Ultra low-dose hormone replacement therapy and bone protection in postmenopausal women

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1 Available online at Maturitas 59 (2008) 2 6 Ultra low-dose hormone replacement therapy and bone protection in postmenopausal women Marco Gambacciani, Barbara Cappagli, Massimo Ciaponi, Antonia Pepe, Francesca Vacca, Andrea Riccardo Genazzani Department of Obstetrics and Gynecology, Pisa University Hospital, Pisa, Italy Received 28 January 2007; received in revised form 31 August 2007; accepted 22 October 2007 Abstract Objectives: The aim of the present study was to evaluate the effects of low doses of hormone replacement therapy (HRT) in normal young postmenopausal women. Methods: In an open trial healthy, non-obese postmenopausal women received for 2 years a low-dose continuous combined HRT (LD-HRT) containing 1 mg estradiol mg norethisterone acetate each pill for 28 days, or 0.5 mg of 17 -estradiol and 0.25 mg of norethisterone acetate (Ultra low dose, Ultra-LD-HRT) along with 1000 mg of calcium per day. Control group consisted of women receiving only 1000 mg of calcium per day, for 2 years. Menopausal symptoms were evaluated by the Green climacteric scale for the first 12 weeks of the study while bleeding profiles, bone mineral density (BMD) and bone turnover were assessed for 24 months. Results: LD-HRT and Ultra-LD-HRT were effective in reducing menopausal clinical symptoms. In the control group, BMD significantly (P < 0.05) decreased at the spine ( 2.8 ± 0.2%), and femoral neck ( 2.8 ± 0.7%). In LD-HRT treated group BMD showed a significant (P < 0.05) increase at the spine (5.2 ± 0.7%), and femoral neck (2.8 ± 0.4%) after 24 months. In the Ultra- LD-HRT treated women spine and femoral neck BMD showed a significant (P < 0.05) increase (2.0 ± 0.3 and 1.8 ± 0.3%, respectively) after 24 months. In these women treated with LD-HRT and Ultra-LD-HRT the BMD values were significantly (P < 0.05) different from those measured in calcium-treated women. Conclusions: LD-HRT and Ultra-LD-HRT can alleviate subjective symptoms providing an effective protection against the postmenopausal decrease of BMD Elsevier Ireland Ltd. All rights reserved. Keywords: Menopause; Low-dose hormone replacement therapy; Bone mineral density; Osteoporosis 1. Introduction Corresponding author at: Department of Obstetrics and Gynecology Piero Fioretti, University of Pisa, Via Roma 67, Pisa, Italy. Tel.: ; fax: address: [email protected] (M. Gambacciani). Osteoporosis is a risk factor for fractures at all skeletal sites [1 2]. Estrogen deficiency is a key factor in the pathogenesis of postmenopausal osteoporosis. The /$ see front matter 2007 Elsevier Ireland Ltd. All rights reserved. doi: /j.maturitas

2 M. Gambacciani et al. / Maturitas 59 (2008) perimenopausal period is associated with a significant bone loss [3,4]. In addition, an accelerated loss accompanies the cessation of ovarian hormone production [5]. Postmenopausal administration of hormones has been used both to prevent and to treat osteoporosis [6,7].Several studies have demonstrated that doses of mg of conjugated estrogens and 2 mg of 17 -estradiol prevent early postmenopausal bone loss. [8 12]. Based on various epidemiological and observational studies, HRT users have a decreased risk of fracture [13 17], and this reduction is confirmed by a clinical randomized trial, the Women s Health Initiative (WHI) trial [18,19]. The minimum effective dose of HRT has been questioned. The usually prescribed dosage of postmenopausal estrogen therapy has declined progressively and in the past 10 years, use of lower dose HRT has grown in popularity. At present, the regimens containing 0.30 mg of conjugated estrogens, or 1 mg micronized oral 17 -estradiol are considered lowdose HRT (LD-HRT). Various studies have assessed the efficacy LD-HRT in the prevention of osteoporosis in postmenopausal women [20 30], while providing symptomatic relief from subjective symptoms associated with menopause and improving quality of life (QoL) [31]. The aim of the present study was to further evaluate the effects of low doses of HRT in normal postmenopausal women. 