BMD is a major determinant of the risk of fragility fractures, but the role of the rate of postmenopausal bone loss is still unclear. In 671 postmenopausal women from the OFELY cohort, we found that the rate of bone loss was significantly associated with fracture risk independently of other well-known predictors including BMD and previous fractures.
Introduction: The level of BMD is a major determinant of the risk of fragility fractures, but the role of the rate of postmenopausal bone loss is still unclear.
Materials and Methods: In the OFELY study, we analyzed the risk of fracture in 671 postmenopausal women (mean age, 62.2 ± 9 years), according to the rate of bone loss. BMD was measured annually by DXA at the forearm, with a mean number of measurements of 10.3 ± 2.6. Peripheral fractures, all confirmed by radiographs, were prospectively registered, and vertebral fractures were evaluated with spine radiographs every 4 years.
Results: During a median (interquartile range [IQ]) of 11.2 years (11–12.3 years) of follow-up, 183 incident fragility fractures including 53 vertebral and 130 nonvertebral fractures were recorded in 134 women. The annual median ± IQ rate of bone loss, calculated from the slope, was −0.30 ± 0.76% at the mid-radius, −0.55 ± 0.79% at the distal radius, and −0.40 ± 0.96% at the ultradistal radius. Women with incident fracture had a rate of bone loss (before fracture) higher by 38–53% than those without fracture (p = 0.0003–0.016). Using multivariate Cox regression models, we found that bone loss in the highest tertile at the mid-radius, distal radius, and ultradistal radius was associated with a significant increased risk of all fractures with an hazard ratio from 1.45 to 1.70 (p = 0.02 to p = 0.009 after adjusting for age, previous fractures, maternal history of fracture, physical activity, grip strength, falls, and baseline BMD).
Conclusions: The rate of bone loss in postmenopausal women is significantly associated with fracture risk independently of other well-known predictors such as BMD and history of fractures.
THE RISK OF fragility fracture in postmenopausal women is mainly determined by a low BMD.(1–3) Because osteoporosis is a systemic disease, measurement of BMD at the spine, hip, and forearm has the same ability to predict all fractures.(2,3) There is, however, a wide overlap of BMD values between fracture cases and controls, because of the multiple determinants of skeletal fragility. Thus, it appears that up to one-half of patients with incident fractures have baseline BMD above the WHO diagnostic threshold of osteoporosis.(4–8)
Several clinical risk factors for fractures have been shown to contribute to fracture probability independently of BMD, such as age, maternal history of hip fracture, prior fragility fractures, and neuromuscular deficit.(9–12) We have previously analyzed clinical risk factors for all fragility fractures in the Os des Femmes de Lyon (OFELY) cohort over 5 years, and seven predictors of incident fractures, independent of each other, were identified.(13)
The rate of bone loss, which is variable among postmenopausal women, has been postulated to be an independent risk factor for fractures.(14–16) However, only two studies have analyzed the association between the rate of bone loss and the risk of fracture. In both, the rate of bone loss was obtained from the forearm site over a short period of time (2 years), whereas fractures were recorded over 5–15 years.(17,18)
The aim of our study was to evaluate the role of postmenopausal forearm bone loss measured over 10 years on the long-term risk of all fragility fractures in a well-defined population based cohort and to analyze the potential interaction of other determinant of fractures such as BMD level and clinical risk factors.
MATERIALS AND METHODS
OFELY is a prospective study of the determinants of bone loss in 1039 volunteer women, recruited between February 1992 and December 1993, 31–89 years of age, randomly selected from the affiliates of a large health insurance company (Mutuelle Générale de l' Education Nationale) from the Rhône district (i.e., Lyon and its surroundings in France), with an annual follow-up. Written informed consent was obtained from each woman, and the study was approved by the local ethical committee. The OFELY cohort has been described elsewhere.(19,20) We followed the 671 postmenopausal women (mean age, 62.2 ± 9 years) from this cohort during 11.2 ± 1.1 years (median ± interquartile range [IQ]). Women were considered postmenopausal if they had not been menstruating for a least 1 year at the entry in the study.
Prior fractures were those that occurred after the age of 40 years, identified by self-reporting during the baseline questionnaire. Incident fractures were reported during each annual follow-up. The information about incident fractures was obtained in 648 women (97%). For women who did not come to the clinical center, a letter was sent every year to identify the occurrence of fractures. All peripheral fractures were confirmed by radiographs or by a surgical report. Only low-trauma fractures (i.e., those occurring with falls from standing height or less) were taken into account, and we excluded fractures of fingers, toes, skull, and face.
