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Journal of the American College of Nutrition, Vol. 24, No. 5, 354-360 (2005)
Published by the American College of Nutrition

Bone Mineral Density and Metabolism at an Early Stage of Menopause When Estrogen and Calcium Supplement Are Not Used and without the Interference of Major Confounding Variables

Priscilla G. Massé, PhD, Juliana Dosy, MS, Jean-Luc Jougleux, MS, Marcel Caissie, MD and David S. Howell, MD

Human Nutrition, University of Moncton, (P.G.M., J.D., J.-L.J.), Moncton, New Brunswick, CANADA
Dumont Hospital (M.C.), Moncton, New Brunswick, CANADA
School of Medicine/VA Medical Center, University of Miami, Florida (D.S.H.)

Address reprint requests to: Dr Priscilla Massé, Dept of Human Nutrition, University of Moncton, Moncton, N.-B., E1A 3E9, Canada. E-mail: massep{at}umoncton.ca


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 SUBJECTS AND METHODS
 RESULTS
 ACKNOWLEDGMENTS
 REFERENCES
 
Objectives: To measure bone mineral density (BMD) and to screen for early biochemical abnormalities in bone mineral metabolism in the first five years of natural menopause when estrogen and calcium supplement are not used and in the absence of major confounding variables.

Setting: Two homogeneous and comparable groups (n = 30) of healthy pre- and postmenopausal Caucasian women living in a northern region (latitude 46° N) were recruited during the mid-Spring/Summer season in a cross-sectional design.

Methods: Volumetric apparent BMAD (g/cm3) was calculated from areal BMD (g/cm2) which was evaluated by dual energy X-ray absorptiometry (Lunar®) at both axial and peripheric (femur) sites using two sets of reference values (WHO criterion expressed as T-score and absolute values of areal density) in combination to bone specific biochemical measurements.

Results: BMD and BM(A)D were significantly lower in postmenopausal women for all lumbar sites, but not for Ward’s triangle and any other femoral sites whereas free deoxypyridinoline (Dpd), urinary biochemical marker of bone resorption, was markedly (p < 0.0001) greater. Their serum calcium and phosphate were significantly higher without a difference in 1,25(OH)2D3 and PTH. The prevalence of osteopenia in pre- and postmenopausal women was about 2-fold lower in both groups (26.6 and 46.9%, respectively) when lumbar (L) spine and femur neck were combined and using the criteria based on reference values of areal density instead of T-scores.

Conclusions: The present study showed that the negative effects of estrogen deficiency on BMD and bone metabolism in early menopause occurred independently of the effect of major calcitropic hormones. Bone loss affects a non negligible proportion of premenopausal women. The prevalence of osteopenia in pre- and postmenopausal women varied according to the criterion used and anatomic site.

Key words: menopause, estrogen, osteopenia, osteoporosis, bone density, bone resorption, plasma minerals, vitamin D, PTH

Abbreviations: BMD = areal bone mineral density • BMAD = (volumetric) bone mineral (apparent) density • Dpd = free deoxypyridinoline • WHO = World Health Organization


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
SUBJECTS AND METHODS
 RESULTS
 ACKNOWLEDGMENTS
 REFERENCES
 
Intense growth and development during infancy and childhood depends upon mineralization of the skeleton which achieves peak bone mass during early adulthood [1]. After that time, a slight decline of bone mass occurs, which is accelerated in women after the menopause, and might lead to excessive bone resorption and eventually to osteoporosis. The earliest mineral loss begins in spine and hip trabecular bone due to its greater turnover than cortical appendicular bone [2]. The rate of bone loss is most rapid in the early postmenopausal period and subsequently begins to level off by 5 years postmenopause [3].

A relatively modest but significant amount of cancellous bone, especially in the vertebral bodies and Ward’s triangle, is lost within 10 years preceding the menopause, whereas cortical bone mass is maintained until the menopause [4]. In other words, perimenopausal bone loss affects mostly trabecular bone, which predominates in the axial and not the appendicular compact cortical skeleton [2]. Ovulatory changes that amplify as women progress through perimenopause are associated with bone loss despite normal estradiol levels and regular menstrual cycles [5]. It is now firmly established that low bone mass (osteopenia) is a significant risk factor for osteoporotic fractures later in life [6].

