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Keywords:

  • osteopenic women;
  • risk factors;
  • fracture;
  • bone turnover markers;
  • bone densitometry

Abstract

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. Acknowledgements
  8. References

About one-half of women with incident fractures have BMD above the WHO diagnostic threshold of osteoporosis. In the OFELY study, low BMD, increased markers of bone turnover, and prior fracture could be used to identify, within osteopenic women, those at high risk of fracture.

Introduction: Recent data suggest that about one-half of women with incident fractures have BMD above the World Health Organization (WHO) diagnostic threshold of osteoporosis (T score ≤ −2.5). We aimed to identify, within osteopenic women, those at high risk of fracture.

Materials and Methods: In the 671 postmenopausal women (mean age: 62 years) belonging to the Os des Femmes de Lyon (OFELY) population-based prospective cohort, we measured at baseline BMD by DXA at the spine and total hip, bone turnover markers (BTM) and clinical risk factors for osteoporosis. All fragility vertebral or nonvertebral fractures, confirmed by radiographs, were assessed during a median follow-up of 9.1 years (IQ: 2.3).

Results: 158 incident fractures were recorded in 116 women: 8% in normal, 48% in osteopenic, and 44% in osteoporotic women. Among osteopenic women, low BMD (−2.5 < T score ≤ −2.0) was associated with an increased fracture risk with an age-adjusted hazard ratio (HR) of 2.5 (1.3-4.6). In addition, age, prior fracture, and high BTM—but not other risk factors—were independently associated with an increased fracture risk with an age-adjusted HR of 2.2 (1.2-4.3) for prior fractures and 2.2 (1.4-3.8) for bone alkaline phosphatase (BALP) in the highest quartile. In the whole group of osteopenic women, a large majority of incident fractures occurred in those with a low BMD, prior fractures, or BALP in the highest quartile, with an age-adjusted HR of 5.3 (2.3-11.8). The 10-year probability of fracture in osteopenic women was 26% if at least one predictor was present, contrasting with 6% in those without any of the three risk factors.

Conclusions: In postmenopausal women with osteopenia, low BMD, increased BTM, and prior fracture are associated with an increased risk of fracture in the subsequent 10 years. Their assessment may play an important role in identifying women at high risk of fracture who could not be adequately detected by BMD measurement alone and who may benefit from a therapeutic intervention.


INTRODUCTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. Acknowledgements
  8. References

PROSPECTIVE STUDIES HAVE shown that low BMD is the most important determinant of fragility fracture. (1–7) There is, however, a wide overlap of BMD values between fracture cases and controls because of the multiple determinants of skeletal fragility. In addition, some recent studies have shown that up to one-half of patients with incident fractures have baseline BMD above the World Health Organization (WHO) diagnostic threshold of osteoporosis (T score ≤ −2.5). (8–10) The relatively poor sensitivity of BMD, contrasting with a high specificity, means that many women who will fracture in their lifetime will not be identified to be at high risk on the basis of BMD assessment alone. Thus, if the treatment decision is taken only on the basis of BMD, using the WHO definition for osteoporosis, about one-half of postmenopausal women prone to sustain fracture(s) would not be considered for treatment. The combination of BMD with risk factors has been suggested to improve the detection of patient at risk (i.e., to increase the sensitivity without a commensurate decrease of specificity). (11)

Several risk factors for hip 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. (1, 11–14) We previously analyzed clinical risk factors for all fragility fractures (including hip and spine) in the Os des Femmes de Lyon (OFELY) cohort over 5 years. Seven predictors of incident fractures, independent of each other, were identified. (15) Moreover, several prospective studies have shown that markers of bone turnover are able to predict osteoporotic fracture risk. (16–18) In the OFELY study, we previously showed over a 5-year follow-up that increased serum bone alkaline phosphatase, as well as other bone turnover markers (BTMs), was associated with increased fracture risk, independently of the level of BMD. (19, 20) The aim of this study was to investigate which risk factors could be used to identify, within osteopenic women, those at high risk of fracture that may need therapeutic intervention.