Lateral X-ray films of the thoracic and lumbar spine were obtained at baseline for 97% of women, and on average after 8.9 ± 2.8 years (range, 2.8–13.8 years) of follow-up for 85% of them. All prevalent and incident vertebral fractures were identified by the semiquantitative method of Genant et al.(21) by a trained rheumatologist. A vertebra was classified as fractured on the baseline radiograph if any vertical height (anterior, middle, and/or posterior) was reduced by >20%. An incident 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. We excluded vertebral fractures that occurred because of major trauma and vertebral deformities due to other causes than osteoporosis such as osteoarthritis and Scheuermann's disease.
Clinical evaluation and physical examination
Women completed a questionnaire at the initial screening visit and at each annual follow-up, described previously.(13) It included medical history, medication use, tobacco use, calcium intake, age of menopause, and family history of fragility fracture. The occurrence of fall(s) during the past 12 months was recorded. Physical activity was expressed by a score calculated from sport or recreation, job, and home activities.(13) Height and body weight were recorded at each visit. The grip strength was measured at baseline by a hand dynamometer (Vigorimeter Martin) on the left and right hand, using a maximum of two readings for each hand.
Forearm BMD was annually measured by pencil beam DXA with a QDR 2000TM device between 1992 and 1999 and with a QDR 1000 + TM between 1999 and 2003 (Hologic, Waltham, MA, USA). A cross-calibration has been obtained from the measurements of 93 women on both devices. There was a linear relationship and functional equivalency between the two QDR scanners with a r2 = 0.99 for the forearm total BMD. Thus, no correction was done.
The number of annual measurements was 10.3 ± 2.6 (SD). The mid-radius, distal radius, and ultradistal radius were measured. The mid-radius is composed mainly (∼95%) of cortical bone, the distal area comprises both cortical and trabecular bone (∼25%), and the ultradistal contains more trabecular bone. The in vivo precision error of DXA, expressed as the CV, was 1.2%, 0.6%, and 1.2% for the mid, distal, and ultradistal areas, respectively. A control phantom was scanned every day, and all DXA measurements were performed by the same experienced operator. The in vitro long-term precision of DXA over the 11-year study was 0.41%.
A valid assessment of the BMD rate of change at the other sites (hip, spine, whole body), measured with a multidetector mode (fan beam) was not obtained in this cohort because of technical problems that specifically affected this mode. A drift in phantom values was observed over time that could not be reliably corrected.
χ2 and unpaired t-tests were used to compare baseline characteristics between women with and without incident fracture. Bone loss was calculated from the mean of the individual slopes divided by the intercept and expressed in percentage per year. The values of BMD obtained after an incident fracture were not used to exclude the bias introduced by a potential accelerated bone loss induced by the fracture itself. Because the tests of normality, skewness, and kurtosis coefficients have shown that bone loss was not normally distributed, nonparametric tests were used to compare bone loss between women with and without fracture. The seven variables that were independently associated with fracture risk in a previous study from the same cohort (age ≥ 65 years, past falls, low BMD, low grip strength, maternal history of fracture, low physical activity, and personal history of fragility fracture)(13) were integrated in a multivariate analysis in addition to bone loss. A Cox proportional hazards regression model based on time to first fracture was used in the analysis of the relationship between potential risk factors and the risk of incident fractures. Risks were expressed as hazard ratios (with 95% CIs). All statistical analyses were performed using the Statistical Analysis Software (SAS V8; SAS Institute, Cary, NC, USA).
The annual median ± IQ rate of bone loss—calculated over a period of 10.0 ± 2.0 years (median)—was −0.30 ± 0.76% at the mid-radius, −0.55 ± 0.79% at the distal radius, and −0.40 ± 0.96% at the ultradistal radius. The frequency distribution of the rate of bone loss is shown in Fig. 1. There was no significant difference of the annual rate of bone loss according to follow-up duration. When the mid-radius BMD was expressed according to years of follow-up, the linear model appeared as the best for the analysis of bone loss, and no accelerated bone loss was found within the study (Fig. 2). A similar pattern of BMD change was found at the distal and ultradistal sites. An accelerated bone loss was observed in women within 5 years of menopause at the ultradistal radius, with a rate of bone loss that was 27% higher (p = 0.02) than after 5 years. Conversely, no significant association between the duration of menopause and the rate of bone loss was found at the mid-radius and distal radius.
During a median of 11.2 years (IQ, 1.1 years) of follow-up, 183 incident fragility fractures including 53 vertebral and 130 nonvertebral fractures were recorded in 134 women (Table 1). The duration of follow-up was 5.6 ± 4.8 years (median ± IQ) before the first fracture, with at least two BMD measurements before the first fracture in 127 women (95%). Fractures were identified by letter in 24 women (i.e., 18%). Table 2 compares baseline characteristics in postmenopausal women with and without incident fractures. Women with incident fractures were significantly older, had more prior fractures, and had a family history of fracture; they had lower physical activity and grip strength and fell more frequently; and their BMD was lower at all sites of the radius. Women with incident fractures had a rate of bone loss that was 38–53% higher than those without fracture (p = 0.0003–0.0016; Fig. 3).