The lack of estrogen in menopause accelerates bone loss. The effect is mediated by mechanisms that are not fully elucidated. Among factors are genetics, reduced calcium intake, reduced calcium absorption, increased urinary excretion and reduced exposure to sunlight (1,7). The active component of intestinal calcium absorption appears to be under relatively rigid hormonal control in which 1,25(OH)2D3 plays a dominant role. The best clinical indicator of this vitamin status is the serum 25(OH)D3 level which varies inversely with PTH (parathyroid hormone) levels [7]. Patel et al [8] demonstrated a highly significant seasonal effect on 25(OH)2D3 concentrations but not on BMD and PTH. To our knowledge, only one study has been reported on the vitamin D status in the phase of early postmenopausal bone loss [9].

Loss of bone tissue can be estimated by measuring bone mineral density (BMD), but BMD is unable to provide direct information on bone metabolism. Also, changes in BMD being late and relatively irreversible, it is important to have a means of identifying high risk individuals and to monitor their treatment before fracture occurs [10]. Biochemical measures may have an advantage over measuring BMD during early stages of bone loss. Combined biochemical and BMD screening may provide better prediction of future fracture risk than BMD alone [11].

Studies on bone loss in menopause are numerous in comparison to those on premenopausal women. Most population studies on postmenopausal women are not well-controlled, including vegetarians, athletes, women taking hormone replacement therapy and/or vitamin D-mineral supplements and hyperlipideamic subjects taking lipid-lowering drugs. The two objectives of the present study on two meticulously selected homogeneous and comparable groups of pre- and postmenopausal women not using estrogen and calcium supplement were: 1) to measure areal and volumetric BMD at both axial and peripheral sites and using two sets of reference values and; 2) to screen for early biochemical abnormalities in bone mineral metabolism in the first five years of natural menopause without the interference of major confounding variables.


   SUBJECTS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 SUBJECTS AND METHODS
RESULTS
 ACKNOWLEDGMENTS
 REFERENCES
 
Female Caucasian volunteers were recruited during mid-spring/summer from a homogeneous urban community of Eastern Canada (latitude 46° 7’ North) in response to public advertisings. Specific criteria were aimed to ensure group homogeneity and to avoid major confounding variables. An initial screening of all respondents was conducted over the phone to exclude non-eligible subjects, smokers and vegetarians. Women who had ceased menstruation for 3 to 5 years and not started taking hormone replacement therapy and premenopausal women aged 35–45 years with a spontaneous menstrual cycle (not taking oral contraceptives) were selected. Other eligibility criteria were to be non-obese (BMI <30 kg/m2) and in good health (as self-assessed) with no history of bone fracture [12] and without regular use of medication (statins, corticosteroids, thiazide diuretics, anticonvulsive drugs, calcitonin and diphosphonates) and calcium supplement.

Women who met the inclusion criteria attended an initial information meeting and signed a consent form. The research protocol was approved by the Ethics Committee on Human Research of the Université de Moncton and by the Review Board of Dumont Hospital, Moncton, New Brunswick, Canada. Subjects who consented to enroll filled out a general questionnaire, which included items on demographics, reproductive characteristics, personal and family medical history.

Anthropometric Measurements
Height was determined using a wall-mounted stadiometer. Body weight was determined to within 100 g using a standard beam platform balance scale detector (Bionetics, St-Laurent, Québec, Canada). Subjects were weighed with indoor clothing without shoes. Body mass index (BMI) was calculated from measured weight (kg) and height (m) as weight/(height)2. Body frame size was assessed by measuring elbow width according to Frisancho & Flegel [13]. Elbow width was measured to the nearest 0.1 cm with a framemeter (Frisancho, Ann Arbor, MI, 1986).

Evaluation of Self-Selected Diets
Subjects were asked to record their food intakes for 3 non-consecutive days (including 1 week-end day) preceding blood collection. Written instructions were given to all of them and explained by a registered dietitian to maximize completeness and accuracy of recording. Subjects were asked not to modify their regular food intakes while recording and to record all foods and beverages immediately after consumption.

Each dietary record was checked for completeness by the same dietitian in the presence of subjects. Daily energy and nutrient intakes were determined using Food Processor® (Version 8.2, 2000, Esha Research, Salem, OR). Intakes of each nutrient were averaged (n = 3 days) to compare the two groups of women and assess nutritional adequacy of their diets with respect to current nutritional standards [14]. Ca:P and Ca:protein ratios were calculated.