2. Materials and methods This study was approved by Ethical Committee of our Department and an informed consent was obtained from each subject. Postmenopausal women (PMW) included in the study were recruited from the Climacteric Clinic of our Department. Women had amenorrhea for at least 12 months before treatment, and plasma gonadotropin and estradiol levels in the postmenopausal range for our laboratory [follicle-stimulating hormone (FSH) > 40 U/L; estradiol (E2) < 25 pg/ml] [32]. All patients were without diseases known to influence calcium metabolism and none had history of glucocorticoid treatment. None had been treated with hormones in the 12 months before the study. In an open trial healthy, non-obese postmenopausal women received for 2 years a lowdose continuous combined HRT (LD-HRT) containing 1 mg estradiol mg norethisterone acetate each pill for 28 days, or 0.5 mg of 17 -estradiol and 0.25 mg of norethisterone acetate (Ultra-low-dose, Ultra-LD- HRT) along with 1000 mg of calcium per day. Control group consisted of women receiving only 1000 mg of calcium per day, for 2 years. The subjective symptoms were evaluated by the visuoanalogic scale, and bleeding pattern was recorded in diaries given to the patient to record the days and characteristics of bleeding episodes during the observation period. The BMD (mg/cm 2 ) of lumbar vertebrae (L2-L4) was measured in supine position with the legs elevated to minimize lordosis, by dual energy X- ray absorptiometry using a Lunar DPX (Lunar Corp., Madison, WI, U.S.A.) [5]. The measurements were performed at baseline and at the end of the 24-month follow up. The long-term stability of the instrument was assessed by measuring a spine phantom every other day for a 2-year period, resulting in a coefficient of variation of 0.5%. Results are reported as the mean ± S.E. Statistical analysis used the factorial analysis of variance to compare baseline values, and the two-way analysis of variance for repeated measures to analyze the longitudinal data, as appropriate. The post hoc comparison was made by Scheffe s F-test. The results are reported as the mean ± S.E. Statistical analysis used the factorial analysis of variance to compare baseline values, and the two-way analysis of variance for repeated measures to analyze the longitudinal data, as appropriate, using Stat View (SAS Institute Inc. 1998, Version 5.0.1). 3. Results The groups were well matched and no significant differences in age, menopausal state, or BMI were present (Table 1). The vasomotor symptoms and the sleep disturbances were evaluated by a visuoanalogic scale (VSA) before and after 12 weeks of treatment (Fig. 1). In women treated with LD-HRT and Ultra-LD- HRT there were significant improvement, presented in VAS score versus corresponding control group values. In the control group, spine and femoral neck BMD significantly (P < 0.05) decreased from the baseline values of ± to ± g/cm 2 ( 2.8 ± 0.2%), and from ± to ± g/cm 2 ( 2.8 ± 0.7%), respectively. In LD-HRT treated group spine and

3 4 M. Gambacciani et al. / Maturitas 59 (2008) 2 6 Table 1 Baseline characteristics of participants who completed the study Control LD-HRT Utra-LD-HRT Age (year) 56.6 ± ± ± 0.5 YSM 6.4 ± ± ± 0.5 BMI (kg/m 2 ) 25.5 ± ± ± 0.6 The results are reported as the mean (±S.E.). Control group: postmenopausal women receiving 1000 mg of calcium per day; LD-HRT: postmenopausal women receiving oral pill containing 1 mg estradiol mg noretisterone acetate per day; Ultra-LD- HRT: postmenopausal women receiving oral pill containing 0.5 mg of 17 -estradiol and 0.25 mg of norethisterone acetate (Ultra low dose,); YSM: years since menopause; BMI: body mass index. femoral neck BMD showed a significant (P < 0.05) increase from the baseline values of ± 0.09 to ± 0.01 g/cm 2 (5.2 ± 0.7%), and from ± to ± g/cm 2 (2.8 ± 0.4%) after 24 months (Fig. 2). In the Ultra-LD-HRT treated women spine and femoral neck BMD showed a significant (P < 0.05) increase from the baseline values of ± 0.09 to ± 0.01 g/cm 2 (2.0 ± 0.3%), Fig. 2. Patterns of BMD (g/cm 2 ) of spine and femoral neck, in women treated with only 1000 mg of calcium per day (control group), LD-HRT (1 mg estradiol mg norethisterone acetate) or Ultra- LD-HRT (0.5 mg of 17 -estradiol and 0.25 mg of norethisterone acetate) along with 1000 mg of calcium per day. The results are expressed as percent of variation vs. basal values. Measured at the end of the 2-year follow up study. *P <.05 vs. corresponding control group values. and from ± to ± g/cm 2 (1.8 ± 0.3%) after 24 months, respectively (Fig. 2). In these women treated with LD-HRT and Ultra-LD-HRT the BMD values were significantly (P < 0.05) different from those measured in calcium-treated women. 