Independent predictors of all osteoporosis-related fractures in healthy postmenopausal women: The OFELY Study

Article Outline

• Abstract
• Introduction
• Methods
  • Patient population
  • Questionnaire
  • Physical examination
  • BMD and radiologic measurements
  • Data analysis
• Results
• Discussion
• Acknowledgements
• References
• Copyright

Abstract 

Several epidemiological studies have identified clinical factors that predict the risk of hip fractures in elderly women independently of the level of bone mineral density (BMD), such as low body weight, history of fractures, and clinical risk factors for falls. Their relevance in predicting all fragility fractures in all postmenopausal women, including younger ones, is unknown. The objective of this study was to identify independent predictors of all osteoporosis-related fractures in healthy postmenopausal women. We prospectively followed for 5.3 ± 1.1 years a cohort of 672 healthy postmenopausal women (mean age 59.1 ± 9.8 years). Information on social and professional conditions, demographic data, current and past medical history, fracture history, medication use, alcohol consumption, caffeine consumption, daily calcium intake, cigarette smoking, family history of fracture, and past and recent physical activity was obtained. Anthropometric and total hip bone mineral density measurements were made. Incident falls and fractures were ascertained every year. We observed 81 osteoporotic fractures (annual incidence, 21 per 1000 women/year). The final model consisted of seven independent predictors of incident osteoporotic fractures: age ≥ 65 years, odds ratio estimate (OR), 1.90 [95% confidence interval (CI) 1.04–3.46], past falls, OR, 1.76 (CI 1.00–3.09), total hip bone mineral density (BMD) ≤ 0.736 g/cm², OR, 3.15 (CI 1.75–5.66), left grip strength ≤ 0.60 bar, OR, 2.05 (CI 1.15–3.64), maternal history of fracture, OR, 1.77 (CI 1.01–3.09), low physical activity, OR, 2.08 (CI 1.17–3.69), and personal history of fragility fracture, OR, 3.33 (CI 1.75–5.66). In contrast, body weight, weight loss, height loss, smoking, neuromuscular coordination assessed by three tests, and hormone replacement therapy were not independent predictors of all fragility fractures after adjustment for all variables. We found that some—but not all—previously reported clinical risk factors for skeletal fragility predicted all fragility fractures independently of BMD in healthy postmenopausal women, although they differed somewhat from those predicting specifically hip fractures in elderly women. These risk factors appear to reflect quality of bone structure (previous fragility fracture), lifestyle habits (physical activity), muscle function and health status (grip strength), heredity (maternal history of fracture), falls, and aging. Measurements of these variables should be included in the clinical assessment of the risk of osteoporotic fractures in postmenopausal women.

Keywords:  Osteoporosis, Fracture, Clinical risk factors, Epidemiology

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Introduction 

The identification of all the determinants of fragility fractures is of critical importance. A better understanding of mechanisms leading to fractures is a crucial step in the identification of patients at risk and for designing therapeutic strategies. Over the past few years, such an approach has been focused on hip fractures because they are associated with an excess of mortality and mobility impairment and because of the high cost of their treatment [1]. However, there are other osteoporosis-related fractures, especially in the spine, that are associated with significant pain, disability, and impairment of quality of life. Vertebral fractures have also been shown to be associated with a significant excess in mortality in both men and women [2], [3].

Most studies of the determinants of fragility fractures have been dedicated to hip fractures [4], [5] and to some extent to those of the upper limb [6], [7]. Those determinants that have been shown to predict the risk of hip fracture may not necessarily be extrapolated to other fractures, because hip fractures occur at a later age than most other fractures and because their mechanism may encompass determinants that may not apply to all other fragility fractures. Few prospective studies have analyzed clinical risk factors for all fragility fractures [8], [9], [10], [11], [12], [13], and most of them have not included a systematic review of potential risk factors. The study of Nguyen has included a variety of risk factors reflecting environment, bone mineral density, and clinical parameters [8]. In that study, restricted to women over the age of 60, hip bone mineral density, quadriceps muscle strength, and gait parameters were independent determinants of the occurrence of fragility fractures.

Excluding young postmenopausal women from such studies may result in a panel of independent risk factors that may be relevant to elderly women, but not necessarily to younger ones. In order to correct this bias, we looked at the ability of a variety of risk factors (familial and personal history of fracture, medical and gynecological history, physical activities, anthropometric parameters, health habits, muscle and coordination clinical testing) as well as of bone mineral density to predict the occurrence of all types of fragility fractures, in a prospective cohort of postmenopausal women, 50–85 years of age, followed annually for an average of 5 years.

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Methods 

Patient population 

The OFELY study is a cohort of 1039 women, 31–89 years of age, stratified by age groups. Subjects were recruited between February 1992 and December 1993. All women are healthy ambulatory Caucasian volunteers, randomly selected from a health insurance company (Mutuelle Générale de l’Education Nationale ) from the Rhône district, i.e., the region around Lyon, France. Eighteen percent of women contacted volunteered to participate in the study. Their demographics are close to those of the general French population, as the age pyramids are quite similar. The Ofely cohort has been described elsewhere [14]. This study has been approved by the local ethical committee.

We followed 672 postmenopausal women (mean age 59.1 ± 9.8 years) for 5 years. Women were considered postmenopausal if they had not been menstruating for a least 1 year. Those that menstruated within the past year with follicle-stimulating hormone (FSH) concentrations above 22.2 U/liter (mean +2 SD of OFELY premenopausal women with regular menstruation, aged 30–45 years) were considered menopaused.

Questionnaire 

All women completed a written standardized baseline health questionnaire at the initial screening visit. The questionnaire included social and professional conditions, current and past medical history, medication use, hormone replacement therapy (HRT), calcium and vitamin D supplementation, alcohol and caffeine consumption, tobacco use, calcium consumption, physical activity, reproductive characteristics, breast-feeding, age of menopause, numbers of years since menopause, and family history of fragility fracture (wrist fracture, humeral fracture, vertebral fracture, and hip fracture). Current daily calcium intake was based on a food frequency questionnaire [15] that has been previously validated in the cohort [16]. Alcohol consumption was documented separately for spirits, wine, and beer. For each category the weekly consumption was documented. The total alcohol consumption was measured in grams per year. Both coffee and tea consumption were recorded as number of cups by week. Tobacco consumption was calculated by pack times years. Wrist fracture, humeral fracture, vertebral fracture, and hip fractures which occurred after age 45 and were identified only by self-reporting during the baseline interview were considered prevalent osteoporosis fractures. Only low-trauma fractures (i.e., those occurring with falls from standing height or less) were taken into account and classified a prevalent fragility fractures. The occurrence of a fall(s) during the past 12 months was recorded.

Physical examination 

Height and weight were measured with participants wearing indoor clothes and no shoes. Body mass index (BMI) was calculated as body weight/height [2]. The grip strength was measured by a hand dynamometer (Vigorimeter Martin) on the left and right hands using a maximum of two readings for each hand. Fat body mass and lean body mass were assessed using total body dual-energy X-ray absorptiometry (DXA) (see below). Walking speed was measured by the time to cover a 5-m distance (back and forth) at a usual walking pace. The tandem walk was recorded as the time to complete a 2-m course, walking heel to toes along a line marked on the floor. For the full-tandem balance test, women were asked to stand with the heel of one foot in front of and touching the toes of the other foot. The procedure is performed first with eyes open and repeated with eyes closed, testing the women’s ability to hold the positions for 10 s. Chair stand was measured as the time to stand up from a standard chair five times; women were asked not to use their arms for assistance, if possible. Women were interviewed on physical activity by a questionnaire inspired by the 7-day physical activity recall (PAR) questionnaire [17], [18]. We explored recent physical activity (sports or recreation, job, home activities) and past physical activity (only sports). For assessing recent and past physical activity, a cumulative physical activity score from 0 to 27 was constructed, derived from the 7-day PAR [19]. Women were classified into two groups: sedentary, with no physical activity or light physical activity, score ≤ 14, and moderate physical activity or high physical activity, score > 14. A fall was defined as “when you land on the floor, or other lower level, by accident.”

