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Parathyroid Responsivity in Postmenopausal Women with Osteoporosis During Treatment with Parathyroid Hormone¹

Clinical Research and Regional Bone Centers (F.C., J.N., L.W., S.G., V.S., R.L.), Helen Hayes Hospital, West Haverstraw, New York 10993; Department of Medicine (F.C., R.L.), Department of Epidemiology (J.N.), Department of Pathology (V.S.), Columbia University, New York, New York 10032

Address correspondence and requests for reprints to: Dr. Felicia Cosman, Regional Bone Center, West Haverstraw, New York 10993.

	Abstract

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Endocrine systems may be affected permanently by administration of supraphysiologic doses of hormone. This is a well known complication of glucocorticoid treatment where the pituitary/adrenal axis may never fully recover, especially when large doses of steroids are needed during significant physical stress. The goal of this investigation was to determine whether responsivity of the parathyroid gland was normal after use of (1–34)PTH daily as an investigational therapy for osteoporosis. Patients were all postmenopausal osteoporotic women treated with estrogen and enrolled in a 3-yr trial of (1–34)PTH by daily subcutaneous injection (400 IU/day) in addition to their estrogen therapy. A volunteer subgroup (n = 10) of this population was recruited for this investigation. All patients had an EDTA-provoked hypocalcemic challenge before beginning PTH treatment. The same patients had repeat EDTA-challenge tests at various times during the 3-yr PTH treatment trial. Three patients had 2 infusions while on PTH treatment (interim and at the end of 3 yr). Ionized calcium declined identically before and during PTH treatment in response to the EDTA stimulus. PTH(1–84) responses were identical before and during PTH therapy. Furthermore, there were no differences in 1,25(OH)₂D elevation or in phosphorus reduction over the course of the EDTA infusion during daily PTH treatment. Osteocalcin levels were higher during PTH treatment, as expected, but responsivity to acute endogenous PTH elevations was the same after PTH treatment. We conclude that 1–34PTH therapy, at 400 IU/day for up to 3 yr, does not suppress parathyroid responsivity and should therefore (at least within this period of treatment) have no permanent adverse effect on the ability of the body to maintain calcium homeostasis. Additionally, there is no difference in target organ responsivity to acute endogenous elevations of PTH after exogenous PTH therapy.

	Introduction

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DATA FROM as early as the 1970s in human studies and even earlier from animal studies have shown that PTH is anabolic to the skeleton (1). Our group is now in final phase of completion of an investigation on the ability of h(1–34)PTH to increase bone mass in postmenopausal osteoporotic women already treated with a standard hormone replacement therapy (HRT) regimen (2). One theoretical problem concerning the use of a supraphysiologic dose of a hormone for treatment of any disorder is that it might suppress endogenous production of the hormone. This has been demonstrated with endocrine systems such as the pituitary/adrenal axis, where it is thought that administration of supraphysiologic glucocorticoid dose for even as short a period as 2–4 weeks might cause suppression of the body’s ability to produce stress doses of glucocorticoid for up to 1 yr (3). For h(1–34)PTH to be considered as a valid therapeutic option for osteoporosis, it should not cause significant suppression of endogenous parathyroid function, an outcome that could adversely affect calcium homeostasis.

To determine whether daily subcutaneous administration of h(1–34)PTH for up to 3 yr might be associated with suppression of parathyroid hormone production, we studied the parathyroid response to EDTA-induced hypocalcemia before and during h(1–34)PTH treatment in postmenopausal osteoporotic women (also treated with HRT). Because basal levels of hormone do not provide adequate information about reserve physiologic endocrine function (3, 4), the EDTA dynamic test was utilized to increase the demand for maximal endogenous PTH production.

	Methods

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Subjects

All subjects were osteoporotic women recruited from our ongoing clinical trial evaluating the effects of daily subcutaneous h(1–34)PTH administration in estrogenized women, in comparison with estrogen alone, on bone mass and bone turnover (2). Details of the patient selection process and PTH treatment protocol have been published previously (2). Briefly, all subjects were postmenopausal, had osteoporosis by criteria of the World Health Organization, and had been on HRT for at least 1 yr. All patients had total calcium intakes of at least 1000 mg/day, either through diet or diet plus calcium supplements.

After assuring that bone mass was stable over at least 1 yr of prospective evaluation, patients (n = 50) were randomly assigned to stay on HRT alone or to receive h(1–34)PTH 400 IU/day in addition to HRT. Ten subjects assigned to the PTH plus HRT arm of the protocol agreed to volunteer for this study. A description of the patients is shown in Table 1.

EDTA infusions

All subjects continued their mineral supplements and PTH injections on the day before the study. On the day of the study, however, no supplements or injections were given that morning. Patients presented to the Clinical Research Center at 0800 hr, after an overnight fast. The EDTA infusions were performed as previously described (5). Two intravenous catheters were inserted in opposite arms: one for phlebotomy and one for EDTA infusion. After two basal blood samples were obtained over a 20-min period, sodium EDTA (50 mg/kg body weight in 500 cc 5% dextrose solution with 7 mL 2% lidocaine) was infused over a 2-h period at 250 mL/hour. Blood was sampled at 30, 60, 90, 120, 180, 240, and 300 min, and at 24 h after starting the infusion. Patients ate a light breakfast and lunch during the study.

