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Bone turnover in young hypoestrogenic women on hormonal therapy
European Journal of Obstetrics & Gynecology and Reproductive Biology 124 (2006) 204–206 www.elsevier.com/locate/ejogrb
Bone turnover in young hypoestrogenic women on hormonal therapy Carina C.W. Chan *, Oi-Shan Tang, Winnie N.T. Lau, Grace W.K. Tang Department of Obstetrics & Gynaecology, Queen Mary Hospital, The University of Hong Kong, 102 Pokfulam Road, Hong Kong SAR, China Received 24 January 2005; received in revised form 2 July 2005; accepted 15 July 2005
Abstract Objective: To compare the biochemical markers of bone turnover in hypoestrogenic women who had been on the standard dosage of Premarin1 0.625 mg to that of the age-matched women who were menstruating spontaneously. Study design: Chinese women between 25 and 40 years of age with a diagnosis of hypoestrogenism who had been on Premarin1 0.625 mg daily for more than 1 year were recruited. The control group comprised age- and parity-matched women who had proven ovulation by midcycle serum luiteinising hormone surge. Serum osteocalcin and serum pyridinoline crosslink, markers of bone formation and resorption, respectively, were measured by enzyme-linked immunosorbent assays. Results: Twenty hypoestrogenic Chinese patients with a mean age of 36.2 were recruited as the study group. The same number of controls was recruited. There were no smokers in either group. The body weight, body height and body mass indices were comparable between the two groups. Both biochemical markers of bone metabolism did not differ between the two groups. Conclusion: The average bone turn-over rate in young hypoestrogenic Chinese women on Premarin1 0.625 mg/day was similar to that of normal menstruating women. # 2005 Elsevier Ireland Ltd. All rights reserved. Keywords: Biochemical markers; Bone turnover; Hormonal therapy; Hypoestrogenism; Young women
1. Introduction In young women [1–5] including Chinese [6] who are hypoestrogenic from any cause, the bone mineral density (BMD) is reduced when compared to normal young women and the levels of circulating bone turnover markers are increased [2–4,6–8]. Treatment with conjugated equine estrogens (CEE) 0.625 mg/day, widely used for at least 20 years [9], has been shown in several studies to result in an increase of BMD in mainly indogermanic populations [2– 4,8]. A reduction to nearly normal levels of a bone resorption marker (N-terminal telopeptide of collagen type 1) [8] and of the bone formation marker osteocalcin [10] has been described for indogermanic and Japanese populations [11]. Genetic [12] and ethnic [13,14] factors affect BMD and bone turnover markers. Hence, confirmation of findings in one ethnicity warrants confirmation in others. We present * Corresponding author. Tel.: +852 28553400; fax: +852 28175374. E-mail address: [email protected] (Carina C.W. Chan).
here information on serum pyridinoline crosslink levels, a bone resorption marker [15] and on osteocalcin, a bone formation marker [15], in hypoestrogenic, Chinese women on Premarin1, 0.625 mg CEE/day for at least 1 year.
2. Materials and methods Chinese women who were between 25 and 40 years of age with a diagnosis of hypoestrogenism and had been on Premarin1 0.625 mg daily for more than 1 year were recruited (CEE group). The control group comprised ageand parity-matched women who were seen at the gynaecology clinic for other gynaecological complaints, and with regular monthly menstrual cycles and proven ovulation by mid-cycle LH surge. All subjects were asked to keep fasted overnight. A blood sample was taken in the next morning. Serum samples were spun down immediately, divided in several aliquots, and stored at 20 8C until analyzed in a single batch. Serum osteocalcin, a marker of bone formation, was measured by enzyme-linked
0301-2115/$ – see front matter # 2005 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ejogrb.2005.07.010
C.C.W. Chan et al. / European Journal of Obstetrics & Gynecology and Reproductive Biology 124 (2006) 204–206
205
Fig. 1. The scatter plot of serum osteocalcin in the two groups.
Fig. 2. The scatter plot of serum PYD in the two groups.
immunosorbent assay (ELISA) method using commercial kits (Metra Osteocalcin, Quidel Corporation, CA, USA). The intra-assay coefficient of variation was 4.8–10.0%, and the inter-assay coefficient of variation was 4.8–9.8%. The monoclonal antiosteocalcin antibody employed in this kit is believed to be conformationally dependent and should therefore only recognize intact osteocalcin and not fragments from resorbed bone tissue. Serum pyridinoline crosslink (PYD), a marker for bone resorption, was determined by commercial ELISA kits (Metra serum PYD, Quidel Corporation, CA, USA). The intra-assay coefficient of variation was 6.3–14.8%, and the inter-assay coefficient of variation was 8.7–11.6%. Results of serum osteocalcin and serum PYD were reported as median (95% CI) and were compared using Mann–Whitney U test. Correlation between the two markers of bone metabolism was performed using Spearman’s correlation. A p value of <0.05 was considered as significant.
dysgenesis, three hypothalamic hypogonadism, one surgical menopause and one post-irradiation ovarian failure. The mean (S.D.) duration of hormonal replacement was 12.0 6.3 years (median 11.5, 95% CI 9.0–15.0). None of patients in either group were smokers. The body weight, body height and body mass indices were comparable between the two groups (Table 1). Both biochemical markers of bone metabolism did not differ between the two groups (Table 1). The scatter plots of serum osteocalcin and serum PYD are shown in Figs. 1 and 2, respectively. There was no correlation between the serum osteocalcin and serum PYD (Spearman’s r = 0.035, p > 0.05). Linear regression analysis did not show any effect of age, BMI, parity and duration of hormone use on osteocalcin nor serum PYD.
3. Results Twenty hypoestrogenic Chinese patients who were being treated with Premarin1 0.625 mg were recruited. The same number of controls was recruited. The mean (S.D.) age was 36.2 3.4 years. All patients were nulliparous with the exception of one patient who had two children. The diagnoses were: 10 premature ovarian failures, six gonadal
4. Comment Both the bone formation and the bone resorption markers in hypoestrogenic Chinese women on CEE were similar to levels in normal women, as seen in women of other ethnicities [8,10,11]. Lifelong hormonal replacement therapy (HRT) in young hypoestrogenic women is mainly instituted for the prevention of osteoporosis. HRT has been shown to carry a likely dose-dependent risk for serious collateral effects, as seen in the WHI [16] and the Million Women studies [17]. Treatment should therefore be determined by the dose with the best benefit/
Table 1 Comparison between the CEE and control groups Body weight (kg) (mean S.D.) Body height (m) (mean S.D.) BMI (kg/m2) (mean S.D.) Osteocalcin (nmol/L) (median, 95% CI) Serum PYD (nmol/L) (median, 95% CI)
CEE group (n = 20)
Control group (n = 20)
p value
55.5 12.9 1.56 0.11 22.6 4.34 1.70, 1.43–2.06 3.26, 2.81–4.24
56.8 8.2 1.59 0.05 22.60 2.99 1.70, 1.28–1.94 3.25, 2.66–3.76
0.849 0.306 0.658 0.602 0.391
206
C.C.W. Chan et al. / European Journal of Obstetrics & Gynecology and Reproductive Biology 124 (2006) 204–206
risk ratio. The dose used here shows maximal efficacy, as judged by the lack of greater effect of high dose HRT on bone turnover markers compared to standard dose HRT [18]. It is likely in the efficacy plateau range of the doseresponse curve and may thus be higher than needed for optimal bone metabolism regulation. This is especially true for Chinese women who, on average, have a lesser build than indogermanic populations. Even for these, studies in postmenopausal women [19–21] show bone protective efficacy at lower doses. The concern of potentially dose-dependent, serious collateral effects of HRT raised by the WHI and the Million Women studies point to the need for dose finding studies in different ethnicities.