MATERIALS AND METHODS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. Acknowledgements
  8. References

Subjects

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. (21, 22) We followed 671 postmenopausal women (mean age, 62.2 ± 9 years) from this cohort for 9.1 ± 2.3 years (median ± IQ). Women were considered postmenopausal if they had not been menstruating for a least 1 year at the entry in the study. They were categorized in three groups according to their baseline BMD values of the lumbar spine and total hip using the WHO criteria: normal (T score at the spine and total hip > −1), osteopenic (lowest T score at the spine or hip between −2.5 and −1), and osteoporotic (T score at the spine or hip ≤ −2.5). Thirty-one percent were normal, 48% were osteopenic, and 21% were osteoporotic. Further analyses were focused on the 322 osteopenic women.

Fracture evaluation

Nonvertebral fractures

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. 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.

Vertebral fractures

Lateral X-ray films of the thoracic and lumbar spine were obtained at baseline for 97% of women and every 4 years for 86% of them. The latest were obtained, on average, after 7.5 ± 1.6 years (range, 2.8-10.3 years) of follow-up. All prevalent and incident vertebral fractures were identified by the semiquantitative method of Genant(23) 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, as described previously. (15) It included medical history, medication use such as hormone replacement therapy (HRT), calcium, and vitamin D supplementation, tobacco use, calcium intake, reproductive characteristics, 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 described previously. (15) 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.

Bone densitometry

BMD was measured by DXA with a QDR 2000 device (Hologic, Waltham, MA, USA) at the lumbar spine and total hip. The in vivo precision error of DXA, expressed as the CV, was 0.9% and 1%, respectively. A control phantom was scanned every day, and all DXA measurements were performed by the same experienced operator.

Biochemistry

Blood samples were collected between 8:00 a.m. and 9:30 a.m. after an overnight fast. Serum samples were stored frozen at −70°C until assayed. Bone formation was evaluated with a human immunoradiometric assay (IRMA) for serum intact osteocalcin (intact OC; ELSA-OST-NAT CIS Biointernational, Gif/Yvette, France) and with an IRMA for bone-specific alkaline phosphatase (BALP; Ostase Beckman-Coulter, San Diego, CA, USA). The intra- and interassay CVs were <10% for both assays. Bone resorption was evaluated by measuring serum C-terminal cross-linking telopeptide of type I collagen (CTx) using an automatic analyzer (Elecsys; Roche Diagnostic) Intra- and interassay CVs were <3% and <8%, respectively. Bone markers were assessed at baseline in all women.

Statistical analysis

χ2 and unpaired t-tests were used to compare baseline characteristics between osteopenic women with and without incident fracture. The seven variables that were associated with fracture risk in a previous study from the OFELY cohort (age ≥ 65 years, past falls, low BMD, low grip strength, maternal history of fracture, low physical activity, and personal history of fragility fracture) in addition with body weight, HRT, and bone marker levels were analyzed. In osteopenic women, a low BMD was defined as a −2.5 < T score ≤ −2.0 according to the intervention threshold for osteoporosis recommended by National Osteoporosis Foundation (NOF) when no risk factor is present. (24) A Cox proportional hazards model based on time to first fracture was used to assess the effects of covariates on the risk of the occurrence of incident fracture. Results were expressed as hazard ratios (with 95% CIs). We used nominal variables based on the quartiles for BTMs. We expressed the fracture relative risk over 10 years, calculated from the 9-year follow-up. Kaplan-Meier curves and log-rank tests were used in the whole postmenopausal cohort to compare fracture occurrence between osteopenic women with and without any risk factor, osteoporotic, and normal women. Considering the number of women, the calculated power to highlight a risk of incident fracture twice as high with a level of statistical significance of 5% is 60% for a given risk factor, when 20% of nonfractured women have been exposed to the risk factor. All statistical analyses were performed using Statistical Analysis Software (SAS V8; SAS Institute, Cary, NC, USA).

RESULTS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. Acknowledgements
  8. References

During a median 9.1 years (IQ: 2.3) of follow-up, 158 incident fractures including 50 vertebral and 108 nonvertebral fractures were recorded in 116 women among the postmenopausal cohort, corresponding to an annual incidence of 19 per 1000 women/year. The duration of follow-up was 4.1 ± 3.6 years (median ± IQ) before the first fracture and 9.1 ± 1.1 years in women who did not sustain a fracture. Thirteen (8%) incident fractures occurred in women with normal BMD, 76 (48%) in osteopenic women, and 69 (44%) in osteoporotic women (Table 1). Subsequent analyses were devoted to the group of osteopenic women. Table 2 compares baseline characteristics in osteopenic women with and without incident fractures. Women with incident fractures were significantly older, had a higher body weight, were less frequent users of HRT, had fallen more often, had more prior fractures, had a lower BMD, and had higher BALP. In a multivariate analysis, age, prior fractures, BMD, and BTMs—but not other clinical risk factors—remained significantly associated with an increased risk of fracture.