4. Discussion Fig. 1. Percent variation over the basal values of the visuoanalogic scale scores referred for hot flushes and sleep disturbances in postmenopausal women treated with only 1000 mg of calcium per day (control group), LD-HRT (1 mg estradiol mg norethisterone acetate) or Ultra-LD-HRT (0.5 mg of 17 -estradiol and 0.25 mg of norethisterone acetate) along with 1000 mg of calcium per day. The results are expressed as percent of variation vs. basal values. Measured at the end of the 12th week of treatment (VAS, a visuoanalogic scale). *P <.05 vs. corresponding control group values. Present data demonstrate that in relatively young postmenopausal women treated with either LD-HRT and Ultra-LD-HRT, significant improvement in vasomotor symptoms was evident. The central HRT indication is the relief of postmenopausal symptoms, with major improvement in QoL [31]. Present study shows that also Ultra-LD-HRT is effective in improving menopausal symptoms and can prevent the bone loss related to the estrogen deprivation. Our data are in line with a 2-year multicenter, double-blind, randomized, placebo-controlled study, which showed that a dose of 17 -estradiol as low as 0.5 mg is effective in prevention of bone mineral density loss in postmenopausal

4 M. Gambacciani et al. / Maturitas 59 (2008) women [33]. However, the addition of NETA seems to enhance the response in BMD observed with lower estradiol doses of [33]. Our data further support the contention that osteoporosis prevention can be considered the main added benefit of very low dose estradiol prescribed in conjunction with low dose norethisterone acetate for subjective symptoms while adjusting the hormone dose to individual patient s needs, preferences and requirements. Recently, it has been reported that even limited HRT use in menopausal women may produce substantial fracture reduction later in life [34]. This is an important information regarding HRT that should not be considered any longer just a tool to reduce subjective symptoms. For the prevention of osteoporosis in postmenopausal women, the benefit-risk balance of lower doses of HRT has not been studied in any large randomised clinical trial. However, lower estrogen doses produce fewer side effects and are expected to generate less risks [35], maintaining a comparable efficacy on symptoms and similar bone sparing effects. Thus, the use of LD-HRT and Ultra-LD-HRT for osteoporosis prevention should be encouraged. In conclusion, LD-HRT and Ultra-LD-HRT can prevent postmenopausal bone loss and appears to be useful alternative to higher dosages in the prevention and treatment of climacteric symptoms. Attention of clinical researchers should focus on the effects of lower dosage estrogen on osteoporotic fractures and other health outcomes. Conflict of interest Authors do not have any financial, personal, political or academic conflict of interest capable of influencing their judgments. Acknowledgements The Authors would like to thank Ms. Enrica Palmeri and Ms. Gabriella Campani for assistance in the completion of the study. References [1] Hui SL, Slemenda CW, Johnston Jr CC. Age and bond mass as predictors of fracture in a prospective study. J Clin Invest 1988;81: [2] Gardsell P, Johnell O, Nilsson BE. Predicting fractures in women by using forearm bone densitometry. Calcif tissue Int 1989;44: [3] Gambacciani M, Spinetti A, Taponeco F, et al. Bone loss in perimenopausal women: a longitudinal study. Maturitas 1994;18(3 Mar): [4] Gambacciani M, Spinetti A, Taponeco F, Cappagli B, Piaggesi L, Fioretti P. Longitudinal evaluation of perimenopausal vertebral bone loss: effects of a low-dose oral contraceptive preparation on bone mineral density and metabolism. Obstet Gynecol 1994;83(3 Mar): [5] Gambacciani M, Spinetti A, de simone L, et al. The relative contributions of menopause and aging to postmenopausal vertebral osteopenia. J Clin Endocrinol Metab 1993;77(5 Nov): [6] Christiansen C, Christensen MS, McNair P, Hagen C, Stocklund K-E, Transbol I. Prevention of early postmenopausal bone loss. Controlled 2-year study in 315 normal females. Eur J Clin Invest 1980;10: [7] Christiansen C, Rils BJ, Nilas L, Rodbro P, Deftos L. Uncoupling of bone formation and resorption by combined oestrogen and progestogen therapy in postmenopausal osteoporosis. Lancet 1987;1: [8] Christensen MS, Hagen C, Christiansen C, Transbol I. Dose response evaluation of cyclic estrogen/gestagen in postmenopausal women. Placebo-controlled trial of its gynecologic and metabolic actions. Am J Obstet Gynecol 1984;144: [9] Horsman A, Jones M, Francis R, Nordin BBC. The effect of estrogen dose on postmenopausal bone loss. N Engl J Med 1983;309: [10] The Writing Group for the PEPI Trial. Effects of hormone replacement therapy on bone mineral density: results from the postmenopausal estrogen/progestin interventions (PEPI) trial. J Am Med Assoc 1996;276: [11] Lindsay R, Hart CM, Clark DM. The minimum effective dose of estrogen for