by GnRH agonist-induced hypogonadism.

We conclude that suppression of sex steroids in elderly men increases the skeletal responsiveness to the bone resorbing effects of PTH infusion but does not affect the response of bone formation markers or 1,25-dihydroxyvitamin D to PTH. These findings may have significance in explaining the mechanism of hypogonadal bone loss in men. Additional studies are needed to assess the cellular and paracrine- mediated mechanisms that may underlie these observations.


   Acknowledgments
 
We thank Dr. Robert Neer for his invaluable comments and suggestions, Dr. David Schoenfeld for his aid in the statistical analyses, and the nurses and staff of the Mallinckrodt General Clinical Research Center for the care of the study volunteers.


   Footnotes
 
1 Supported by NIH Grant RR-1066; NIH Grant K24-DK-02759 (to J.S.F.); a Doris Duke Charitable Foundation Clinical Scientist Award, NIH Clinical Associate Physician Award (5M01-RR-1066–20), and CaPCURE (to M.R.S.); and an NIH National Research Service Award (1-F32-AR08574–01; to B.Z.L.). Back

Received July 18, 2000.

Revised October 13, 2000.

Accepted October 16, 2000.


   References
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 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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