Table Table 1.. Incident Fractures Among Postmenopausal Women From the OFELY Cohort: 183 Fractures Occurred in 134 Women During a Follow-up of 11.2 ± 1.1 Years (Median ± IQ)
Table Table 2.. Baseline Characteristics of Postmenopausal Women With and Without Incident Fragility Fracture
Using multivariate Cox regression models, we found that, among the seven variables that where independently associated with an increased risk of fracture over 5 years in a previous analysis from the same cohort, five of them remained independent predictors of fracture incidence over an 11-year follow-up (i.e., age, baseline BMD, previous fractures, family history of fracture, and physical activity; Table 3). Conversely, left grip strength and past falls were no longer associated with an increased risk of fracture. When we added the rate of bone loss in that multivariate analysis, we found that a bone loss in the highest tertile at the mid, distal, and ultradistal radius (i.e., >0.55%, 0.70%, and 0.81%, respectively) was associated with a significant increased risk of all fractures with a hazard ratio from 1.45 to 1.70 (p = 0.02 to p = 0.009) after adjusting for age, previous fractures, maternal history of fracture, physical activity, grip strength, falls, and baseline BMD (Table 4). The results did not change if we introduced hormone replacement therapy in the model.
Table Table 3.. Multivariate Analysis of Fracture Risk in Postmenopausal Women
Table Table 4.. Multivariate Analysis of Fracture Risk in Postmenopausal Women With a High Rate of Bone Loss
Our data indicate that the rate of bone loss in postmenopausal women is significantly associated with fracture risk independently of other well-known predictors such as BMD, age, and history of fractures.
A recent cross-sectional study suggested that bone loss—evaluated by QCT of the forearm, spine and hip—is linear over time at cortical sites, and that at the trabecular sites, bone loss begins before the menopause with no significant acceleration of bone loss after the menopause.(22) There have been relatively few long-term longitudinal studies on the rate of bone loss. Longitudinal data provide better estimates of the rate of bone loss than cross-sectional evaluation, because age-related changes in bone size within an individual are less than those seen across the aging population.(23) The age-related bone loss has been shown to persist at a significant rate in elderly women.(24,25) Melton et al.(23) have shown that the longitudinal rate of bone loss assessed at several skeletal sites was generally greater among individuals ≥70 years of age compared with younger women, but part of the difference might be related to a greater proportion of younger women on hormone replacement therapy, whose rate of bone loss was slower.
Contrasting with previous longitudinal studies,(16,26) but in agreement with others(27) and a previous study from the same cohort,(28) we did not find an accelerated bone loss in the first years after menopause at the distal radius and mid-radius, in which compact bone is predominant. In contrast, the rate of loss measured at the ultradistal radius, containing a large proportion of trabecular bone, was higher within 5 years of menopause than after 5 years.
To our knowledge, there are only two studies that have correlated the rate of bone loss with the risk of fractures. In a study from Riis et al.,(17) 182 women within 3 years of menopause were followed longitudinally for 15 years. Forearm bone mass was measured nine times over the first 2 years by single photon absorptiometry, and a group of “fast bone losers” losing >3% per year was identified. At 15 years, 23 women had experienced a Colle's fracture and 25 had a spinal fracture. The fracture group had significantly lower bone mass at baseline and had a higher rate of bone loss after menopause than the group without fracture. Low bone mass and high bone loss contributed to the same extent to the risk of fractures with odds ratios of 1.9 and 2.0, respectively. In women with both low bone mass and increased rate of bone loss, the odds ratio increased to 3.0. In another prospective study, BMD was measured at the proximal and distal radius 2 years apart in 656 postmenopausal women. During an average follow-up of 5.4 years after the second BMD measurement, 121 nonspinal fractures were detected. The 2-year rate of bone loss at the proximal radius was significantly associated with the subsequent fracture risk in women below and over 65 years of age, even after adjusting for baseline BMD. In women >65 years of age, the rate of bone loss at the proximal radius—but not other predictors such as baseline BMD and history of fractures—was the only predictor of incident fractures. In contrast, the rate of bone loss measured at the distal radius was not related to the risk of fractures.(18)
The methodology of our study was different because bone loss was measured annually and calculated until the occurrence of fracture and not only in the first 2 years. Moreover, these two previous studies used single photon absorptiometry to measure changes in BMD, whereas in our study, DXA—with its better reproducibility—was used. In addition, we studied a population-based cohort and not patients referred to a clinical center, and we assessed prospectively fractures both at vertebral (every 4 years) and nonvertebral (annually) sites. Finally, the design of our study allowed us to assess whether the association of fractures with the rate of bone loss is related to other well-characterized risk factors for fractures.