Biochemistry:

Serum was analyzed for ionized calcium (Ca) and total phosphorus (by standard techniques), PTH1–84 (by immunoradiometric assay, Allegro Intact PTH, Nichols Institute, San Juan Capistrano, Ca), 1,25-dihydroxyvitamin D (by radioreceptor assay), and osteocalcin (by immunoradioreceptor assay, human osteocalcin, Nichols Institute, Ca). All intraassay coefficients of variation were less than 8% and all interassay coefficients of variation were less than 10%, as published previously (5, 6).

Analysis

During-treatment results of EDTA infusion were pooled and an analysis of variance was performed using duration of PTH treatment as a covariate. As duration of treatment was not found to be a significant influence on parathyroid response, the remainder of the analysis was performed with the during-treatment results pooled. For the three patients who had two during-drug infusions, only the second (3-yr) infusion results were used for this pooled analysis. Changes in biochemical indices over time and group differences in biochemistry before and during treatment (0.5–3 yr) were evaluated by repeated measures analysis of variance and contrast transformation for time/group effects and time/group interactions.

	Results

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This cohort of patients (Table 1) was representative of the total volunteer sample in our clinical trial of PTH treatment (2). All biochemical indices were the same at baseline in patients pre-PTH treatment and post-PTH treatment with the exception of osteocalcin. Sustained increments in biochemical indices of bone formation during PTH treatment have been shown previously (2).

The expected decline in mean serum ionized calicum during EDTA infusion was very similar before and during PTH treatment, with the nadir at the end of the infusion and a return to baseline within 24 h. Mean levels of (1–84)PTH (Fig. 1A) increased during EDTA infusion and remained elevated after the infusion was discontinued. There was no difference in the parathyroid response as a result of h(1–34)PTH treatment. Levels of PTH were still significantly higher than baseline 24 h after the start of EDTA infusion, both before and during h(1–34)PTH treatment (P < 0.02).

View larger version (23K): [in this window] [in a new window]   Figure 1. Changes in biochemical homeostasis variables during infusion of sodium EDTA (50 mg/kg over 2 hr) in estrogenized postmenopausal women before PTH treatment and during daily subcutaneous h(1–34)PTH treatment (400IU/day) • for 6–36 months. *, significant time trend, all P < 0.005.

Figure 2 shows a representative individual subject’s calcium and PTH responses in one of the 3 patients who had EDTA infusions before treatment, during treatment (6 or 12 months), and then after 3 yr of treatment. There were both interindividual and intraindividual variabilities in the PTH response to hypocalcemic challenge. There was, however, no indication of any lessening of parathyroid response as a result of daily h(1–34)PTH administration.

View larger version (17K): [in this window] [in a new window]   Figure 2. Ionized calcium and PTH responses to EDTA infusion in one representive postmenopausal estrogenized woman before h(1–34)PTH treatment , at 12 months during treatment •, and after 3 yr of treatment .

	Discussion

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Our study also shows that there does not appear to be any lessening of the effect of acute endogenous elevations of PTH on target organs such as renal 1,25(OH)₂D production or renal phosphorus handling after daily PTH treatment. Theoretically this might have been expected based on downregulation of receptors in association with high exogenous PTH levels. Again, this might have been mitigated by the kinetics of the PTH response (7), with rapid return of PTH levels to baseline after the injection.

This study indicates that the theoretical possibility of suppressed endogenous parathyroid function after daily subcutaneous hPTH administration for up to 3 yr does not occur. This finding provides further important information about the safety of this compound in relatively long-term trials and adds to the body of literature indicating the potential usefulness of h(1–34)PTH in treatment of osteoporosis.

	Footnotes

 
¹ This work was supported in part by NIH Grants AR-39191 and DK-46381.

Received August 7, 1997.

Revised November 5, 1997.

Revised November 21, 1997.

Accepted November 25, 1997.

	References

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1. Dempster DW, Cosman F, Parisien M, Shen V, Lindsay R. 1993 Anabolic actions of parathyroid hormone on bone. Endocr Rev. 14:690–709.[CrossRef][Medline]
2. Lindsay R, Nieves JW, Formica C, et al. 1997 Parathyroid hormone increases vertebral bone mass and may reduce vertebral fracture incidence in estrogen treated postmenopausal women with osteoporosis. Lancet. 350:550–555.[CrossRef][Medline]
3. Axelrod L. 1995 Corticosteroid Therapy. In: Becker KL, ed. Principals and Practice of Endocrinology and Metabolism, Second Edition, Philadelphia: J.B. Lippincott Company. pp. 695–706.
4. Graber AL, Ney R, Nicholson WE, et al. 1965 Natural history of pituitary-adrenal recovery following long-term suppression with corticosteroids. J Clin Endocrinol Metab. 25:11.
5. Cosman F, Nieves J, Horton J, Shen V, Lindsay R. 1994 Effects of estrogen on response to EDTA infusion in postmenopausal osteoporotic women. J Clin Endocrinol Metab. 78:939–943.[Abstract]
6. Cosman F, Morgan DC, Nieves JW, et al. 1997 Resistance to bone resorbing effects of PTH in black women. J Bone Miner Res. 12:958–966.[CrossRef][Medline]
7. Lindsay R, Nieves J, Henneman E, Shen V, Cosman F. 1993 Subcutaneous administration of the amino terminal fragment of human parathyroid hormone (1–34hPTH): kinetics and biochemical response in estrogenized osteoporotic patients. J Clin Endocrinol Metab. 77:1535–1539.[Abstract]
8. Doherty GM, Norton JA, Wells SA. 1995 Surgery of the Parathyroid Glands. In: Becker KL, ed. Principals and Practice of Endocrinology and Metabolism, Second Edition. Philadelphia: J.B. Lippincott Company. pp.554–566.

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