References [1] Sourander L, Rajala T, Raiha I, Makinen J, Erkkola R, Helenius H. Cardiovascular and cancer morbidity and mortality and sudden cardiac death in postmenopausal women on oestrogen replacement therapy (ERT). Lancet 1998;352:1965–9. [2] Kinoshita T, Yasumizu T, Kato J. Decreased bone mineral density in premenopausal women with amenorrhea. Nippon Sanka Fujinka Gakkai Zasshi 1996;48:793–8. [3] Metka M, Holzer G, Heytmanek G, Huber J. Hypergonadotropic hypogonadic amenorrhea (World Health Organization III) and osteoporosis. Fertil Steril 1992;57:37–41. [4] Soong YK, Hsu JJ, Tzen KY. Measurement of bone mineral density in amenorrheic women with dual photon absorptiometry. Taiwan Yi Xue Hui Za Zhi 1989;88:1097–103. [5] Cann CE, Martin MC, Genant HK, Jaffe RB. Decreased spinal mineral content in amenorrheic women. JAMA 1984;251:626–9. [6] Yu Q, Lin S, He F. The profile of low bone mass in amenorrhea with elevated follicle stimulating hormone. Zhonghua Fu Chan Ke Za Zhi 1999;34:78–81. [7] Amama EA, Taga M, Minaguchi H. The effect of gonadotropinreleasing hormone agonist on type I collagen C-telopeptide and Ntelopeptide: the predictive value of biochemical markers of bone turnover. J Clin Endocrinol Metab 1998;83:333–8. [8] Prior JC, Vigna YM, Wark JD, et al. Premenopausal ovariectomyrelated bone loss: a randomized, double-blind, one-year trial of conjugated estrogen or medroxyprogesterone acetate. J Bone Miner Res 1997;12:1851–63.
[9] Lindsay R, Hart DM, Clark DM. The minimum effective dose of estrogen for prevention of postmenopausal bone loss. Obstet Gynecol 1984;63:759–63. [10] Stepan JJ, Presl J, Broulik P, Pacovsky V. Serum osteocalcin levels and bone alkaline phosphatase isoenzyme after oophorectomy and in primary hyperparathyroidism. J Clin Endocrinol Metab 1987;64: 1079–82. [11] Honjo S, Mizunuma H, Soda M, Igarashi M. Effect of estrogen replacement therapy on the serum osteocalcin level in the postmenopausal and castrated women. Nippon Sanka Fujinka Gakkai Zasshi 1989;41:1571–6. [12] Garnero P, Arden NK, Griffiths G, Delmas PD, Spector TD. Genetic influence on bone turnover in postmenopausal twins. J Clin Endocrinol Metab 1996;81:140–6. [13] Meier DE, Luckey MM, Wallenstein S, Lapinski RH, Catherwood B. Racial differences in pre- and postmenopausal bone homeostasis: association with bone density. J Bone Miner Res 1992;7:1181–9. [14] Parfitt AM, Han ZH, Palnitkar S, Rao DS, Shih MS, Nelson D. Effects of ethnicity and age or menopause on osteoblast function, bone mineralization, and osteoid accumulation in iliac bone. J Bone Miner Res 1997;12:1864–73. [15] Garnero P, Delmas PD. Biochemical markers of bone turnover. Applications for osteoporosis. Endocrinol Metab Clin North Am 1998;27:303–23. [16] Rossouw JE, Anderson GL, Prentice RL, et al. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women’s Health Initiative randomized controlled trial. Writing Group for the Women’s Health Initiative Investigators. JAMA 2002;288:321–33. [17] Million Women Study Collaborators. Breast cancer and hormonereplacement therapy in the Million Women Study. Lancet 2003;362: 419–27. [18] Arrenbrecht S, Boermans AJ. Effects of transdermal oestradiol delivered by a matrix patch on bone density in hysterectomized, postmenopausal women: a 2-year placebo-controlled trial. Osteoporos Int 2002;13:176–83. [19] Genant HK, Lucas J, Weiss S, et al. Low-dose esterified estrogen therapy: effects on bone, plasma estradiol concentrations, endometrium, and lipid levels. Estratab/Osteoporosis Study Group. Arch Intern Med 1997;157:2609–15. [20] Recker RR, Davies KM, Dowd RM, Heaney RP. The effect of lowdose continuous estrogen and progesterone therapy with calcium and vitamin D on bone in elderly women: a randomized, controlled trial. Ann Intern Med 1999;130:897–904. [21] Lindsay R, Gallagher JC, Kleerekoper M, Pickar JH. Effect of lower doses of conjugated equine estrogens with and without medroxyprogesterone acetate on bone in early postmenopausal women. JAMA 2002;287:2668–76.
Bone turnover in young hypoestrogenic women on hormonal therapy Carina C.W. Chan *, Oi-Shan Tang, Winnie N.T. Lau, Grace W.K. Tang Department of Obstetrics & Gynaecology, Queen Mary Hospital, The University of Hong Kong, 102 Pokfulam Road, Hong Kong SAR, China Received 24 January 2005; received in revised form 2 July 2005; accepted 15 July 2005
Abstract Objective: To compare the biochemical markers of bone turnover in hypoestrogenic women who had been on the standard dosage of Premarin1 0.625 mg to that of the age-matched women who were menstruating spontaneously. Study design: Chinese women between 25 and 40 years of age with a diagnosis of hypoestrogenism who had been on Premarin1 0.625 mg daily for more than 1 year were recruited. The control group comprised age- and parity-matched women who had proven ovulation by midcycle serum luiteinising hormone surge. Serum osteocalcin and serum pyridinoline crosslink, markers of bone formation and resorption, respectively, were measured by enzyme-linked immunosorbent assays. Results: Twenty hypoestrogenic Chinese patients with a mean age of 36.2 were recruited as the study group. The same number of controls was recruited. There were no smokers in either group. The body weight, body height and body mass indices were comparable between the two groups. Both biochemical markers of bone metabolism did not differ between the two groups. Conclusion: The average bone turn-over rate in young hypoestrogenic Chinese women on Premarin1 0.625 mg/day was similar to that of normal menstruating women. # 2005 Elsevier Ireland Ltd. All rights reserved. Keywords: Biochemical markers; Bone turnover; Hormonal therapy; Hypoestrogenism; Young women
1. Introduction In young women [1–5] including Chinese [6] who are hypoestrogenic from any cause, the bone mineral density (BMD) is reduced when compared to normal young women and the levels of circulating bone turnover markers are increased [2–4,6–8]. Treatment with conjugated equine estrogens (CEE) 0.625 mg/day, widely used for at least 20 years [9], has been shown in several studies to result in an increase of BMD in mainly indogermanic populations [2– 4,8]. A reduction to nearly normal levels of a bone resorption marker (N-terminal telopeptide of collagen type 1) [8] and of the bone formation marker osteocalcin [10] has been described for indogermanic and Japanese populations [11]. Genetic [12] and ethnic [13,14] factors affect BMD and bone turnover markers. Hence, confirmation of findings in one ethnicity warrants confirmation in others. We present * Corresponding author. Tel.: +852 28553400; fax: +852 28175374. E-mail address: [email protected] (Carina C.W. Chan).
here information on serum pyridinoline crosslink levels, a bone resorption marker [15] and on osteocalcin, a bone formation marker [15], in hypoestrogenic, Chinese women on Premarin1, 0.625 mg CEE/day for at least 1 year.
2. Materials and methods Chinese women who were between 25 and 40 years of age with a diagnosis of hypoestrogenism and had been on Premarin1 0.625 mg daily for more than 1 year were recruited (CEE group). The control group comprised ageand parity-matched women who were seen at the gynaecology clinic for other gynaecological complaints, and with regular monthly menstrual cycles and proven ovulation by mid-cycle LH surge. All subjects were asked to keep fasted overnight. A blood sample was taken in the next morning. Serum samples were spun down immediately, divided in several aliquots, and stored at 20 8C until analyzed in a single batch. Serum osteocalcin, a marker of bone formation, was measured by enzyme-linked
0301-2115/$ – see front matter # 2005 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ejogrb.2005.07.010
C.C.W. Chan et al. / European Journal of Obstetrics & Gynecology and Reproductive Biology 124 (2006) 204–206
205
Fig. 1. The scatter plot of serum osteocalcin in the two groups.
Fig. 2. The scatter plot of serum PYD in the two groups.
immunosorbent assay (ELISA) method using commercial kits (Metra Osteocalcin, Quidel Corporation, CA, USA). The intra-assay coefficient of variation was 4.8–10.0%, and the inter-assay coefficient of variation was 4.8–9.8%. The monoclonal antiosteocalcin antibody employed in this kit is believed to be conformationally dependent and should therefore only recognize intact osteocalcin and not fragments from resorbed bone tissue. Serum pyridinoline crosslink (PYD), a marker for bone resorption, was determined by commercial ELISA kits (Metra serum PYD, Quidel Corporation, CA, USA). The intra-assay coefficient of variation was 6.3–14.8%, and the inter-assay coefficient of variation was 8.7–11.6%. Results of serum osteocalcin and serum PYD were reported as median (95% CI) and were compared using Mann–Whitney U test. Correlation between the two markers of bone metabolism was performed using Spearman’s correlation. A p value of <0.05 was considered as significant.
dysgenesis, three hypothalamic hypogonadism, one surgical menopause and one post-irradiation ovarian failure. The mean (S.D.) duration of hormonal replacement was 12.0 6.3 years (median 11.5, 95% CI 9.0–15.0). None of patients in either group were smokers. The body weight, body height and body mass indices were comparable between the two groups (Table 1). Both biochemical markers of bone metabolism did not differ between the two groups (Table 1). The scatter plots of serum osteocalcin and serum PYD are shown in Figs. 1 and 2, respectively. There was no correlation between the serum osteocalcin and serum PYD (Spearman’s r = 0.035, p > 0.05). Linear regression analysis did not show any effect of age, BMI, parity and duration of hormone use on osteocalcin nor serum PYD.
3. Results Twenty hypoestrogenic Chinese patients who were being treated with Premarin1 0.625 mg were recruited. The same number of controls was recruited. The mean (S.D.) age was 36.2 3.4 years. All patients were nulliparous with the exception of one patient who had two children. The diagnoses were: 10 premature ovarian failures, six gonadal
4. Comment Both the bone formation and the bone resorption markers in hypoestrogenic Chinese women on CEE were similar to levels in normal women, as seen in women of other ethnicities [8,10,11]. Lifelong hormonal replacement therapy (HRT) in young hypoestrogenic women is mainly instituted for the prevention of osteoporosis. HRT has been shown to carry a likely dose-dependent risk for serious collateral effects, as seen in the WHI [16] and the Million Women studies [17]. Treatment should therefore be determined by the dose with the best benefit/
Table 1 Comparison between the CEE and control groups Body weight (kg) (mean S.D.) Body height (m) (mean S.D.) BMI (kg/m2) (mean S.D.) Osteocalcin (nmol/L) (median, 95% CI) Serum PYD (nmol/L) (median, 95% CI)
CEE group (n = 20)
Control group (n = 20)
p value
55.5 12.9 1.56 0.11 22.6 4.34 1.70, 1.43–2.06 3.26, 2.81–4.24
56.8 8.2 1.59 0.05 22.60 2.99 1.70, 1.28–1.94 3.25, 2.66–3.76
0.849 0.306 0.658 0.602 0.391
206
C.C.W. Chan et al. / European Journal of Obstetrics & Gynecology and Reproductive Biology 124 (2006) 204–206
risk ratio. The dose used here shows maximal efficacy, as judged by the lack of greater effect of high dose HRT on bone turnover markers compared to standard dose HRT [18]. It is likely in the efficacy plateau range of the doseresponse curve and may thus be higher than needed for optimal bone metabolism regulation. This is especially true for Chinese women who, on average, have a lesser build than indogermanic populations. Even for these, studies in postmenopausal women [19–21] show bone protective efficacy at lower doses. The concern of potentially dose-dependent, serious collateral effects of HRT raised by the WHI and the Million Women studies point to the need for dose finding studies in different ethnicities.
References [1] Sourander L, Rajala T, Raiha I, Makinen J, Erkkola R, Helenius H. Cardiovascular and cancer morbidity and mortality and sudden cardiac death in postmenopausal women on oestrogen replacement therapy (ERT). Lancet 1998;352:1965–9. [2] Kinoshita T, Yasumizu T, Kato J. Decreased bone mineral density in premenopausal women with amenorrhea. Nippon Sanka Fujinka Gakkai Zasshi 1996;48:793–8. [3] Metka M, Holzer G, Heytmanek G, Huber J. Hypergonadotropic hypogonadic amenorrhea (World Health Organization III) and osteoporosis. Fertil Steril 1992;57:37–41. [4] Soong YK, Hsu JJ, Tzen KY. Measurement of bone mineral density in amenorrheic women with dual photon absorptiometry. Taiwan Yi Xue Hui Za Zhi 1989;88:1097–103. [5] Cann CE, Martin MC, Genant HK, Jaffe RB. Decreased spinal mineral content in amenorrheic women. JAMA 1984;251:626–9. [6] Yu Q, Lin S, He F. The profile of low bone mass in amenorrhea with elevated follicle stimulating hormone. Zhonghua Fu Chan Ke Za Zhi 1999;34:78–81. [7] Amama EA, Taga M, Minaguchi H. The effect of gonadotropinreleasing hormone agonist on type I collagen C-telopeptide and Ntelopeptide: the predictive value of biochemical markers of bone turnover. J Clin Endocrinol Metab 1998;83:333–8. [8] Prior JC, Vigna YM, Wark JD, et al. Premenopausal ovariectomyrelated bone loss: a randomized, double-blind, one-year trial of conjugated estrogen or medroxyprogesterone acetate. J Bone Miner Res 1997;12:1851–63.
[9] Lindsay R, Hart DM, Clark DM. The minimum effective dose of estrogen for prevention of postmenopausal bone loss. Obstet Gynecol 1984;63:759–63. [10] Stepan JJ, Presl J, Broulik P, Pacovsky V. Serum osteocalcin levels and bone alkaline phosphatase isoenzyme after oophorectomy and in primary hyperparathyroidism. J Clin Endocrinol Metab 1987;64: 1079–82. [11] Honjo S, Mizunuma H, Soda M, Igarashi M. Effect of estrogen replacement therapy on the serum osteocalcin level in the postmenopausal and castrated women. Nippon Sanka Fujinka Gakkai Zasshi 1989;41:1571–6. [12] Garnero P, Arden NK, Griffiths G, Delmas PD, Spector TD. Genetic influence on bone turnover in postmenopausal twins. J Clin Endocrinol Metab 1996;81:140–6. [13] Meier DE, Luckey MM, Wallenstein S, Lapinski RH, Catherwood B. Racial differences in pre- and postmenopausal bone homeostasis: association with bone density. J Bone Miner Res 1992;7:1181–9. [14] Parfitt AM, Han ZH, Palnitkar S, Rao DS, Shih MS, Nelson D. Effects of ethnicity and age or menopause on osteoblast function, bone mineralization, and osteoid accumulation in iliac bone. J Bone Miner Res 1997;12:1864–73. [15] Garnero P, Delmas PD. Biochemical markers of bone turnover. Applications for osteoporosis. Endocrinol Metab Clin North Am 1998;27:303–23. [16] Rossouw JE, Anderson GL, Prentice RL, et al. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women’s Health Initiative randomized controlled trial. Writing Group for the Women’s Health Initiative Investigators. JAMA 2002;288:321–33. [17] Million Women Study Collaborators. Breast cancer and hormonereplacement therapy in the Million Women Study. Lancet 2003;362: 419–27. [18] Arrenbrecht S, Boermans AJ. Effects of transdermal oestradiol delivered by a matrix patch on bone density in hysterectomized, postmenopausal women: a 2-year placebo-controlled trial. Osteoporos Int 2002;13:176–83. [19] Genant HK, Lucas J, Weiss S, et al. Low-dose esterified estrogen therapy: effects on bone, plasma estradiol concentrations, endometrium, and lipid levels. Estratab/Osteoporosis Study Group. Arch Intern Med 1997;157:2609–15. [20] Recker RR, Davies KM, Dowd RM, Heaney RP. The effect of lowdose continuous estrogen and progesterone therapy with calcium and vitamin D on bone in elderly women: a randomized, controlled trial. Ann Intern Med 1999;130:897–904. [21] Lindsay R, Gallagher JC, Kleerekoper M, Pickar JH. Effect of lower doses of conjugated equine estrogens with and without medroxyprogesterone acetate on bone in early postmenopausal women. JAMA 2002;287:2668–76.