BMD and radiologic measurements 

BMD was measured by DXA on a Hologic QDR 2000 device (Hologic Inc., Waltham, MA, USA). The coefficients of variation (CV) were 0.9% for the lumbar spine, 1.2% for the femoral neck, 1.7% for the trochanter, and 1% for the total hip region and at the radius, respectively, 1.2, 0.6, and 1.2% for the mid, distal, and ultradistal regions [14]. A phantom scan was performed every day, and the system calibrated once a week. Results are expressed in grams per square centimeter. For statistical analysis of hip BMD, we used only total hip area. Women were followed once a year for a mean (± SD) of 5.3 ± 1.1 years. Fracture incidence was assessed during the yearly visit. For women who did not come to the clinical center, a letter was sent every year to identify the occurrence of fractures. Information about incident fractures was obtained in 89.9% of the cohort. Lateral X-ray films of the thoracic and lumbar spine were obtained at baseline for all women and at follow-up for 79% of them after an average of 3.8 years (2.8–5.3 years). All vertebral prevalent and incident fractures were identified by the semiquantitative method of Genant [20] by a trained rhumatologist. A vertebra was classified as having a prevalent fracture on the baseline radiograph if any vertical height (anterior, middle, and/or posterior) was reduced by more than 20%. A new fracture was defined by a decrease of 20% or more and of least 4 mm in any vertebral height of one or more thoracic or lumbar vertebrae between follow-up and baseline X-ray films [21], [22]. All peripheral fractures were confirmed by the radiologist and/or by the surgical report [23]. Vertebral fracture, hip fracture, distal forearm fracture, ankle fracture, patella fracture, pelvis fracture, sacrum fracture, and proximal arm fracture were considered osteoporotic fractures. We excluded fractures that occurred because of major trauma, such as motor vehicle accident, and fractures of toes and hands.

Data analysis 

Fracture incidence is calculated by dividing the number of women with one or more fragility fracture by the number of women in the entire cohort; χ² and t tests were used to compare baseline characteristics between women with and without fragility fractures. A logistic regression model was used in the analysis of the relationship between potential risk factors and the risk of fragility fractures. From basic parameter estimates of the model, odds ratios (OR) with confidence intervals (95% CI) were computed. Because osteoporotic fracture incidence is low, OR represent a good approximation of the relative risk of fracture. We expressed the osteoporotic fracture relative risk over 5 years. Multivariate analysis was performed in addition to the univariate analyses, allowing us to estimate the effect of a variable after adjustment for the effect of other variables. All variables that were important in the univariate analyses, or were considered of interest a priori, were further analyzed in multivariate analysis. We used nominal variables based on the quartiles for BMD total hip, grip strength, age, and physical activity. Interactions were systematically tested. All statistical analyses were performed using the package Staview, version 4.5 (SAS Institute Inc., USA).

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Results 

During a follow-up of 5.3 ± 1.1 years there were 75 women with at least one incident fracture among the 672 healthy postmenopausal women (Table 1). The annual incidence of fragility fractures was 21 per 1000 women/year. During the follow-up, daily calcium intake, caffeine consumption, alcohol consumption, tobacco consumption, anthropometrics measurements, and physical activity were stable (data not shown). Baseline characteristics of women with and without incident fragility fracture are given in Table 2. Women with incident fractures were 9 years older than those without. Women with fractures have a higher percentage of prevalent fractures and falls. None of the gynecology history variables—nulliparity, breast-feeding, number of childbirths, age of menarche, hysterectomy, ovariectomy—were associated with the risk of osteoporotic fracture, but the percentage of women on HRT was smaller in those with than in those without incident fractures. The score of physical activity was lower in women with fractures. Right and left hand grip strengths were smaller in women with fractures. Women with fractures had significantly worse gait and balance measures. We observed a significant weight loss from 25 years of age to inclusion in women with fractures. Women with fracture have a significantly lower BMD at all sites of measurement. Table 3 shows significant predictors of fragility fractures in univariate analysis. In contrast, there was no consistent association between smoking, alcohol consumption, caffeine consumption, and daily intake of calcium and the risk of osteoporotic fracture. Diabetes mellitus, thyroid or parathyroid disorders, renal insufficiency, rheumatoid arthritis, hypertension, gastric or intestinal surgery or malignancy, and stroke were uncommon and not significantly associated with an increased risk of fragility fractures (data not shown).

Table 1. Numbers of incident fragility fractures during a 5-year follow-up

Note. There were 81 fractures in 75 women.

Table 2. Baseline characteristics of women with and without incident fragility fracture

Table 3. Univariate correlates of fragility fractures in healthy postmenopausal women

Logistic regression analysis disclosed that personal history of fracture, femoral hip BMD, age, left grip strength, physical activity, falls, and maternal history of fractures are significant and independent predictors of fractures. Maximum likelihood estimates (odds ratio) and associated statistics are given in Table 4. We observed that fractures occurred most frequently in subjects in the lowest total hip bone mineral density quartile (≤ 0.736 g/cm²), after 65 years of age, in those in the lowest left grip strength quartile (≤ 0.60 bar), with sedentary or moderate physical activity (score ≤ 14), with personal history of fall, with personal history of fragility fracture, and with maternal history of fracture. In our study BMD at all sites of measure was a strong predictor of future incident fractures, especially at the total hip (OR, 3.15; CI, 1.75–5.66). The total deviance (R²) of fragility fractures explained by the multivariate model was 17%. The total deviance of fracture explained only by the total hip BMD was 10%.

Table 4. Multivariable model for prediction of 5-year risk of fragility fractures in 649 healthy postmenopausal women

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Discussion 

The incidence of fragility fractures among women in the OFELY cohort, with an age of 59.0 ± 9.7 years was 21 per 1000 women/year. This rate is close to that observed in American women more than 35 years of age (22/1000 women/years) [24] and lower than that of Australian women more than 60 years of age (29.5/1000 women/year) [2], [25] and of American women more than 65 years of age (30/1000 women/year) [26]. The incidence is low compared to that in studies in elderly women. In the “Dunedin program,” the incidence of fragility fractures among elderly women (73.0 ± 5.3 years) was 44.2/1000 women/year [12]. The rate was even higher (47.9/1000 women/year) in Dutch elderly women aged 80.3 ± 5.6 years [27].

We found that some—but not all—of the previously reported risk factors for fragility fractures were independent predictors of all osteoporotic fractures in our cohort of postmenopausal women. Several aspects differ in our study from previous reports: (1) our cohort was younger (mean age 59 years) than previous ones, including earlier postmenopausal women; (2) we did a comprehensive analysis of all potential predictors of fractures previously identified, including inherited and environmental clinical risk factors, by an extensive questionnaire, measurements of BMD, fat and lean body mass, as well as a battery of tests of neuromuscular function and physical activity; (3) we analyzed all fragility fractures—not only of the hip—as a primary end point. The best predictors were previous fragility fractures and low BMD. Several other prospective studies have found similar results for different osteoporotic fracture types [4], [7], [27], [28]. While previous fractures may reflect impaired bone microarchitecture they may also indicate an increased likelihood of falls [29]. In our multivariate model history of fall is a weak but independent predictor of fragility fractures. In such a young cohort history of fragility fractures is more likely to reflect bone strength through architectural parameters unrelated to bone mass per se. Prospective studies [8], [30], [31], [32], [33], [34], [35], [36] have shown that BMD is a major determinant of fragility fracture risk (hip, vertebral, and other types). We found that in women with a total hip BMD in the lowest quartile, i.e., ≤ 0.736 g/cm² (T score ≤ −1.79), the relative risk of fracture is even higher (3.15) than that in previous studies [37], stressing the importance of bone mass in relatively young postmenopausal women compared to other risk factors. There is, however, a wide overlap of BMD values between fracture cases and controls, because of the multiple determinants of skeletal fragility [37], [38], [39]. This limitation stresses the need to identify other determinants, independent of BMD, to improve the assessment of the absolute risk of fracture.

We found that five clinical variables (physical activity, grip strength, age, maternal history of fracture, and falls in decreasing order of importance) can predict the risk of fragility fractures in postmenopausal women independently of the level of BMD and of the personal history of fractures. In our study, women with sedentary or moderate physical activity had a twofold increased risk of fracture compared to those more active. Regular walking for exercise has been associated with a decreased risk of hip fracture [4], [40]. While physical inactivity and immobility have been associated with an increased risk of hip fracture [12], [41], [42], [43], [44], [45], [46], this relation has not been found for wrist and vertebral fractures [47]. A study suggested that past physical activity and moderate levels of recent physical activity have independent protective effects against the risk of hip fracture in postmenopausal women [48]. The mechanisms explaining this association are complex. Physical fitness has been found to be associated with BMD in one study [49] but not in another [50]. In our cohort BMD and physical activity were not significantly correlated after adjustment for confounding variables. Physical activity predicts hip fracture risk after adjustment for self-rated health [4] and may reflect unidentified determinants of skeletal fragility.

The relationship between hand grip strength and hip fracture has been shown in women and in men in some [51], [52], [53] but not all [4], [5] studies. While two studies failed to find an association with other osteoporotic fractures [54], [55] we found that women with hand grip strength in the lowest quartile had an a twofold increased risk of all osteoporotic fractures. Grip strength reflects overall muscle strength. Hand grip strength predicts functional limitations and grade disability and estimates the risk of disability and the risk of mortality in nondisabled older people [56], [57], [58], [59]. Actually hand grip strength may also be decreased by cognitive impairment, joint disorders, diabetic neuropathy, and pain, especially in the elderly. The association of muscle strength with functional status, independently of coexisting medical problems, has been assessed [60]. Grip strength was strongly associated with Instrumental Activities of Daily Living independence [61] and a weak hand grip strength was a strong predictor of functional decline in elderly people [62]. Hand grip strength is probably a marker of health status independent of several other risk factors, as shown in our study.

Age predicts fracture independently of BMD level [63] but also of history of fractures, falls, physical activity, and grip strength. Age is probably a surrogate marker of one or several unidentified risk factors. A maternal history of fractures after menopause was also an independent predictor of fractures independently of other risk factors, as previously reported by Cummings in more elderly women [4], probably capturing inherited determinants of bone strength (e.g., architecture and morphology) independent of BMD. In contrast to other studies [4], [8], [64], we found that history of falls in the past 12 months was a predictor of fragility fractures independent of neuromuscular functions assessed by a battery of clinical tests. The propensity to fall depends on a variety of determinants, also including visual impairment, cognitive function, the use of anxiolytic drugs, as well as the type of falls [65].

In our study, alcohol consumption, calcium intake, smoking, and low body weight did not predict incident fractures after adjusting for other variables. Body weight is significantly correlated with BMD [66], [67], [68], [69] and does not predict hip fractures after adjustment for BMD [70]. Weight loss has been found to predict the risk of hip fracture in elderly women [70], [71], probably reflecting frailty and poor health. Interestingly, weight loss did not predict all fragility fractures in our younger cohort of postmenopausal women.

Our study has some limitations: the number of incident fractures is relatively limited (81) and does not have the power to identify risk factors specific to a given type of fracture, nor to analyze the role of risk factors according to age. In addition, participants were community dwelling white volunteers and our findings may not apply to other races, more disabled women, or men. The number of fractures is not very important but the incidence is similar to those of other studies in the world. The follow-up was not very long; perhaps with an increase in follow-up all variables would have a different predictive performance.

In conclusion we identified seven independent predictors of fragility fractures in postmenopausal women reflecting different potential mechanisms. By decreasing order of importance, they were prevalent fragility fractures (probably reflecting the quality of bone structure), BMD (reflecting the interaction between peak bone mass and bone loss), physical activity (lifestyle), grip strength (a marker of muscle function and health), aging, maternal history of fractures (heredity), and history of falls. We suggest that these items should be included in the clinical assessment of risk for osteoporosis fracture in postmenopausal women.

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Acknowledgements 

We thank E. Vey-Marty and A. Bourgeaud-Lignot for excellent technical support, Dr. Bauer for critical revision of the manuscript, and P. Garnero for helpful discussion.

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