Self-Assessment of Physical Activity
Subjects also recorded their daily physical activities (occupational and leisure time) for 7 consecutive days according to 5 categories of physical activity varying from 1 (very low level in energy expenditure expressed as kcal/kg/min) to 5 (very high level) [15]. Instructions and a list of examples of diverse physical activities in each category were reviewed with each subject. Subjects were encouraged to maintain their habitual activity pattern at the time of recording. Daily records solicited information on day of the week, type of activity and duration (min), all activities being listed under the most appropriate category. To ensure that no activity was omitted, the subjects were asked to sum up for each day the total duration of all categories to amount to 1440 minutes (24 h) including sleeping time.

Evaluation of Bone Mineral Density (BMD)
The BMD of the anteroposterior lumbar spine and standard femoral sites was measured by dual energy X-ray absorptiometry (DEXA, Lunar Corp., Madison, WI) at the same time of blood and urine collection. The instrument was calibrated on a daily basis according to the manufacturer’s instructions. Reproducibility was calculated as a coefficient of variation (CV) obtained by weekly measurements of a standard aluminum bar phantom on the instrument and by repeated measurements obtained in three patients of different ages. The CV of our instrument was 0.5% with the standard phantom; in vivo we calculated a CV of 1.1% for the lumbar spine, 1.5% for the neck of femur, 1.8% for trochanter and 3.2% for Ward’s triangle. Areal BMD (g/cm2) was measured at diverse lumbar and femoral sites and true apparent volumetric (BMAD) (g/cm3) was calculated to take into consideration bone size [16] to aid in the diagnosis of osteopenia [17]. According to WHO experts [18], osteopenia is defined as a value of BMD between 1.0 SD and 2.5 SD below the average value (T-score) of the peak bone of 30-yr-old healthy adults. The absolute reference values of Mazess [19] and Morabito et al [20] (<0.9 g/cm2 for lumbar spine and 0.795 g/cm2 for femur neck, respectively) were also used and in combination as suggested by Abrahamsen et al [21].

Blood Collection and Biochemistry
Venous blood and urine samples were collected from all subjects after an overnight fast. The blood from premenopausal subjects was drawn during the ovulation phase of their menstrual cycle (from day 12 to day 16 after the first day of the last menses). All samples were kept frozen at –70°C until analyses. Serum estradiol, calcium, inorganic phosphorus, intact (i) PTH and urinary creatinine were determined by automated routine procedures. Plasma free deoxypyridinoline (Dpd), bone marker of resorption, and vitamin D were analysed in a laboratory of Palo Alto VA Medical Center, CA, by their methods that were validated and reported previously [22,23]. Free Dpd was measured on nonhydrolyzed urine samples using a competitive enzyme immunoassay (Metra DPD, Quidel Corporation, San Diego, CA). Values were corrected for the urinary concentration of creatinine. Plasma calcidiol (25-hydroxycholecalciferol abbreviated as [25(OH)D3]) concentration was determined following extraction of serum in reagent alcohol (90% ethanol, 5% methanol, 5% isopropanol) with a competitive protein-binding assay kit (Nichols Institute Diagnostics, San Juan Capistrano, CA). Plasma calcitriol [1,25(OH)2D3] concentration was measured using radioimmunoassay (RIA) from Nichols Institute Diagnostics. The intra-assay CV for all assays was less than 8%.

Statistical Analyses
Data were analyzed using InStat (Version 2.0, 1998, GraphPad Software, San Diego, CA). Descriptive statistics were calculated and normality was assessed. All variables were normally distributed and were analyzed using Student’s two-tailed unpaired t test. Relationships between pertinent biochemical variables were analysed using Pearson’s correlation coefficient (r). A value of p ≤ 0.05 was considered significant.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 SUBJECTS AND METHODS
 RESULTS
ACKNOWLEDGMENTS
 REFERENCES
 
Among the two hundred women who responded to public advertisings, 30 pre- and 30 postmenopausal women fulfilled all criteria and consented to enroll in the study. The two groups were similar in several aspects: geographic region (latitude 46° N), socioeconomic background, ethnicity, physical activity level, parity, lactation and age at menarche (Table 1). Height, body weight and frame did not differ significantly. Mean serum estradiol of the postmenopausal group was lower than the cut-off of 217 pmol/L established in our laboratory to characterize menopausal status.


