Changes in Serum Calcium and Vitamin D3 Levels After Tibolone Treatment and Their Correlations with Health-Related Quality of Life

International Journal of Gynecology and Obstetrics 128 (2015) 174–176

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International Journal of Gynecology and Obstetrics

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CLINICAL ARTICLE

Changes in serum calcium and vitamin D3 levels after tibolone treatment and their correlations with health-related quality of life

Sudhindra M. Bhattacharya a,b,⁎, Mainak Ghosh c a Department of Obstetrics and Gynecology, S.C. Das Memorial and Research Center, Kolkata, India b KPC Medical College, Kolkata, India c Department of Pharmacology, Murshidabad Medical College, Berhampore, India article info abstract

Article history: Objective: To assess the effects of tibolone on serum calcium and vitamin D3 levels, the effects on health-related Received 11 April 2014 quality of life (HRQOL), and the relationship between these variables. Methods: An open-label, prospective, Received in revised form 28 July 2014 parallel-arm study was conducted at S.C. Das Memorial Medical and Research Center, Kolkata, India, between Accepted 23 September 2014 July 2012, and June 2013. Women aged 34–55 years were eligible when they were experiencing surgical menopause and were symptomatic. Group A comprised patients who chose to receive tibolone (2.5 mg daily for Keywords: 6 months) and group B comprised those who refused treatment. At baseline and 6 months, body mass index Calcium (BMI), serum calcium and vitamin D levels and HRQOL were assessed. Results: Of 79 participants, 53 were in Menopause 3 fi Tibolone group A and 26 in group B. After 6 months, BMI had increased signi cantly in both groups. The vitamin D3 fi Vitamin D3 level had increased signi cantly from baseline in group A (P = 0.02), and was higher than that in group B (P =0.01).HRQOLhadalsoimprovedsignificantly from baseline in group A (P = 0.001), and was significantly better than that in group B (P b 0.001). In group A, a significant correlation was found between HRQOL improve-

ment and vitamin D3 levels (P b 0.001). Conclusion: Tibolone signiﬁcantly increases the serum vitamin D3 level and improves HRQOL in menopausal women. Clinical Trial Registry India: CTRI/2012/06/002752. © 2014 International Federation of Gynecology and Obstetrics. Published by Elsevier Ireland Ltd. All rights reserved.

1. Introduction Postmenopausal women need a recommended dietary allowance of 1000 mg of elemental calcium. Calcium supplementation should be The onset of menopause is associated with a number of health chal- provided to bridge the shortfall between dietary intake and the recom- lenges for women. For example, the risks for osteoporosis and fractures mended dietary allowance and it should also be given to patients at high are increased after menopause. Dietary factors, in particular calcium risk of fractures [8]. intake, have been implicated as risk factors in the etiology of osteopo- The main source of vitamin D (a fat-soluble steroid hormone pre- rosis. Calcium produces beneficial effects through the protection of cursor) is sunlight exposure of the skin and its major storage form bone mass and through bone remodeling [1]. Vitamin D has important in the human body is the 25-hydroxy form [9]. In elderly patients, roles in calcium and phosphorus metabolism and in bone mineraliza- dietary vitamin D supplementation can lower the risks of fractures tion. Poor intake of calcium and vitamin D can increase the risk of os- and falling [10], and in selected individuals measurement of serum teoporosis and fractures. Furthermore, a low calcium intake along with 25-hydroxyvitamin D can be helpful. vitamin D deficiency in older patients can lead to a negative calcium bal- Hormone replacement therapy (HRT) is one of several treatments ance [2], which causes age-associated secondary hyperparathyroidism. used to alleviate the symptoms associated with menopause. To date, Hypovitaminosis D is also associated with cardiovascular disease, meta- no single treatment has been proven to be superior. Notably, few studies bolic syndrome, diabetes mellitus type 2, various malignancies, in- have reported the effects of different HRT regimens on serum calcium creased mortality, depression, impaired cognitive function, personality and vitamin D3 levels and their inter-relationship with health-related traits and a deterioration of general health and well-being [3–5].There- quality of life (HRQOL). The assessment of HRQOL to evaluate patient fore, optimum levels of serum calcium and vitamin D should be main- satisfaction with a specific level of function is gaining importance in tained [6]. However, in India, vitamin D deficiency is highly prevalent clinical practice. It helps to assess the effects of an illness and its treat- in asymptomatic women from different socioeconomic groups [7]. ment as perceived by the patients themselves [11]. Tibolone, a synthetic steroid that is structurally related to nor- ethynodrel, is used as HRT in menopausal women. After oral adminis- ⁎ Corresponding author at: 5 New Raipur, Flat-4, Kolkata, 700084 India. Tel.: +91 98 31079839; fax: +91 33 24836330. tration, it is converted to three active metabolites [12], each of which E-mail address: [email protected] (S.M. Bhattacharya). has tissue-specific effects. Tibolone has been shown to have protective