Table Table 1.. Incident Fractures Among Postmenopausal Women From the OFELY Cohort According to the WHO Classification for BMD
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Table Table 2.. Baseline Characteristics of Osteopenic Women With and Without Incident Fragility Fracture
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In the whole group of osteopenic women, low BMD, defined as −2.5 < T score ≤ −2.0, was associated with an increased fracture risk with an age-adjusted hazard ratio (HR) of 2.5 (1.3-4.6). In addition, age, prior fracture, and BTMs were independently associated with an increased fracture risk. The age-adjusted HR was 2.2 (1.2-4.3) for history of prior fractures and 2.2 (1.4-3.8) for BALP in the highest quartile. Women with one or more of these three risk factors (i.e., low BMD, prior fracture, high BALP) were associated with an age-adjusted HR of 5.3 (2.3-11.8) to sustain a fracture. When serum CTx or serum osteocalcin was used instead of BALP, the corresponding HRs were significant but somewhat lower (data not shown). In osteopenic women, the 10-year probability of fractures was 25.6% if at least one predictor is present, contrasting with 6% in those without any of the three risk factors. Table 3 shows that, in osteopenic women, a large majority of incident fractures occurred in those that had one or more of the three risk factors.

Table Table 3.. Fracture Risk in Osteopenic Women With Low BMD, High Bone Turnover, or Prior Fracture(s)
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Survival probability without fracture was analyzed in the whole postmenopausal cohort according to the WHO criteria of BMD. Figure 1 shows that the risk of fracture in osteopenic women with one or more of the three risk factors was almost as high as that in osteoporotic women, irrespective of their risk factor profile. In contrast, the risk of fracture in osteopenic women without any of the risk factors was close to that in normal women. This pattern was even more apparent in women <65 years of age (Fig. 2).

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Figure FIG. 1.. Survival probability without fracture in postmenopausal women according to the WHO criteria of BMD (n = 671). Osteoporosis was defined by a T score at the lumbar spine or hip ≤ −2.5; osteopenia by the lowest T score at the lumbar spine or hip between −2.5 and −1; normal by a T score at the spine and total hip > −1. Among osteopenia, women were categorized in two groups: osteopenia with one or more risk factor(s) (RF+) and osteopenia without risk factor(s) (RF−). RF = low BMD (−2.5 < lowest T score ≤ −2.0), prior fracture, high level BTM.20

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Figure FIG. 2.. Survival probability without fracture in postmenopausal women <65 years of age (n = 441). Osteoporosis was defined by a T score at the lumbar spine or hip ≤ −2.5; osteopenia by the lowest T score at the lumbar spine or hip between −2.5 and −1; normal by a T score at the spine and total hip > −1. Among osteopenia, women were categorized in two groups: osteopenia with one or more risk factor(s) (RF+) and osteopenia without risk factor(s) (RF−). RF = low BMD (−2.5 < lowest T score ≤ −2.0), prior fracture, high level BTM.20

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DISCUSSION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. Acknowledgements
  8. References

This study shows that, in postmenopausal women with BMD values in the osteopenic range, low BMD, increased markers of bone turnover, and history of prior fracture are associated with an increased risk of fracture occurring in the subsequent 10 years. In our study, their combination allowed identification of the majority of women who will have an incident fracture. This improved sensitivity is obtained at the expense of a decreased specificity, and the HR of the risk of fracture was significantly higher (5.3; 95% CI, 2.3-11.8) in those with any of the three risk factors than in the whole osteopenic population.