prevention of postmenopausal bone loss. Obstet Gynecol 1984;63: [12] Lindsay R, Bush TL, Grady D, Speroff I, Lobo RA. Therapeutic controversy:estrogen replacement in menopause. J Clin Endocrinol Metab 1996;81: [13] Cauley JA, Seeley DG, Ensrud K, Ettinger B, Black D, Cummings SR. Estrogen replacement and fractures in older women: Study of Osteoporosis Fractures Research Group. Ann Inter Med 1995;122:9 16. [14] Kiel DP, Felson DT, Anderson JJ, Wilson PWF, Moskowitz Ma. Hip fracture and the use of estrogen in postmenopausal women: the Framingham Study. N Engl J Med 1987;317: [15] Altman DG. A meta-analysis of hormone replacement for fracture prevention. J Am Med Assoc 2001;286: [16] Torgerson DJ, Bell-Syer SEM. Hormone replacement therapy and prevention of non-vertebral fractures. A meta-analysis of randomized trials. J Am Med Assoc 2001;285: [17] Torgerson DJ, Bell-Syer SEM. Hormone replacement therapy and prevention of vertebral fractures. A meta-analysis of randomized trials. BMC Musculoskeletal Disord 2001;2:7. [18] Rossouw JE, Anderson GL, Prentice RL, et al. Risks and benefits of estrogen plus progestin in healthy postmenopausal

5 6 M. Gambacciani et al. / Maturitas 59 (2008) 2 6 women: principal results from the Women s Health Initiative randomized controlled trial. J Am Med Assoc 2002;288: [19] Cauley JA, Robbins J, Chen Z, et al. Effects of estrogen plus progestin on risk of fracture and bone mineral density. The Women s Health Initiative randomized trial. J Am Med Assoc 2003;290: [20] Genant HK, Lucas J, Weiss S, et al. Low-dose esterified estrogen therapy: effects on bone, plasma, estradiol concentration, endometrium, and lipid levels. Arch Intern Med 1997;157: [21] Recker RR, Davies Jm, Down RM, Heaney Rp. The effect of low-dose continuous estrogen and progesterone therapy with calcium and vitamin D on bone in elderly women: a randomized, controlled trial. Ann Intern Med 1999;130: [22] Gambacciani M, Ciaponi M, Cappagli B, Genazzani AR. Effects of low-dose continuous combined conjugated estrogens and medroxyprogesterone acetate on menopausal symptoms, body weight, bone density, and metabolism in postmenopausal women. Am J Obstet Gynecol 2001;185: [23] Prestwood KM, Thompson DL, Kenny AM, Seibel MJ, Pilbeam CC, Raisz LG. Low dose estrogen and calcium have an addictive effect on bone resorption in older women. J Clin Endocrinol Metab 1999;84: [24] Lees B, Stevenson JC. The prevention of osteoporosis using sequential low-dose hormone replacement therapy with estradiol-17 beta and dydrogesterone. Osteoporos Int 2001; 12(4): [25] Ettinger B, Genant HK, Steiger PM, Madvig P. Low dosage micronized 17 -estradiol prevents bone loss in postmenopausal women. Am J Obstet Gynecol 1992;166: [26] Gambacciani M, Ciaponi M, Cappagli B, et al. Postmenopausal femur bone loss: effects of a low dose hormone replacement therapy. Maturitas 2003;45(3 Jul 25): [27] Ettinger B. Personal perspective on low-dosage estrogen therapy for postmenopausal women. Menopause 1999;6: [28] Gambacciani M, Monteleone P, Genazzani AR. Low-dose hormone replacement therapy: effects on bone. Climacteric 2002;5(2 Jun): [29] Lindsay R, Gallagher C, Kleerekoper M, Pickar J. Effect of lower doses of conjugated equine estrogens with and without medroxyprogesterone acetate on bone in early postmenopausal women. JAMA 2002;287: [30] Delmas PD, Confavreux E, Garnero P, et al. A combination of low dose of 17 -estradiol and norethisterone acetate prevents bone loss and normalizes bone turnover in postmenopausal women. Osteoporos Int 2000;11: [31] Gambacciani M, Ciaponi M, Cappagli B, et al. Effects of lowdose, continuous combined estradiol and noretisterone acetate on menopausal quality of life in early postmenopausal women. Maturitas 2003;44: [32] Gambacciani M, Melis GB, Paoletti AM, et al. Pulsatile luteinizing hormone release in postmenopausal women: effect of chronic bromocriptine administration. J Clin Endocrinol Metab 1987;65: [33] Greenwald MW, Gluck OS, Lang E, Rakov V. Oral hormone therapy with 17beta-estradiol and 17beta-estradiol in combination with norethindrone acetate in the prevention of bone loss in early postmenopausal women: dose-dependent effects. Menopause 2005;12(6): [34] Bagger YZ, Tankó LB, Alexandersen P, et al. Two to three years of hormone replacement treatment in healthy women have longterm preventive effects on bone mass and osteoporotic fractures: the PERF study. Bone 2004;34: [35] Grodstein F, Manson JE, Colditz GA, et al. A prospective, observational study of postmenopausal hormone therapy and primary prevention of cardiovascular disease. Ann Intern Med 2000;133: