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Clinical Profile of Spanish Postmenopausal Women With a Diagnosis of Osteoporosis and Risk Factors for Endometrial Pathology, Breast Cancer, and Cardiovascular Disease
Palacios, Santiago MD, Neyro, Jos Luis MD, Puertas, Jos Chaves PhD, Fernandez de Cabo, Susana PhD Menopause. 2013;20(8):852-859.

Abstract and Introduction

Abstract

Objective: GINERISK was designed to assess the clinical profile of Spanish postmenopausal women with a diagnosis of osteoporosis and to establish the presence of other risk factors. Methods: In this Spanish cross-sectional, epidemiological, observational study, gynecologists sequentially invited postmenopausal women with osteoporosis under their care to complete a predefined questionnaire during a routine visit. Risk factors for bone fractures, endometrial pathology, breast cancer, and cardiovascular disease were assessed. Results: In addition to being postmenopausal and having diagnosed osteoporosis, 49.8% (2,070/4,157) of eligible participants had one or more risk factors for bone fractures, 96.8% (4,023/4,157) had one or more risk factors for breast cancer, and 83.4% (3,469/4,157) had one or more risk factors for cardiovascular disease. Furthermore, 20.1% (n = 835) of the women presented with high cardiovascular risk, 16.6% (n = 692) were at high risk for bone fractures, and 14.5% (n = 423) were at high risk for developing breast cancer in the next 5 years, whereas only 9.2% (n = 301) of participants were identified as having high endometrial risk. Conclusions: In addition to the increased risk of bone fractures, women with osteoporosis are also at risk for endometrial pathology, breast cancer, and cardiovascular disease. These risks should be evaluated and taken into consideration when choosing an osteoporosis treatment for postmenopausal women.
Introduction

Osteoporosis is a progressive and systemic skeletal disorder characterized by low bone mass and microarchitectural deterioration of bone tissue, with a consequent increase in bone fragility and susceptibility to fracture. It is a major public health concern, particularly in postmenopausal women,[1,2] and is estimated to affect 200 million women worldwide.[3] Postmenopausal women are disproportionately affected by the condition owing to declining endogenous estrogen levels.[1,2] Estrogen deficiency can lead to excessive bone resorption accompanied by inadequate bone formation. Estrogens suppress the proliferation of osteoblast progenitors, suppress the apoptosis of osteoblasts and osteocytes, and modulate osteoblast differentiation; therefore, production and maintenance of bone cells are affected by estrogen levels both directly and indirectly. In addition, drugs that reduce estrogen production (eg, aromatase inhibitors used for the treatment of breast cancer) are known to increase osteoporosis and fracture rates in postmenopausal women.[4-6] Osteoporosis affects approximately one third of postmenopausal women in the United States and European Union, increasing to more than 80% of women older than 80 years.
[7,8]

Osteoporosis is defined based on bone mineral density (BMD) assessment. According to World Health Organization (WHO) criteria, osteoporosis is defined as a BMD that lies 2.5 SDs or more below the average value for young healthy women (T-score <-2.5 SDs).[9] The most widely validated technique for measuring BMD is dual-energy x-ray absorptiometry (DXA), and diagnostic criteria based on the T-score for BMD are a recommended entry criterion for the development of pharmaceutical interventions for osteoporosis.[9] The prevention of osteoporosis and its associated fractures is considered essential to the maintenance of health, quality of life (QoL), and independence of women during later life.[3,9] The agents most commonly used to prevent/treat postmenopausal osteoporosis include bisphosphonates, estrogen, parathyroid hormone, calcitonin, selective estrogen receptor modulators, strontium ranelate, and denosumab.[10,11] Although existing pharmacological agents have been effective in preventing bone loss and fractures in postmenopausal women, the need to provide women new therapeutic options with improved tolerability profiles

remains.[12] Having a clear understanding of the risk factors associated with osteoporosis in postmenopausal women will facilitate the development of new appropriate treatment strategies.[13] In addition to an increased risk of osteoporosis, the onset of menopause is associated with a heightened risk of several other conditions, such as endometrial pathology, breast cancer, cardiovascular disease, and rheumatoid arthritis. However, there is a distinct lack of available epidemiological data to assess potential relationships between these conditions or at least the risk factors associated with them. The primary objective of this study was to determine the clinical profile of Spanish postmenopausal women with a diagnosis of osteoporosis using a comprehensive health approach. A secondary objective was to establish possible associations between women with osteoporosis and the presence of risk factors for other conditions, such as endometrial pathology, breast cancer, and cardiovascular disease.

Methods
Study Design

GINERISK was a cross-sectional, epidemiological, observational study in which 539 gynecologists from Spanish outpatient centers, hospitals, and/or clinics each sequentially invited 10 postmenopausal women with osteoporosis under their care to participate in the study during a routine visit (study visit). The gynecologists completed individual case report forms (CRFs) with predefined fields using a combination of information collected at the visit (a questionnaire administered by the gynecologist and vital medical statistics) and supplementary data supplied from patient records. The preliminary section of the CRF defined the inclusion and exclusion criteria to ensure that only eligible women proceeded with the study. Data were collected from November 2010 until February 2011. The study database was locked in May 2011.
Participants

Eligible participants were postmenopausal women (12 mo since the last menstrual bleed due to natural menopause or surgically/pharmacologically induced menopause) with a diagnosis of osteoporosis (spinal BMD T-score <-2.5 as measured by DXA in accordance with WHO criteria[9]) within the last 2 years. Any woman receiving any psychiatric treatment or hormone therapy (HT) was excluded from the study. HT would have affected endometrial thickness; thus, endometrial risk assessment (endometrial thickness measured by ultrasound) would have been undermined. Women received treatment and/or medical care for their disease in accordance with the physician's clinical judgment.
Ethics

An informed consent form was obtained from every woman who agreed to enter the study. The study was governed by the basic ethical principles contained in the 1964 Declaration of Helsinki and its later amendments. Subsequent approval was gained from a certified nationwide ethics committee (Hospital de la Princesa, Madrid, Spain) according to Spanish national regulatory requirements.
Measurements

After confirmation of osteoporosis, the sociodemographic data, medical data, and lifestyle choices of each participant were recorded in the CRF. Sociodemographic data included age, employment status, educational level, and living environment. Participant employment status was split into six categories (employed, housewife, retired, unemployed because of illness or disability, temporarily out of work, and unemployed), and educational level was divided into five categories (no education, primary education, secondary education, diploma, and university education). Living environment was categorized by population size: rural (10,000 inhabitants), suburban (10,001-30,000 inhabitants), urban (30,001-200,000 inhabitants), and metropolitan (>200,000 inhabitants). The following medical data were collected: weight (kg); body mass index (BMI; kg/m2); height (cm); resting heart rate (beats/min); bone densitometry scan from the last 2 years; a mammogram performed within the last 2 years (nonmandatory); cholesterol levels measured within the last year; a vaginal ultrasound conducted within the last year (nonmandatory); and blood glucose levels (nonmandatory) and blood pressure measured at study visit. BMI was categorized as underweight (<18.5 kg/m2), normal weight (18.5-24.9 kg/m2), overweight (25-29.9 kg/m2), obese (30-39.9 kg/m2), and morbidly obese (40 kg/m2). The concomitant pathologies recorded were diabetes mellitus, arterial hypertension, rheumatoid arthritis, anorexia nervosa,

gastrectomy, hyperparathyroidism, hyperthyroidism, pernicious anemia, chronic liver disease, and malabsorption syndrome. A clinical evaluation of osteoporosis included the following: date of osteoporosis diagnosis, bone mass, risk factors for bone fractures, current treatment received for osteoporosis, and previous osteoporotic fractures experienced by the participant or a family member. Lifestyle factors comprised alcohol intake, smoking status, diet, and exercise. Tobacco use was categorized as nonsmoker, ex-smoker (6 mo since smoking cessation), and current smoker (1-10 cigarettes/d, 11-20 cigarettes/d, or >20 cigarettes/d). Alcohol consumption was categorized as no alcohol, less than 30 g/day, or 30 g/day or higher. Data collated in the CRFs were used to perform the following assessments (parameters in parentheses are associated with higher risk): (i) Bone fracture risk, based on BMI (<20 kg/m2, underweight), smoking status (smoker), alcohol consumption (>30 g/d), history of osteoporotic fractures, family history of osteoporosis and/or hip fractures, presence of rheumatoid arthritis, and use of corticosteroids; (ii) Endometrial pathology risk, based on nonmandatory vaginal ultrasound to measure endometrial thickness (5 mm); (iii) Breast cancer risk during specific periods of time, based on the Gail model,[14] which assesses age at first menstrual period (<12 y), number of previous breast biopsies (two or more), presence of atypical hyperplasia in breast biopsy, age at first live birth (30 y), having first-degree relatives (mother, sisters, and daughters) with a history of breast cancer, and age (50 y); (iv) Cardiovascular risk, based on blood lipid levels (inadequate according to European Society of Cardiology/European Atherosclerosis Society guidelines [15]), age (65 y), presence/previous diagnosis of hypertension, smoking status (current smoker), BMI (30 kg/m2, obese), and presence of diabetes mellitus, in addition to the use of the low-risk European version of the SCORE risk charts,[16,17] which evaluates an asymptomatic and apparently healthy persons total risk of a fatal cardiovascular event in the next 10 years, taking into consideration sex, age, smoking status, and systolic blood pressure; and (v) QoL of Spanish postmenopausal women based on the Cervantes Scale.[18] Data related to the risk factors for bone fracture risk, endometrial pathology, breast cancer, and cardiovascular disease are reported here. QoL data (based on the Cervantes Scale and the 12-Item Short Form Health Survey) will be reported elsewhere.
Statistical Analysis

Descriptive analyses of all variables are presented. Results are expressed as absolute and relative frequencies for qualitative variables and as measures of normality and distribution for quantitative variables. Frequency (%) data were calculated based on the number of participants contributing data within each category. For independent comparisons between qualitative variables, Pearson's 2 test, Fisher's exact test, or likelihood ratios were used. For quantitative variables, Student's t test, analysis of variance, or nonparametric equivalents (Mann-Whitney U test or Kruskal-Wallis test) were used. Parametric tests included assessments of normality and homogeneity. Statistical significance was set to P < 0.05. Data were analyzed using SPSS Statistics software, version 17 or higher (SPSS Inc, Chicago, IL).

Results
The study was conducted in 479 centers throughout Spain, specifically Andaluca (n = 58), Aragn (n = 16), Navarre (n = 4), Canary Islands (n = 19), Cantabria (n = 6), Leon (n = 24), Castile-La Mancha (n = 24), Catalonia (n = 74), Ceuta (n = 1), Valencia (n = 85), Extremadura (n = 10), Galicia (n = 36), Balearic Islands (n = 5), La Rioja (n = 5), Madrid (n = 50), Melilla (n = 2), Basque Country (n = 30), Asturias (n = 9), and Murcia (n = 21). Data were evaluable for 4,157 (92%) of the 4,517 participants included in the study; 70% to 100% of evaluable women contributed data to each of the study variables. Of the 360 (8.0%) women considered nonevaluable, 4.7% (n = 17) were not postmenopausal, 8.3% (n = 30) did not have a diagnosis of osteoporosis (measured by DXA within the last 2 y, in accordance with WHO criteria), 16.4% (n = 59) did not provide an informed consent form to participate in the study, 56.7% (n = 204) were receiving HT, and 13.9% (n = 50) did not fulfill two or more of the inclusion criteria.
General Characteristics and Sociodemographics

General characteristics and sociodemographic data are reported in . The mean (95% CI) age and BMI of the sample were 60.9 (60.7-61.2) years and 25.8 (25.6-25.9) kg/m2, respectively; most women (81.5%) were classified as normal weight or overweight according to their BMI. The mean SD (95% CI) blood pressure among the participants was 131.2/77.5 15.1/10.3 (130.7131.7/77.1-77.8) mm Hg.
Table 1. General characteristics and sociodemographics of all participants (N = 4,157)

Characteristics Age <40 y 40-49 y 50-54 y 55-59 y 60-64 y 65 y Missing data Body mass index Underweight (<18.5 kg/m2) Normal (18.5-24.9 kg/m2) Overweight (25.0-.29.9 kg/m2) Obese (30.0-39.9 kg/m2) Morbidly obese (40.0 kg/m2) Missing data Systolic blood pressure <120 mm Hg 120-139 mm Hg 140-159 mm Hg 160-179 mm Hg 180 mm Hg Missing data Cigarette consumption Nonsmoker Ex-smoker Current smoker 1-10 cigarettes/d 11-20 cigarettes/d >20 cigarettes/d Missing data Alchohol consumption

n (%)a

3 (0.1) 168 (4.1) 617 (14.9) 1,117 (26.9) 1,044 (25.2) 1,196 (28.8) 12 (0.3) b

206 (5.0) 1,760 (42.8) 1,590 (38.7) 454 (11.0) 101 (2.5) 46 (1.1) b

602 (15.3) 2,530 (64.5) 575 (14.6) 200 (5.1) 18 (0.5) 232 (5.6) b

2,752 (66.6) 747 (18.0) 636 (15.4) 281 (46.6) 226 (37.5) 96 (15.9) 22 (0.5) b

No Yes Occasional <30 g/d 30 g/d Missing data Total cholesterol levels <150 mg/dL 150-199 mg/dL 200-249 mg/dL 250-299 mg/dL 300 mg/dL Missing data Concomitant pathologies Diabetes mellitus Hypertension Rheumatoid arthritis Anorexia nervosa Gastrectomy Hyperparathyroidism Hyperthyroidism Pernicious anemia Chronic liver disease Malabsorption syndrome None Missing data Employment status Employed Housewife Retired

3,374 (82.4) 723 (17.6) 104 (14.4) 573 (79.2) 46 (6.4) 60 (1.4) b

142 (3.6) 1,123 (28.7) 2,096 (53.5) 511 (13.0) 46 (1.2) 239 (5.7) b

366 (9.0) 997 (24.3) 239 (5.9) 15 (0.4) 9 (0.2) 19 (0.5) 101 (2.5) 7 (0.2) 33 (0.8) 20 (0.5) 2,686 (65.1) 33 (0.8)

1,335 (32.3) 1,663 (40.2) 876 (21.2)

Unemployed (because of illness/disability) 37 (0.9) Temporarily unemployed Unemployed Missing data Education level (highest) No education Primary education 329 (7.9) 1,474 (35.6) 89 (2.2) 133 (3.2) 24 (0.6) b

Secondary education Higher education diploma University education Missing data Living environment Rural (10,000 inhabitants) Suburban (10,001-30,000 inhabitants) Urban (30,001-200,000 inhabitants) Metropolitan (>200,000 inhabitants) Missing data

1,150 (27.8) 650 (15.7) 539 (13.0) 15 (0.4) b

440 (10.6) 886 (21.4) 1,104 (26.6) 1,719 (41.4) 8 (0.2) b

a Percentage calculated from the total number of participants contributing data to a given category/variable. b Percentage calculated from the total number of evaluable women in the study (N = 4,157).

The mean (95% CI) blood chemistry data were as follows: glucose, 94.9 (94.3-95.4) mg/dL; triglycerides, 121.9 (120.4-123.5) mg/dL; creatinine, 0.83 (0.82-0.84) mg/dL; total cholesterol, 213.8 (212.6-215.0) mg/dL; high-density lipoprotein cholesterol, 65.5 (64.6-66.4) mg/dL; low-density lipoprotein cholesterol, 130.9 (129.7-132.1) mg/dL. Among participants with available data (n = 4,135), only 15.4% (n = 636) were smokers, 18.1% (n = 747) were ex-smokers, and 66.6% (n = 2,752) had never smoked. In addition, 17.6% (723/4,097) of participants regularly or occasionally drank alcohol. Almost a quarter of women were hypertensive (24.3%); other concomitant pathologies present in more than 5% of participants were diabetes mellitus (9.0%) and rheumatoid arthritis (5.9%). Around two thirds of women were either housewives or retired, and one third of women were still employed, whereas a small proportion of women were unemployed/temporarily unemployed ( ). Although most had received some formal education, around one third of women were not educated beyond primary education. Almost one third of women completed secondary education, with the remaining one third achieving higher education diploma or university degree ( ). More than two thirds of women lived in urban or metropolitan areas; the remaining one third lived in rural or suburban areas ( ).
Table 1. General characteristics and sociodemographics of all participants (N = 4,157)

Characteristics Age <40 y 40-49 y 50-54 y 55-59 y 60-64 y 65 y Missing data Body mass index Underweight (<18.5 kg/m2) Normal (18.5-24.9 kg/m2) Overweight (25.0-.29.9 kg/m2)

n (%)a

3 (0.1) 168 (4.1) 617 (14.9) 1,117 (26.9) 1,044 (25.2) 1,196 (28.8) 12 (0.3) b

206 (5.0) 1,760 (42.8) 1,590 (38.7)

Obese (30.0-39.9 kg/m2) Morbidly obese (40.0 kg/m2) Missing data Systolic blood pressure <120 mm Hg 120-139 mm Hg 140-159 mm Hg 160-179 mm Hg 180 mm Hg Missing data Cigarette consumption Nonsmoker Ex-smoker Current smoker 1-10 cigarettes/d 11-20 cigarettes/d >20 cigarettes/d Missing data Alchohol consumption No Yes Occasional <30 g/d 30 g/d Missing data Total cholesterol levels <150 mg/dL 150-199 mg/dL 200-249 mg/dL 250-299 mg/dL 300 mg/dL Missing data Concomitant pathologies Diabetes mellitus Hypertension Rheumatoid arthritis Anorexia nervosa

454 (11.0) 101 (2.5) 46 (1.1) b

602 (15.3) 2,530 (64.5) 575 (14.6) 200 (5.1) 18 (0.5) 232 (5.6) b

2,752 (66.6) 747 (18.0) 636 (15.4) 281 (46.6) 226 (37.5) 96 (15.9) 22 (0.5) b

3,374 (82.4) 723 (17.6) 104 (14.4) 573 (79.2) 46 (6.4) 60 (1.4) b

142 (3.6) 1,123 (28.7) 2,096 (53.5) 511 (13.0) 46 (1.2) 239 (5.7) b

366 (9.0) 997 (24.3) 239 (5.9) 15 (0.4)

Gastrectomy Hyperparathyroidism Hyperthyroidism Pernicious anemia Chronic liver disease Malabsorption syndrome None Missing data Employment status Employed Housewife Retired

9 (0.2) 19 (0.5) 101 (2.5) 7 (0.2) 33 (0.8) 20 (0.5) 2,686 (65.1) 33 (0.8)

1,335 (32.3) 1,663 (40.2) 876 (21.2)

Unemployed (because of illness/disability) 37 (0.9) Temporarily unemployed Unemployed Missing data Education level (highest) No education Primary education Secondary education Higher education diploma University education Missing data Living environment Rural (10,000 inhabitants) Suburban (10,001-30,000 inhabitants) Urban (30,001-200,000 inhabitants) Metropolitan (>200,000 inhabitants) Missing data 440 (10.6) 886 (21.4) 1,104 (26.6) 1,719 (41.4) 8 (0.2) b 329 (7.9) 1,474 (35.6) 1,150 (27.8) 650 (15.7) 539 (13.0) 15 (0.4) b 89 (2.2) 133 (3.2) 24 (0.6) b

a Percentage calculated from the total number of participants contributing data to a given category/variable. b Percentage calculated from the total number of evaluable women in the study (N = 4,157).

Table 1. General characteristics and sociodemographics of all participants (N = 4,157)

Characteristics Age <40 y

n (%)a

3 (0.1)

40-49 y 50-54 y 55-59 y 60-64 y 65 y Missing data Body mass index Underweight (<18.5 kg/m2) Normal (18.5-24.9 kg/m2) Overweight (25.0-.29.9 kg/m2) Obese (30.0-39.9 kg/m2) Morbidly obese (40.0 kg/m2) Missing data Systolic blood pressure <120 mm Hg 120-139 mm Hg 140-159 mm Hg 160-179 mm Hg 180 mm Hg Missing data Cigarette consumption Nonsmoker Ex-smoker Current smoker 1-10 cigarettes/d 11-20 cigarettes/d >20 cigarettes/d Missing data Alchohol consumption No Yes Occasional <30 g/d 30 g/d Missing data Total cholesterol levels <150 mg/dL

168 (4.1) 617 (14.9) 1,117 (26.9) 1,044 (25.2) 1,196 (28.8) 12 (0.3) b

206 (5.0) 1,760 (42.8) 1,590 (38.7) 454 (11.0) 101 (2.5) 46 (1.1) b

602 (15.3) 2,530 (64.5) 575 (14.6) 200 (5.1) 18 (0.5) 232 (5.6) b

2,752 (66.6) 747 (18.0) 636 (15.4) 281 (46.6) 226 (37.5) 96 (15.9) 22 (0.5) b

3,374 (82.4) 723 (17.6) 104 (14.4) 573 (79.2) 46 (6.4) 60 (1.4) b

142 (3.6)

150-199 mg/dL 200-249 mg/dL 250-299 mg/dL 300 mg/dL Missing data Concomitant pathologies Diabetes mellitus Hypertension Rheumatoid arthritis Anorexia nervosa Gastrectomy Hyperparathyroidism Hyperthyroidism Pernicious anemia Chronic liver disease Malabsorption syndrome None Missing data Employment status Employed Housewife Retired

1,123 (28.7) 2,096 (53.5) 511 (13.0) 46 (1.2) 239 (5.7) b

366 (9.0) 997 (24.3) 239 (5.9) 15 (0.4) 9 (0.2) 19 (0.5) 101 (2.5) 7 (0.2) 33 (0.8) 20 (0.5) 2,686 (65.1) 33 (0.8)

1,335 (32.3) 1,663 (40.2) 876 (21.2)

Unemployed (because of illness/disability) 37 (0.9) Temporarily unemployed Unemployed Missing data Education level (highest) No education Primary education Secondary education Higher education diploma University education Missing data Living environment Rural (10,000 inhabitants) Suburban (10,001-30,000 inhabitants) 440 (10.6) 886 (21.4) 329 (7.9) 1,474 (35.6) 1,150 (27.8) 650 (15.7) 539 (13.0) 15 (0.4) b 89 (2.2) 133 (3.2) 24 (0.6) b

Urban (30,001-200,000 inhabitants) Metropolitan (>200,000 inhabitants) Missing data

1,104 (26.6) 1,719 (41.4) 8 (0.2) b

a Percentage calculated from the total number of participants contributing data to a given category/variable. b Percentage calculated from the total number of evaluable women in the study (N = 4,157).

Table 1. General characteristics and sociodemographics of all participants (N = 4,157)

Characteristics Age <40 y 40-49 y 50-54 y 55-59 y 60-64 y 65 y Missing data Body mass index Underweight (<18.5 kg/m2) Normal (18.5-24.9 kg/m2) Overweight (25.0-.29.9 kg/m2) Obese (30.0-39.9 kg/m2) Morbidly obese (40.0 kg/m2) Missing data Systolic blood pressure <120 mm Hg 120-139 mm Hg 140-159 mm Hg 160-179 mm Hg 180 mm Hg Missing data Cigarette consumption Nonsmoker Ex-smoker Current smoker 1-10 cigarettes/d 11-20 cigarettes/d >20 cigarettes/d

n (%)a

3 (0.1) 168 (4.1) 617 (14.9) 1,117 (26.9) 1,044 (25.2) 1,196 (28.8) 12 (0.3) b

206 (5.0) 1,760 (42.8) 1,590 (38.7) 454 (11.0) 101 (2.5) 46 (1.1) b

602 (15.3) 2,530 (64.5) 575 (14.6) 200 (5.1) 18 (0.5) 232 (5.6) b

2,752 (66.6) 747 (18.0) 636 (15.4) 281 (46.6) 226 (37.5) 96 (15.9)

Missing data Alchohol consumption No Yes Occasional <30 g/d 30 g/d Missing data Total cholesterol levels <150 mg/dL 150-199 mg/dL 200-249 mg/dL 250-299 mg/dL 300 mg/dL Missing data Concomitant pathologies Diabetes mellitus Hypertension Rheumatoid arthritis Anorexia nervosa Gastrectomy Hyperparathyroidism Hyperthyroidism Pernicious anemia Chronic liver disease Malabsorption syndrome None Missing data Employment status Employed Housewife Retired

22 (0.5) b

3,374 (82.4) 723 (17.6) 104 (14.4) 573 (79.2) 46 (6.4) 60 (1.4) b

142 (3.6) 1,123 (28.7) 2,096 (53.5) 511 (13.0) 46 (1.2) 239 (5.7) b

366 (9.0) 997 (24.3) 239 (5.9) 15 (0.4) 9 (0.2) 19 (0.5) 101 (2.5) 7 (0.2) 33 (0.8) 20 (0.5) 2,686 (65.1) 33 (0.8)

1,335 (32.3) 1,663 (40.2) 876 (21.2)

Unemployed (because of illness/disability) 37 (0.9) Temporarily unemployed Unemployed Missing data Education level (highest) 89 (2.2) 133 (3.2) 24 (0.6) b

No education Primary education Secondary education Higher education diploma University education Missing data Living environment Rural (10,000 inhabitants) Suburban (10,001-30,000 inhabitants) Urban (30,001-200,000 inhabitants) Metropolitan (>200,000 inhabitants) Missing data

329 (7.9) 1,474 (35.6) 1,150 (27.8) 650 (15.7) 539 (13.0) 15 (0.4) b

440 (10.6) 886 (21.4) 1,104 (26.6) 1,719 (41.4) 8 (0.2) b

a Percentage calculated from the total number of participants contributing data to a given category/variable. b Percentage calculated from the total number of evaluable women in the study (N = 4,157).

Bone Fracture Risk

The mean (95% CI) age of women at the time of osteoporosis diagnosis was 58.8 (58.3-59.0) years. The mean (95% CI) time from diagnosis was 2.3 (2.2-2.4 y) years. Of the 3,250 women who had their spinal BMD measured (T-score) with DXA during the study visit, 77.6% (n = 2,521) had a T-score lower than -2.5 (osteoporosis) and 22.4% (n = 729) had a T-score of -2.5 or higher (nonosteoporotic). The mean (95% CI) BMD DXA T-score was -2.40 (-2.44 to -2.35). Overall, apart from being postmenopausal and having a T-score lower than -2.5 upon diagnosis, 50.2% (2,087/4,157) of women did not present any other risk factors for bone fractures; 33.1% (n = 1,378) had one risk factor, 13.7% (n = 569) had two risk factors, 2.6% (n = 109) had three risk factors, and the rest (0.3%; n = 14) had four or more risk factors. One or more risk factors for bone fractures were identified in 49.8% (n = 2,070) of participants. The subsets of women presenting individual risk factors for bone fractures are presented in Figure 1; a family history of osteoporosis and/or hip fractures was the most commonly reported risk factor for bone fractures. Overall, 16.6% (n = 692) of women were at high risk (two or more risk factors) for bone fractures (Fig. 2).

Figure 1.

Proportion of women with individual risk factors (RFs) for bone fractures (N = 4,157) other than being postmenopausal and having a T-score lower than -2.5 (measured by dual-energy x-ray absorptiometry in accordance with World Health Organization criteria9).

Figure 2.

Proportion of women with osteoporosis with a high risk of bone fractures (two or more risk factors), a high endometrial risk (endometrial thickness 5 mm), a high risk of developing breast cancer in the next 5 years (Gail index 1.66% 14), and a high cardiovascular risk (three or more risk factors).
Endometrial Pathology Risk

Endometrial thickness was measured in 3,268 participants; the mean (95% CI) endometrial thickness was 2.69 (2.64-2.75) mm. An endometrial thickness of 5 mm or higher (indicative of high endometrial risk) was seen in 9.2% (n = 301) of women (Fig. 2).
Breast Cancer Risk

At least one risk factor for breast cancer was identified in 96.8% (4,023/4,157) of women (according to the Gail model): 58.6% (n = 2,436) had one risk factor, 30.5% (n = 1,266) had two risk factors, 7.0% (n = 292) had three risk factors, and the remainder (0.7%; n = 29) had four or more risk factors. The proportions of women with individual risk factors for breast cancer are presented in Figure 3. As expected, the most commonly presented risk factor for breast cancer was an age of 50 years or older. Overall, 14.5% (n = 423) of participants presented with a high risk of developing breast cancer in the next 5 years (Gail index 1.66%; Fig. 2). Based on the Gail model, the mean (95% CI) risk of developing breast cancer in the next 5 years was 0.95% (0.94-0.96) for this sample population.

Figure 3.

Proportion of women with individual risk factors (RFs) for breast cancer (N = 4,157).
Cardiovascular Risk

One or more cardiovascular risk factors were identified in 83.4% (3,469/4,157) of women. Most participants were at relatively low risk for cardiovascular events: 34.9% (n = 1,451) had one risk factor, 28.5% (n = 1,183) had two risk factors, 13.2% (n = 547) had three risk factors, 5.4% (n = 224) had four risk factors, and the rest (1.5%; n = 64) had five or six risk factors. The numbers of women with individual cardiovascular risk factors are presented in Figure 4; inadequate lipid levels (according to European Society of Cardiology/European Atherosclerosis Society guidelines [15]) were the cardiovascular risk factor most commonly identified. Overall, 20.1% (n = 835) of participants presented with a high cardiovascular risk (three or more risk factors; Fig. 2). In contrast, women with a current T-score of -2.5 or higher but lower than -1 had the lowest cardiovascular risk; only 15.9% (n = 80) had three or more cardiovascular risk factors (P < 0.05).

Figure 4.

Proportion of women with individual risk factors (RFs) for cardiovascular disease (N = 4,157). ESC, European Society of Cardiology; EAS, European Atherosclerosis Society. According to SCORE risk charts, the mean (95% CI) risk of a fatal cardiovascular event in the next 10 years among participants who were assessed (n = 3,740) was 2.23% (2.15-2.31). SCORE risk was low (<1%) in 36.3% (n = 1,358) of women, mild (1%-2%) in 51.6% (n = 1,555) of women, moderate (3%-4%) in 12.6% (n = 470) of women, and high (5%) in 9.5% (n = 357) of women.
Osteoporosis Treatment

Overall, 85.0% (3,535/4,157) of women received osteoporosis treatment ( ); of these, 83.6% (n = 2,956) received pharmacological treatment, and 89.8% (n = 3,175) used nonpharmacological treatments or interventions, such as supplements and exercise. Osteoporosis treatment use among women with a high risk of bone fractures (two or more risk factors), a high endometrial risk (endometrial thickness 5 mm), and a high risk of developing breast cancer in the next 5 years (Gail index 1.66%) is presented in . The majority (>85%) of women with a high risk of bone fractures, endometrial pathology, or breast

cancer were using osteoporosis treatments; of these, more than 80% were using pharmacological treatments ( ). A significantly higher proportion of women with two or more risk factors (high risk) for bone fractures were receiving treatment (any) for osteoporosis compared with those who had one or no risk factors (P < 0.01); this was also the case for those receiving pharmacological osteoporosis treatment (P < 0.001).
Table 2. Use of osteoporosis treatments among all participants and among those with a high risk of bone fractures (two or more risk factors), a high endometrial risk (endometrial thickness 5 mm), and a high risk of developing breast cancer in the next 5 years (Gail index 1.66%)14

Treatment All women (N = 4,157) Osteoperosis (total) Supplements/exercise Calcium Calcium + vitamin D Exercise Pharmacological treatments Biophosphonates Selective estrogen receptor modulators Other Missing data

n (%)

3,535 (85.0) 3,175 (89.8) 363 (11.4) 2,529 (79.7) 1,304 (41.1) 2,956 (83.6) 1,437 (48.6) 1,237 (41.8) 211 (7.1) 71 (2.4)

Women with a high risk of bone fractures (two or more risk factors; n = 692) Any osteoperosis treatment (total) Pharmacological treatment Bisphosphonates Selective estrogen receptor modulators Other 617 (89.4) 539 (87.4) 275 (51.0) 205 (38.0) 59 (10.9)

Women with a high edometrial risk (thickness 5 mm; n = 301) Any osteoporosis treatment (total) Pharmacological treatment Bisphosphonates Selective estrogen receptor modulators Other 256 (85.0) 207 (80.9) 103 (49.8) 87 (42.0) 18 (8.7)

Women with a high risk of breast cancer (Gail index 1.66%; n = 423) Any osteoporosis treatment (total) Pharmacological treatment Bisphosphonates Selective estrogen receptor modulators Other "Other" treatments for osteoporosis include strontium and denosumab. 368 (87.0) 309 (84.0) 152 (49.2) 135 (43.7) 19 (6.1)

Table 2. Use of osteoporosis treatments among all participants and among those with a high risk of bone fractures (two or more risk factors), a high endometrial risk (endometrial thickness 5 mm), and a high risk of developing breast cancer in the next 5 years (Gail index 1.66%)14

Treatment All women (N = 4,157) Osteoperosis (total) Supplements/exercise Calcium Calcium + vitamin D Exercise Pharmacological treatments Biophosphonates Selective estrogen receptor modulators Other Missing data

n (%)

3,535 (85.0) 3,175 (89.8) 363 (11.4) 2,529 (79.7) 1,304 (41.1) 2,956 (83.6) 1,437 (48.6) 1,237 (41.8) 211 (7.1) 71 (2.4)

Women with a high risk of bone fractures (two or more risk factors; n = 692) Any osteoperosis treatment (total) Pharmacological treatment Bisphosphonates Selective estrogen receptor modulators Other 617 (89.4) 539 (87.4) 275 (51.0) 205 (38.0) 59 (10.9)

Women with a high edometrial risk (thickness 5 mm; n = 301) Any osteoporosis treatment (total) Pharmacological treatment Bisphosphonates Selective estrogen receptor modulators Other 256 (85.0) 207 (80.9) 103 (49.8) 87 (42.0) 18 (8.7)

Women with a high risk of breast cancer (Gail index 1.66%; n = 423) Any osteoporosis treatment (total) Pharmacological treatment Bisphosphonates Selective estrogen receptor modulators Other "Other" treatments for osteoporosis include strontium and denosumab.
Table 2. Use of osteoporosis treatments among all participants and among those with a high risk of bone fractures (two or more risk factors), a high endometrial risk (endometrial thickness 5 mm), and a high risk of developing breast cancer in the next 5 years (Gail index 1.66%)14

368 (87.0) 309 (84.0) 152 (49.2) 135 (43.7) 19 (6.1)

Treatment All women (N = 4,157) Osteoperosis (total) Supplements/exercise Calcium Calcium + vitamin D Exercise Pharmacological treatments Biophosphonates Selective estrogen receptor modulators Other Missing data

n (%)

3,535 (85.0) 3,175 (89.8) 363 (11.4) 2,529 (79.7) 1,304 (41.1) 2,956 (83.6) 1,437 (48.6) 1,237 (41.8) 211 (7.1) 71 (2.4)

Women with a high risk of bone fractures (two or more risk factors; n = 692) Any osteoperosis treatment (total) Pharmacological treatment Bisphosphonates Selective estrogen receptor modulators Other 617 (89.4) 539 (87.4) 275 (51.0) 205 (38.0) 59 (10.9)

Women with a high edometrial risk (thickness 5 mm; n = 301) Any osteoporosis treatment (total) Pharmacological treatment Bisphosphonates Selective estrogen receptor modulators Other 256 (85.0) 207 (80.9) 103 (49.8) 87 (42.0) 18 (8.7)

Women with a high risk of breast cancer (Gail index 1.66%; n = 423) Any osteoporosis treatment (total) Pharmacological treatment Bisphosphonates Selective estrogen receptor modulators Other "Other" treatments for osteoporosis include strontium and denosumab. 368 (87.0) 309 (84.0) 152 (49.2) 135 (43.7) 19 (6.1)

Discussion
The main objectives of this epidemiological study were to identify the clinical profile of Spanish postmenopausal women with a diagnosis of osteoporosis and to establish possible associations between women with osteoporosis and the presence of risk factors for other conditions. The data clearly show that, in addition to the increased risk of bone fractures, women with osteoporosis are also at risk for endometrial pathology, breast cancer, and cardiovascular disease. As expected in an osteoporotic population, almost half of the study participants had at least one risk factor for bone fractures

