Bone Mineral Density at 45 Years of Age, Before Menopause

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Bone Mineral Density at 45 Years of Age, Before Menopause Mario Newton Leitão de Azevedo, MD; João Vieira Nunes, MD; Henrique A. Pasqualette, MD; Maria de Fátima F. Tuma, MD; Lenita Celia Ferreira Nunes, MD

Objective: The objectives of this study were to investigate variations in bone mineral density values in 45-year-old women from a community sample in the City of Rio de Janeiro, in the same-name Brazilian state, and to compare them with US norms and international standards. Design: In this cohort study, the age of 45 years is significant for the design, since clinical observation in this community indicates that it is approximately 5 years before menopause can be confirmed, thus preceding the typical postmenopause acceleration of the rate of bone loss. Nine hundred fifty-nine such women volunteered to participate in the investigation, conducted in 2 Rio de Janeiro teaching hospitals. Informed of procedures, potential risks, and benefits, they were screened for the inclusion criteria: (a) being 45 years old; (b) being healthy (without obvious or diagnosed systemic disease, metabolic disease, endocrine disease, liver disease, cardiac disease, infectious disease, pulmonary disease, neurologic disease, dermatologic disease, inflammatory bowel disease, kidney disease, hereditary, or congenital conditions); (c) having regular and intact menstrual cycles; (d) having had normal healthy development to date; (e) having had high protein intake from birth to date; (f) having at least completed high school; (g) living in a dwelling equipped with running water, electricity, and public sewer; (h) being nonsmoking and non–drug abusing. Racial distinction was not among the inclusion criteria. After further informed consent, the 146 women who met all inclusion criteria had bone mineral density quantified—using the dual energy x-ray absorptionmetry method—and compared with US-born density norms for L2-L4 and the neck of the femur for young adults and the sample age group, which are endorsed by the World Health Organization and by the International Osteoporosis Foundation. Results: About three-quarters of the sample had normal bone mineral density values, 22.61% had osteopenia, and 2.73% had osteoporosis. Conclusion: These findings, obtained from women whose regular and intact menstrual cycles demonstrated premenopausal hormonal levels, seem to attest to the importance of genetic predisposition, yet they warrant the authors’ recommendation that interventions be instituted before age 45, specifically aimed at increasing the chances of all women, especially those genetically predisposed, of avoiding osteoporosis and its deleterious consequences. Keywords: bone n obstetrics/gynecology

Author Affiliations: Rheumatology Service, Clementino Fraga Filho University Hospital, Rio de Janeiro Federal University Medical School, Rio de Janeiro, Brazil (Dr Leitão de Azevedo, professor of medicine and chief; Dr Tuma, professor of medicine); Department of Behavioral Medicine, Sophie Davis School of Biomedical Education/CUNY Medical School, at City College of New York, New York, New York (Dr Vieira Nunes, associate medical professor and chairman; Dr Ferreira Nunes, adjunct professor); Women’s Center for Study and Research (Dr Pasqualette, master of medicine and medical director), Rio de Janeiro, Brazil. Corresponding Author: João Vieira Nunes, MD, Associate Medical Professor and Chairman, Department of Behavioral Medicine, Sophie Davis School of Biomedical Education/CUNY Medical School, at City College of New York, 160 Convent Ave, Ste H-201, New York, NY 10031 ([email protected]).

Introduction

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n this article we document variations in bone mineral density (BMD) of healthy 45-year-old premenopausal women, using the dual energy x-ray absorptiometry (DEXA) method, and compare the values obtained with US norms and international standards. The women who participated in the study are part of a community in which the age of 45 years has been determined clinically to be, on average, 5 years before menopause can be confirmed. We deemed it essential to make certain to investigate BMD values in a cohort of premenopausal women, before the typical bone loss acceleration rate of menopause could become a confounding element. Women’s bone mineral content increases markedly from the start of puberty to the end of adolescence.1-4 Bone mineral content, ie, bone mass, is an individualized finding with no maximum value, and depends (80%5) on genetic inheritance. It also depends on diet, exercise,6 and the mechanical forces that muscle exerts upon bone. This markedly influences the often obvious man-woman bone mass dimorphism that favors men,7 who typically have a bulkier muscle mass than do women. On the other hand, bone mass values are in direct relationship with adipose tissue mass,8 a fact that favors women, who, in the aggregate have a greater adipose tissue mass relative to men. After puberty, women’s bone resistance and mineral content continue to increase until achieving a state of steady equilibrium in which any bone loss is readily replaced. Around the fourth decade of life, both sexes begin to experience a gradual age-related loss of bone mass,9-12 a loss that gradually predominates over bone replacement. The result is net

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bone loss,13 yet, as it is attested to in the pertinent literature, although women’s estrogen reduction of menopause increases net bone loss, only 10% to 20% of women develop clinical osteoporosis. This is because additional factors converge to contribute to its development (Box 1).14

Methods Study Sites This cohort study, in which we document variation in BMD in a sample of premenopause, healthy 45-year-old women, was conducted at the rheumatology service of the Clementino Fraga Filho University Hospital of Rio de Janeiro Federal University Medical School (Clementino), and the Center for Women’s Study and Research (CWSR). The 2 institutions, both located in Rio de Janeiro, Brazil, are university-affiliated teaching hospitals with a full complement of medical and surgical services. Clementino is a full-fledged university hospital, while CWSR is dedicated to the health care of women. The authors posted invitations for women to volunteer to participate in a bone density study. The invitations were strategically placed at highly conspicuous locations of the rheumatology service of Clementino and of the medical services of the CWSR. The rheumatology service of Clementino was chosen as a site, along with CWSR services, because women are strongly represented there and because it considers differential diagnoses that include those related to bone loss. The study was conducted simultaneously at both institutions.

Informed Consent All participants gave informed consent. The study followed all the ethical principles for medical research involving human subjects, in accordance with the Declaration of Helsinki. The study was approved by the ethics committee in both institutions. Volunteers were informed they were signing up to be screened and that a smaller number would be selected for full participation in the study. Those who did not meet inclusion criteria would still benefit from the expert screening, medical

advice, and proper referral where appropriate. In addition to this benefit, those selected would avail themselves of the properly explained results of bone density studies, and of attendant referrals where appropriate.

Participants Nine hundred fifty-nine women volunteered for the study. After screening, 146 met the inclusion criteria: (a) to be 45 years old; (b) to be healthy (no obvious or diagnosed: systemic disease, metabolic disease, endocrine disease, liver disease, cardiac disease, infectious disease, pulmonary disease, neurologic disease, dermatologic disease, inflammatory bowel disease, kidney disease, hereditary or congenital conditions); (c) to have regular and intact menstrual cycles; (d) to have had normal healthy development to date; (e) to have had high protein intake from birth to date; (f) to have at least completed high school; (g) to live in a dwelling equipped with clean running water, electricity, and public sewer; (h) to be nonsmoking, non–drug abusing. The authors did not use any racial distinction among the participants as an inclusion criterion.

Procedures, Equipment, Definitions Bone densitometry apparatus and methods. All scans were obtained from lumbar vertebrae, L2 to L4, and from the neck of the femur using the DPX – L (GE Lunar Corp, Madison, Wisconsin) apparatus and the DEXA method, in an appropriately dedicated room at CWSR, maintained at the temperature of 20ºC. All readings were compared with established norms for US women obtained using the same method following the standard values presented in the table below and used as standard for the evaluation of bone mineral density by the World Health Organization and by the International Osteoporosis Foundation (Box 2). Determination of normal bone mineral density, osteopenia, or osteoporosis. Determination of normal BMD, osteopenia, or osteoporosis was made according to norms established by the World Health Organization, using standard deviation (Z) for young adults,16 relative to BMD in g/cm2. Normal BMD = -1 < Z < 0 SD, and would absorb a drop of up to 10% relative to young-

Box 1. Factors That Contribute to the Development of Clinical Osteoporosis14 1. 2. 3. 4.

Low bone mineral density at the start of menopause Low plasma concentration of steroid sex hormones Other factors known to intensify bone resorption Faulty postmenopausal compensatory bone formation mechanisms

Box 2. Bone Mineral Density Norms (US Population, Dual Energy X-ray Absorptiometry Method)15 Age 30-39 40-49 SD

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L2-L4 Neck of Femur 0.958 g/cm2 1.207 g/cm2 1.170 g/cm2 0.950 g/cm2 2 0.12 g/cm 0.12 g/cm2

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adult norms (L2-L4, 1.080 g/cm2 < BMD < 1.32 g/cm2; neck of femur, 0.838 g/cm2 < BMD < 1.078 g/cm2). Definitions. We adopted the following definitions from the 1996 Merriam Webster Medical Desk Dictionary: (a) Osteopenia is “reduction in bone volume to below normal levels especially due to inadequate replacement of bone lost to normal lysis.” The diagnosis of osteopenia accepts 2.5 < Z < -1 SD, or a drop between 10% and 25% from the same young-adult parameters (L2-L4, 0.900 g/cm2 < BMD <1.080 g/cm2; neck of femur, 0.658 g/cm2 < BMD < 0.838 g/cm2). (b) Osteoporosis is “a condition…characterized by a decrease in bone mass with decreased density and enlargement of bone spaces producing porosity and fragility.” Therefore, osteoporosis and osteopenia differ in the degree of bone demineralization. While there may be clinical manifestations, the diagnosis of osteoporosis is densitometric: Z < -2.5, or a drop in BMD of more than 25% from US young-adult norms: L2-L4, 0.900 g/cm2; neck of the femur, 0.658 g/cm2. Calculations of Z and T. Calculations of Z and T are based on values established for young adults and for the age group to which individuals being evaluated belong. Thus the calculation of Z takes into account individual and population data.

Statistical Analysis Statistical analysis was performed using Epi Info version 6.0 (Centers for Disease Control, Atlanta, Geor-

gia). The significance level was established at 95% and statistical significance was established at p < .05, labeled (s). Any finding that was not significant equaled p > .05 value, which was labeled (ns). The authors followed the prescribed procedures to determine mean, standard deviation, Student t test, and c2. The study was conducted in a time period of 4 months. Percentage and median with standard deviation were used to calculate reduction of BMD values in the sample. All sample BMD results and standard data were done in ordinal and parametric values with normal distribution and, for this reason, the t test was used.

Results

Overall, mean L2-L4 BMD values were slightly decreased (1.15%) relative to the US young-adult norms and slightly increased (1.3%) relative to US norms for the age group. Neck of the femur BMD was diminished 3.1% and 2.5% relative to the US young-adult and age group norms, respectively. L2-L4 BMD values revealed that 77.39% of our sample had no osteopenia, showing instead mean increases relative to young adult (3.5%) and to age group norms (6.0%). Neck of the femur values revealed that 74.65% had no osteopenia, but a BMD increase of 0.6% and 1.3% relative to young-adult and age group norms, respectively (Tables 1 and 2). In 22.61% of the sample we found L2-L4 osteopenia (mean reduction of 17.8% and 14.75% relative to young-

Table 1. Study Cohort Bone Mineral Density From Lumbar Column and Neck of Femur Compared With US Norms L2-L4 Neck of femur US norms p

Bone Mineral Density, g/cm2 1.186 SD 0.14-0.11 0.920 SD 0.11 1.170 SD 0.12 NS

Z +0.13 –0.31 0 NS

Z Study Cohort –0.25 0 NS

Abbreviations: NS, not significant; Z, age matched. p t test.

Table 2. Comparison Between Lumbar Column and Neck of Femur Bone Mineral Density Values in Women With Normal Results (No Osteopenia, or - 1 < Z) and US Norms L2-L4, BMD >1.08 g/cm2, n = 113 or 77.39% Sample BMD norms p

Bone Mineral Density, g/cm2 T

Neck of femur, BMD > 0.838 g/cm2, n = 109 or 74.39% Sample BMD norms p

Z

1.243 SD 0.10 1.170 SD 0.12 NS

+0.35 0 NS

+0.6 0

0.966 SD 0.1 g/cm2 0.950 SD 0.12 NS

+0.06 g/cm2 NS

Z GE + 0.13 0 0 NS

Abbreviations: BMD: bone mineral density; NS, not significant; T, young adult; Z, age matched. T value for young adults aged 40 years; Z value age matched. P t test.

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adult and age group norms, respectively. We also found that in the neck of the femur, 25.34% of the sample had a mean BMD reduction of 14.5% and 13.9% relative to young-adult and age group norms, respectively (Tables 3 and 4). We found densitometric osteoporosis in 2.73% of the sample in both L2-L4 and the neck of the femur (BMD 28.1% and 25.6%), lower than US young adult and age group norms, respectively (Table 5).

Discussion

For the study reported in this article we adopted the strategy of documenting variation in BMD of healthy 45-

year-old premenopausal women who met stringent inclusion criteria. This allowed us to compare our findings with US norms and international standards. The strategy also permitted us to concentrate the understanding gleaned from such comparisons on illuminating aspects of low BMD at the start of menopause, while minimizing the relative importance of the other factors that contribute to the development of clinical osteoporosis.14 About one-quarter of the women in our sample showed BMD values lower than 10% less than US norms for both L2-L4 and the neck of the femur. The other three-quarters had excellent, robust BMD values relative to US young-adult and age group norms. Therefore,

Table 3. Osteopenia Cluster (Bone Mineral Density Loss >10% [ -1 > Z ]): Lumbar and Neck of Femur Compared to Norms Bone Mineral Density, g/cm2 T 2 L2-L4, BMD <1.08 g/cm , n=33 or 22.61% BMD, g/cm2 T Z Sample 0.993 SD 0.07 –1.78 Norm 1.179 SD 0.12 0 p S S Neck of femur, BMD < 0.838 g/cm2, n = 37 or 25.34% Sample 0.783 SD 0.04 –1.45 Norm 0.950 SD 0.12 0 p S S

Z

–1.47 0 S –1.39 0 S

Abbreviations: BMD: bone mineral density; S: significant (P > 0.05); SD: standard deviation; T, young adult; Z, age matched. p t test.

Table 4. Osteoporosis: Lumbar and Neck of Femur Bone Mineral Density in Women With Bone Loss Between 10% and 25% (BMD = -2.5 < Z < -1) Compared to Norms Bone Mineral Density, g/cm2 T L2-L4, BMD 0.900 g/cm2 < BMD < 1.08 g/cm2, n = 29 or 19.88% Sample 1.012 SD 0.05 –1.56 Norms 1.179 SD 0.12 0 p S S Bone Mineral Density, g/cm2 2 Neck of femur, BMD 0.658 g/cm < BMD < 0.838 g/cm2, n = 37 or 25.34% Sample 0.783 SD 0.04 Norms 0.950 SD 0.12 p S

Z –1.31 0 S

Z YA

Z ag

–1.45 0 S

–1.39 0 s

Abbreviations: AG: age group or age-matched results; BMD: bone mineral density; S: significant (P > 0.05); SD: standard deviation; T, young adult; YA: young adult norms; Z, age matched. p t test.

Table 5. Lumbar Column and Neck of Femur Bone Mineral Density in Women With Bone Loss Greater Than 25% ( Z < -2,5, or Densitometric Osteporosis) Compared to Norms L2-L4, BMD < 0.900 g/cm2, n = 4 or 2.73% BMD Norms p Neck of femur, BMD < 0.658 g/cm2, n = 0

Bone Mineral Density, g/cm2 T 0.862 SD 0.03 g/cm2 1.179 SD 0.12 S

–2.81 0 S

Z –2.56 0 S

Abbreviations: BMD: bone mineral density; S: significant (P > 0.05); SD: standard deviation; T, young adult; Z, age matched. p t test.

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about one-quarter of the women in our sample had at least osteopenia despite premenopausal hormonal levels, as suggested by regular and intact menstrual cycles. To our minds, this finding underscores the importance of genetic predisposition, which is in keeping with assertion in the literature that bone mineral content depends primarily (80%5) on genetic inheritance. This lead us to conclude that genetic inheritance predisposes many women to have baseline BMD that is lower than that of their nonpredisposed counterparts. Predisposed women, then, have a lifelong disadvantage that menopause may widen to consequently produce densitometric and clinical osteoporosis. The strategy we adopted permits us to propose interventions that could be generally applied to all women. Given the risks and consequences of osteoporosis, we propose routine densitometry for women in the dawn of the fourth decade, before menopause; that is, before bone demineralization picks up momentum. We propose further that should routine densitometry reveal a lower BMD than established norms, a regimen be instituted with the following components: education, psychosocial support, proper diet with calcium and vitamin D supplements, proper exercise, relevant lifestyle changes, and prophylactic medication.17 Instituted early enough prior to the onset of menopause, such a regimen may diminish the impact of postmenopausal acceleration of bone loss and its consequences. The above combination, we suggest, can become a valuable prevention tool. Besides, if continued long term, the regimen should benefit even women who initially respond unusually weakly because they might undergo a correction with continued intervention, as the principle of regression to the mean suggests.18,19 In the case of osteoporosis, there is a good chance that genetics need not be destiny.

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