http://dx.doi.org/10.1016/j.ijgo.2014.08.010 0020-7292/© 2014 International Federation of Gynecology and Obstetrics. Published by Elsevier Ireland Ltd. All rights reserved. S.M. Bhattacharya, M. Ghosh / International Journal of Gynecology and Obstetrics 128 (2015) 174–176 175 effects against vertebral and nonvertebral fractures even among women At baseline and after 6 months, every participant used the MRS to as- at a low risk of fractures [8]. It has also been shown to suppress acceler- sess their HRQOL. The scale was developed in the early 1990s because ated bone turnover induced by a combination of oophorectomy and low there was a lack of standardized scales to assess the severity of meno- dietary calcium [13,14]. pausal symptoms and their impact on HRQOL. It is easy for any woman Tibolone increases the serum level of insulin-like growth factor 1 to complete the scale herself. A decrease in the MRS score indicates an through increased secretion of growth hormone, leading to increases improvement in HRQOL. The scale includes 11 items, each of which is in the synthesis of muscle protein, the number of myogenic satellite rated between 0 (no symptoms) and 4 (very severe symptoms). cells, and the synthesis of tendon collagen [15].Thisisimportant On the basis of a pilot study and assuming a standard deviation in because vitamin D deficiency and consequent secondary hyperpara- MRS of 3.5 in each group and a dropout rate of 10%, with two patients thyroidism can lead to reduced muscle mass and lower muscle in group A for every one patient in group B, the minimum sample strength [16], which in turn leads to an increased tendency to fall and size required to detect a difference of five points on the MRS was sustain fractures. 29 (20 in group A; nine in group B). The following tests were used The aim of the present study was to assess the effects of HRT with as appropriate: unpaired or paired t test, Mann Whitney U test, tibolone on serum calcium and 25-hydroxyvitamin D3 levels in symp- Wilcoxon signed-rank matched-pair test, and Spearman rank correla- tomatic women after surgical menopause, to evaluate the effects tion test. The variables were tested for normality; all had an accept- on HRQOL as measured using the Menopause Rating Scale (MRS), and able Kolmogorov–Smirnov coefficient and were thus tested with to assess the relationship between variables. parametric tests, apart from the MRS score, which required a nonpara- metric analysis. The analyses were performed with InStat version 2. Materials and methods 3.0 (GraphPad Software, La Jolla, CA, USA). P b 0.05 was considered statistically significant. The present open-label, prospective, parallel-arm study was conducted at S.C. Das Memorial Medical and Research Center in 3. Results Kolkata, India, between July 1, 2012, and June 30, 2013. Women aged 34–55 years were eligible for inclusion when they had been experiencing Of 79 participants, 53 agreed to undergo treatment with tibolone surgical menopause for 3–4 months (attributable to benign gynecologic (group A) and 26 declined HRT for fear of adverse effects (group B) causes) and had menopausal symptoms. The ethics committee of S.C. (Fig. 1). No significant differences in age, BMI, calcium or vitamin D3 Das Memorial Medical and Research Center approved the study. levels, or MRS score were recorded between the two groups at Informed written consent was obtained from all participants. baseline (Table 1).

After taking a detailed history and clinical examination for every After 6 months of follow-up, the serum vitamin D3 level was signif- participant, the body mass index (BMI) was calculated (weight in icantly higher in group A than in group B (Table 1). BMI increased sig- kilograms divided by the square of height in meters). All women were nificantly between baseline and 6 months in both groups, but no counseled about the importance of HRT and were offered tibolone. Pa- difference between groups at either stage was recorded (Table 1). tients who agreed to undergo treatment with tibolone (group A) were There was no change in the serum calcium level after 6 months. MRS advised to take one tablet of tibolone (2.5 mg; Livial, Organon, Mumbai, score decreased significantly between baseline and 6 months in India) daily for 6 months. Compliance was verified verbally and pill group A, and was significantly lower in group A than in group B at counts were performed at follow-up visits. Patients who refused treat- 6 months (Table 1). The MRS score was also significantly correlated ment with tibolone (group B) were advised to continue with their with the vitamin D3 levelingroupA(Table 2). usual lifestyle pattern and to attend follow-up visits. All women underwent measurement of their serum calcium 4. Discussion and 25-hydroxyvitamin D3 levels at baseline and after 6 months. The serum calcium level was measured with the cobas c system The present study has shown that tibolone causes a significant

(Roche Diagnostics, Mannheim, Germany). The serum vitamin D3 level rise in the serum vitamin D3 level among menopausal women after was measured using the Elecsys 2010 analyzer (Roche Diagnostics, 6 months of treatment. However, no signiﬁcant change in calcium Mannheim, Germany). level was recorded. Both groups had a signiﬁcant rise in BMI after

Enrollment Enrolled patients (n=79)

Allocation Group A (n=53) Group B (n=26)

Followed up at 6 Followed up after 6 Follow-up months (n=53) months (n=26)

Fig. 1. Flow of patients through the study. 176 S.M. Bhattacharya, M. Ghosh / International Journal of Gynecology and Obstetrics 128 (2015) 174–176

Table 1 Comparisons between groups at baseline and after 6 months.a

Variable Group A (n = 53) Group B (n = 26) P values (intergroup comparison)

Baseline 6 months P value Baseline 6 months P value Baseline 6 months (intragroup comparison) (intragroup comparison)

Age, y 44.3 ± 4.6 NA NA 45.7 ± 4.5 NA NA 0.2b NA BMIc 26.0 ± 3.7 27.1 ± 3.7 b0.001d 25.9 ± 3.4 26.6 ± 3.4 0.002d 0.9b 0.5b Calcium, mmol/L 2.27 ± 0.15 2.31 ± 0.12 0.08d 2.27 ± 0.16 2.28 ± 0.16 0.08d 0.9b 0.1b d d b b Vitamin D3, nmol/L 37.72 ± 21.79 49.26 ± 30.00 0.02 32.04 ± 15.43 34.49 ± 16.36 0.08 0.18 0.01 MRS score 23.7 ± 5.4 14.1 ± 6.5 b0.001e 22.3 ± 6.2 21.2 ± 4.6 0.12e 0.1f b0.001f

Abbreviations: BMI, body mass index; MRS, Menopause Rating Scale; NA, not applicable. a Values are given as mean ± SD unless indicated otherwise. b Unpaired t test. c Calculated as weight in kilograms divided by the square of height in meters. d Paired t test. e Wilcoxon signed-rank matched-pair test. f Mann Whitney U test.

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