We found that the association between bone loss and risk of fracture is independent of other factors, including BMD. Few studies have analyzed long-term fracture prediction with BMD. Most of them show that BMD remains a significant predictor of >5 years and up to 20 years after BMD assessment.(2,3,29–31) However, despite the strong association between BMD and fracture risk, less than one-half of incident fractures occur in women with osteoporosis defined with the WHO criteria (i.e., with a BMD T score ≤ −2.5), underlying the importance of risk factors for fracture independant of BMD level.(3,32) Finally, the rate of bone loss was still associated with an increased risk of fracture if the BMD measurement closest to the time of fracture was introduced in the multivariate model instead of the baseline BMD (data not shown). Thus, the role of the rate of bone loss on the risk of fracture seems to be independent of the low bone mass induced by the rate of bone loss itself. In a previous study from the same cohort, we identified seven variables independently associated with an increased fracture risk over 5 years in postmenopausal women.(13) Although most of them remained significantly associated with an increased risk of fracture over an 11-year follow-up, past falls and grip strength were no longer predictive. These risk factors might have a short-term effect on fragility fractures that does not persist with time. Moreover, in our previous study, history of falls was a weak predictor of fragility fractures. Age, prior fracture, maternal history of fractures, and physical activity were associated with an increased risk of fracture over 11 years, a finding consistent with previous studies.(33–39)
Bone loss after menopause is clearly attributed to an increased bone turnover rate with an excess of bone resorption over formation, and previous longitudinal studies have shown that high bone turnover measured by biochemical markers of bone turnover is associated with an increased rate of bone loss.(14,40–42) The identification of women at risk for fracture should therefore consider not only a measurement of bone mass status but also a determination of the postmenopausal rate of loss either by estimation from biochemical markers of bone turnover or by repeated bone mass measurement. In a previous study from the same cohort, we found that women with levels of markers of bone turnover in the highest quartile or above the upper limit of the premenopausal range had a greater rate of bone loss(41) and an increased risk of osteoporotic fractures(42) during a mean of 5 years of follow-up.
In this study, the rate of bone loss measured over 11 years at the mid and distal radius was still correlated with baseline serum C-terminal cross-linking telopeptide of type 1 collagen (CTx; r = −0.31 and −0.27, respectively) and osteocalcin (r = −0.23 and −0.22, respectively) and weakly with bone alkaline phosphatase (r = −0.11 and −0.10, respectively), but not the ultradistal rate of loss. When baseline markers were entered in the Cox model, the prediction of fracture risk by the rate of bone loss was unchanged (data not shown). Thus, although the increased risk of fracture associated with a rapid rate of bone loss is likely to be mediated, at least in part, by an increased rate of bone turnover, it cannot be captured by baseline bone turnover markers over a long period of time. A high rate of bone loss might be associated with a deterioration of trabecular bone structure (e.g., plate perforation and loss of connectivity), leading to an increased risk of fracture.(43) Thus, an increased rate of bone loss could enhance skeletal fragility independently of the level of bone mass.
Our study has strengths and limitations. We followed a well-characterized cohort of postmenopausal women for a long period of time. All fragility fractures were prospectively assessed and radiographically confirmed. The repetition of spine radiographs every 4 years allowed an optimal ascertainment of vertebral fractures because only a small proportion of them reach clinical attention. The application of a Cox's proportional hazards model was limited by the fact that the time to fracture for vertebral fracture could not be determined completely. Another limitation is that bone loss was only measured at the radius. That site has a low precision error and is therefore suitable for longitudinal assessment of bone loss. Forearm BMD predicts all osteoporotic fractures as well as spine and hip measurements. Indeed, although spine and hip BMD are the best sites to predict spine and hip fractures, respectively, the increased risk of all fragility fractures is similar for a 1 SD decrease of BMD at the radius, spine, or hip.(2) In addition, women were community-dwelling white volunteers, and our findings may not be generalized to other populations. Thus, our results should be confirmed in larger longitudinal studies.
In conclusion, our data show that the long-term rate of bone loss in postmenopausal women is significantly associated with fracture risk independently of other well-known predictors such as BMD and history of fractures.
The authors thank A Bourgeaud, B Vey-Marty, and N Omari for excellent technical assistance. This work was supported by a contract INSERM-MSD-Chibret (OFELY Study).