(in addition to being postmenopausal and having a T-score <-2.5, as measured by DXA). Moreover, at least one risk factor for breast cancer and at least one risk factor for cardiovascular disease were identified in 96.8% and 83.4% of participants, respectively. When the magnitude of risk was assessed, 20.1% of women presented with a high cardiovascular risk (three or more risk factors), 16.6% were at high risk for bone fractures (two or more risk factors, in addition to being postmenopausal and having a T-score <-2.5), and 14.5% were at high risk for developing breast cancer in the next 5 years, whereas less than 10% were identified as having a high endometrial risk. Although each of these conditions share a number of risk factors with osteoporosis (such as age, BMI, smoking status, and other lifestyle choices), it remains to be seen whether each of these conditions is linked with osteoporosis, or indeed with each other, by common pathophysiological mechanisms. Both pharmacological and nonpharmacological treatments/interventions for osteoporosis were used by most women in the study. Furthermore, use of pharmacological and nonpharmacological treatments was evenly matched among the high-risk groups for bone fractures, endometrial pathology, and breast cancer. Bisphosphonates and selective estrogen receptor modulators were used by around 50% and 40% of those using pharmacological treatment, respectively. Because these women were under the care of a gynecologist and were aware of their osteoporosis, it is not surprising that most of them were being treated for the condition. Treatment utilization among the general population of postmenopausal women with osteoporosis will not be as high because a large proportion of women will remain undiagnosed. Of note, a significantly higher proportion of participants with a high risk for bone fractures were receiving pharmacological and/or nonpharmacological osteoporosis treatment, compared with those who had one or no risk factors (P < 0.01). Again, it is possible that high-risk women had been advised by their prescribing gynecologist to use these treatments or interventions. However, regardless of individual clinical risk stratifications across the high-risk groups (ie, whether women were at high risk for bone fractures, endometrial pathology, or breast cancer), the proportion of women treated and/or the type of treatment they received seemed comparable. The epidemiology of osteoporotic bone fractures has been reviewed in the literature. In agreement with the current study, risk factors for bone fractures were identified as follows: female sex, estrogen deficiency associated with the postmenopausal period, young age at menarche, previous fractures, family history of fractures, cigarette smoking, excessive alcohol consumption, and low BMI.[1] Moreover, these risk factors have been commonly observed among postmenopausal women with osteopenia or osteoporosis, as shown in previous epidemiological studies using an approach similar to that of the current study (ie, interviews or questionnaires).[19-22] To our knowledge, no prior epidemiology studies have investigated the presence of risk factors for bone fractures, endometrial pathology, breast cancer, and cardiovascular disease in postmenopausal women with osteopenia and osteoporosis. Nevertheless, in line with the current findings, earlier studies have identified possible associations between osteoporosis and other conditions (such as rheumatoid arthritis,[23] breast cancer,[5,24,25] and cardiovascular disease[26-36]) in perimenopausal and postmenopausal women. The sample of women in this study, which included a broad range of medical characteristics and sociodemographics, was generally representative of Spanish postmenopausal women with osteoporosis who are visiting their gynecologist. Gynecologists were chosen as the recruiters for this study because they are the primary point of care for Spanish women seeking health checks or treatment of perimenopausal and postmenopausal symptoms or conditions. However, as with any study where participants are voluntarily seeking treatment from a healthcare provider, there will be an inherent bias in the sample, and this constitutes one of the limitations of this study. Women in this study will have received advice from their gynecologist regarding treatments and lifestyle interventions, such as diet, exercise, smoking, and alcohol intake, all of which may have altered the prevalence of risk factors for the other conditions investigated, including endometrial pathology, breast cancer, and cardiovascular disease. Furthermore, because these women were seeking advice from their gynecologist, it is possible that they may be more health-conscious and treatment-compliant than the general population they are intended to represent. In addition, another limitation of this study is that self-reporting questionnaires are often subject to underreporting and recall bias, particularly with respect to topics such as lifestyle choices and family history. An example of this is the proportion of participants (66.6%) who reported to have never smoked cigarettes, which is much higher than expected for this population. Of note, among women who underwent BMD scans during the study visit, around 20% were deemed to be nonosteoporotic (ie, they had a T-score >-2.5). These women had been diagnosed with osteoporosis within the last 2 years (as per inclusion criteria) and had received treatment and advice under the care of their gynecologist, which subsequently led to a reversal of their osteoporosis. A comprehensive WHO initiative has led to the development of an online fracture risk assessment tool (FRAX tool)[37,38] that enables physicians to estimate the individual risk of fracture for a particular individual. Although the FRAX tool is countryspecific, the Spanish version is not yet widely used among practicing gynecologists in Spain because several studies have

shown that it underestimates the risk of major osteoporotic fractures by nearly 50% and that it shows poor discriminative and predictive capacity overall.[39,40] Although previous data have described a possible association between osteoporosis and breast cancer and cardiovascular disease,[5,24-36] data from this study have highlighted the coexistence of risk factors for these conditions (and, additionally, endometrial pathology) in postmenopausal women who have recently been diagnosed with osteoporosis. Because many of the cardiovascular risk factors are modifiable (such as BMI, smoking, and diet), healthcare providers should use the time of diagnosis and treatment of postmenopausal osteoporosis as opportunities to also advise women on measures that can be taken to prevent cardiovascular outcomes. Although most of the identified risk factors for breast and endometrial cancer are nonmodifiable, healthcare providers caring for perimenopausal and postmenopausal women should remain diligent in assessing any possible risk factors for these conditions when treating women for osteoporosis to ensure that the most suitable pharmacological and nonpharmacological interventions are chosen. Equally, the bone health of women receiving treatment for endometrial pathology, breast cancer, or cardiovascular disease should be carefully monitored. During the transition through menopause, women should be encouraged to have regular and frequent health checks and to adopt a healthy lifestyle to reduce the risk of future illnesses.[13]

Conclusions
The findings from this study provide valuable insights into risk factors for conditions other than bone fracture that are present in women with osteoporosis. These risks should be evaluated and taken into consideration when choosing an osteoporosis treatment for postmenopausal women. Choice of osteoporosis therapy should be individualized based on consideration of efficacy, safety, cost, convenience (ie, dosing regimen and delivery), and other non-osteoporosis-related benefits associated with each agent. New studies that further analyze the therapeutic needs of women with osteoporosis are needed.
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