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  		Table 1. Basic Characteristics of Subject Groups Including Some Pertinent Anthropometrical Data1

 
Energy and nutrient dietary intakes of both groups did not differ significantly except for vitamin D and copper (Table 2). Calcium and vitamin D intakes were below the newly established nutritional requirements in both groups. However, their Ca:P and Ca:protein ratios were high. High ratios have been associated with larger BMD [24,25].


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  		Table 2. Pertinent Mean Daily Dietary Data as Estimated from 3-D Food Record1

 
According to WHO criterion, 60.0 and 88.9% of pre- and postmenopausal women, respectively, were osteopenic at one bone site or more, predominantly the lumbar spine. The prevalence of osteopenia was much lower (26.6 and 46.9%, respectively) when lumbar spine and femur neck were combined as suggested by Abrahamsen et al [21] and using the criteria based on absolute reference values of areal density (g/cm2) proposed by Mazess [19] and Morabito et al [20]. As depicted by Fig. 1A) and 1B), BMD and BMAD were significantly lower in postmenopausal group for all lumbar sites. Mean coefficient of variation (SD / x 100) for all bone sites, taken altogether, was significantly greater for this group whatever the mode of expression used. Using BMAD helped to reduce significantly data variability for L1–L4 site, in particular, which showed the greatest variability in postmenopausal women. No significant differences between groups were found for Ward’s triangle and any other femoral sites, including cortical diaphysis.



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  		Fig. 1. A) BMD at the spine [lumbar (L) vertebrea] and hip (femur neck, Ward’s triangle, trochanter, Troch, and cortical diaphysis, Diap), B), BM(A)D at the spine of pre- (n = 30) and postmenopausal women (n = 30). Mean ± SD ***p < 0.001 **p < 0.01.

 
Free Dpd, marker of bone resorption, was markedly greater in the postmenopausal group of women as compared to premenopausal controls (Table 3). Serum calcium and phosphate concentrations were significantly greater in postmenopausal women but remained within normal range. Both minerals were correlated (p < 0.001) with Dpd confirming the shift of minerals from the skeleton. The abnormality in serum mineral homeostasis in early menopause occurred independently of the effect of the major calcitropic hormones, 1,25(OH)2D3 and PTH. Control premenopausal women had borderline vitamin D status as assessed by plasma 25(OH)D3 (cut-off of 62 nmol/L) [26]. Dietary intakes of postmenopausal women being more deficient (p < 0.0001) (Table 1) than that of premenopausal women, their plasma 25(OH)D3 was surprisingly greater (p < 0.01). PTH was found to be inversely correlated with 25(OH)D3 (r = –0.46; p = 0.0002). This D metabolite was positively associated to age (r = 0.30; p = 0.0294).


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  		Table 3. Biochemical Data Related to Bone and Mineral Metabolism1

 

   DISCUSSION
 
First, the present study with strict inclusion criteria and without the interference of confounding variables demonstrated that a non negligible proportion of women had osteopenia before the age of menopause. Spinal bone loss particularly affected postmenopausal women, even at an early stage, whereas femur sites were then spared. The prevalence of osteopenia in pre- and postmenopausal women (average age of 41.9 and 54.0 y, respectively) varied according to the criterion used and anatomic site. In the study of Abrahamsen et al. [21], involving women of similar age, the prevalence of osteopenia was 52.1%, a finding slightly higher than that obtained for postmenopausal women in the present study when using the same criterion, that is, absolute reference values of areal density (g/cm2) of lumbar and femur neck combined. The presence of bone loss in premenopausal women and early postmenopausal women indicates that they either had not achieved a maximal peak bone mass in their twenties and thirties or that a progressive age-related deterioration in bone matrix followed the achievement of peak bone mass, or both combined. In adult age, women gradually lose bone mass until menopause, when losses accelerate dramatically and then gradually reach a threshold [2,27]. The higher prevalence of osteopenia in the postmenopausal group as compared to premenopausal controls was confirmed biochemically by a greater urinary excretion of Dpd (collagen metabolite), a marker of bone resorption.

Both serum calcium and phosphate concentrations were significantly greater in postmenopausal women as compared with control premenopausal women, in agreement with other studies [5,28,29]. There is certainly a close relationship between the abnormality in calcium/phosphate homeostasis and the accelerated loss of bone mass that occurs at an early stage of menopause. BMD studies on postmenopausal women including both serum mineral concentrations and plasma vitamin D determinations are limited. The abnormality in blood mineral homeostasis found in the present study occurred independently of the effect of the major calcitropic hormones, PTH and 1,25(OH)2D3, as demonstrated by two other investigators [28,29], suggesting a direct effect of estrogen deficiency on bone but not on renal function and intestine. PTH, is the main hormonal regulator of renal tubular handling of phosphate and 1,25(OH)2D3, active form of vitamin D (calcitriol), is synthesized by normal kidney cells to stimulate intestinal calcium absorption. Serum calcium is closely controlled, and an elevation would inhibit PTH release, perhaps explaining why serum PTH levels tended to be lower (although not significantly) in postmenopausal women of the present study. The magnitude of hyperphosphatemia required to stimulate PTH secretion is quite high, and it is questioned whether it has any physiological significance [30]. According to a recent study [31], estrogen has a distinct vitamin D-independent effect at the genomic level of active duodenal calcium absorption mechanisms, mainly through a major upregulation of the calcium influx channel CaT1. Neither of the calcitropic hormones under investigation showed a significant difference between pre- and postmenopausal women groups in the present study. According to Prince et al [32], PTH, calcitriol and phosphate begin to rise only after 10 years of postmenopause.

Pre-menopausal women had borderline vitamin D status as assessed by plasma 25(OH)D3. The level proposed as adequate to prevent compensatory hypersecretion of PTH vary from 62 to 100 nmol/L [33]. The cut-off used in the present study was 62 nmol/L. For reasons that are not entirely clear, variability in this end-point is very large across population studies [34]. Surprisingly, plasma 25(OH)D3 level of postmenopausal women was significantly greater than that of pre-menopausal women although their vitamin D intake was significantly lower. Plasma 25(OH)D3 reflects either the diet or endogenous source from skin synthesis on exposure to ultraviolet B rays (or artificial ultraviolet radiation). All subjects were recruited during the same mid-Spring/Summer season and sun exposure was not evaluated in our questionnaire because such an information is hardly reliable considering that endogenous synthesis varies with types of sunscreens used and skin pigmentation. A significantly positive correlation was found between 25(OH)D3 concentration and age in the present study corroborating two investigators having shown that this hepatic vitamin D metabolite has a tendency to increase with age [35,36]. This relationship could also underline the greater opportunity for postmenopausal women to travel to sunny countries during wintertime and/or their greater use of artificial ultraviolet radiation.

Sample size of the present study was small (although statistically valid) in comparison to that of population studies. Its strengths resided in: 1) the homogeneity of the two comparison groups due to rigorous eligibility criteria at study entry level and; 2) the use of both areal BMD and volumetric BMAD (to take into consideration the size of vertebrae) combined to a biochemical marker of bone resorption, in addition to biochemical analyses of serum minerals and two major calcitropic hormones. It also included other influencing factors such as physical activity, anthropometric and dietetic data. Given the heterogeneity between anatomic regions of bone, a combination of spinal and femoral densitometry should be used in the diagnosis of bone disorders. Longitudinal studies on a large number of women, after peak bone mass has been reached and prior to the onset of menopause, are warranted. Vitamin D nutritional status [(plasma 25(OH)D3)] prior to the onset of menopause needs to be addressed.


   ACKNOWLEDGMENTS
TOP
 ABSTRACT
 INTRODUCTION
 SUBJECTS AND METHODS
 RESULTS
 ACKNOWLEDGMENTS
REFERENCES
 
The authors gratefully acknowledge the dedicated assistance of Janice Payne who performed the bone densitometry at the Department of Radiology of Dumont Hospital, Moncton, New Brunswick, and the personnel of the Out-Patient Clinic. We wish to thank Leah Holloway from the VA Medical Center, Palo Alto, CA, USA. for her skilled technical assistance in the analyses of biochemical markers of bone status, Bahram Arjmandi, Ph.D. (Oklahoma State University) and Sharon Donovan, Ph.D. (University of Illinois, Urbana) for their careful revision of the manuscript. Funding for the study was provided by the Canadian Institutes of Health Research (grant GH-60658 for PGM) and New-Brunswick Innovation Fund (for JLJ).

Received October 9, 2004. Accepted June 12, 2005.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 SUBJECTS AND METHODS
 RESULTS
 ACKNOWLEDGMENTS
 REFERENCES
 

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