BMD measurements are widely used to estimate the risk of osteoporotic fractures. However, many fractures occur in women with BMD above the WHO threshold of −2.5. In our study, 48% of women who sustained a fragility fracture over 9 years had a baseline BMD in the osteopenic range and 8% were in the normal range. Data from the National Osteoporosis Risk Assessment (NORA) population showed that 52% of the women experiencing an incident osteoporotic fracture within 1 year had a T score measured peripherally between −1 and −2.5 and 82% had a T score > −2.5. (25) In the Rotterdam Study, only 44% of all nonvertebral fractures—including fractures that resulted from high-energy trauma—occurred in women with a T score below −2.5. (10) Our results show that BMD still predicted fragility fractures among osteopenic women with a 2.5fold increased risk of fracture in women with −2.5 < T score ≤ −2.0.

Our results regarding the risk of subsequent fracture after a prior fracture are consistent with other reports that suggest that there is at least a 2-fold increased risk of subsequent fracture after a prior fracture. Several prospective studies have shown that fragility fractures increase the risk of subsequent fractures. (26–32) Results from the Multiple Outcomes of Raloxifene Evaluation (MORE) trial have shown that severity of vertebral fracture at baseline was a stronger predictor of nonvertebral fracture risk than low BMD. (33) Several studies found that the excess risk of further fracturing is fairly consistent over time, with up to 20 years of follow-up. (28, 30, 34)

Several prospective studies have shown a positive association between level of bone turnover and osteoporotic fracture risk. (18–20, 35, 36) However, studies relating levels of bone formation markers to risk of fracture have yielded somewhat conflicting results. Indeed, either a decrease, (37) no difference, (38) or an increase(17, 19) in bone formation markers has been reported to be associated with increased fracture risk. The difference between studies may be related to the type of fracture, the population studied, or the duration of follow-up. Recently, a large prospective study over 20 years failed to show an association between biochemical markers of bone turnover and risk of fracture, but the authors pointed out that the tests used (serum total alkaline phosphatase, urinary hydroxyproline, and a first-generation radioimmunoassay of serum osteocalcin) had lower sensitivity and specificity than those used currently. (39) In all studies showing that increased bone turnover is associated with an increased risk of fracture, the upper limit of premenopausal women—which corresponds approximately to the upper quartile of postmenopausal women—seems to be an adequate threshold. Indeed, the relationship between BTMs and fracture risk is not linear, with an increased risk that is significant for values above the normal premenopausal range. (18, 19, 36, 38, 40)

As previously reported in the same cohort after 5 years of follow-up, (19) we have shown that women with BALP levels in the upper quartile have an increased risk of fracture. Within the osteopenic population, BMD level was significantly associated with fracture risk. Although the association is linear, we selected a threshold corresponding to the NOF threshold for therapeutic intervention (i.e., a T score of −2). (24) Thus, most incident fractures occurred in women with any combination of one or more of these three risk factors (previous fracture, high BTMs, low BMD), a pattern that may be useful for identification of postmenopausal women at risk.

The other clinical risk factors for fractures were not predictors of fracture in osteopenic women in the multivariate analysis. In a previous study from the same cohort, we identified seven independent variables associated with an increased fracture risk in all postmenopausal women. (15) In those with a BMD in the osteopenic range, only age, BMD, and prior fractures were still predictors of fragility fractures. This discrepancy could be explained by a longer follow-up in this analysis (9 versus 5 years), because grip strength, physical activity, and falls could have a short-term effect on fragility fractures that does not persist with time. In addition, the risk profile for fractures might be different in the subgroup of osteopenic women compared with the general population of postmenopausal women. In a very large cohort of osteopenic women from NORA, previous fractures, low BMD at a peripheral site, poor health status, and poor mobility were identified as the most important determinants of short-term fracture occurring over 1 year. Nevertheless, bone markers were not analyzed in that study. (41)

Because low BMD is the major determinant of fracture in postmenopausal women, the assessment of BMD is currently an important tool to determine whether women are candidates for therapeutic intervention. Current clinical guidelines recommend treatment in the presence of osteoporosis as defined by the WHO criteria. (42) Recently, the IOF recommended that treatment be offered to women with a BMD T score above the −2.5 diagnostic threshold in the presence of independent risk factors. (43) Our findings are consistent with this by showing that the risk of fracture in osteopenic women with prior fractures or high BTM is close to that in osteoporotic women. In contrast, osteopenic women with no risk factor could be assimilated to normal women in terms of risk of fragility fracture.

When previous vertebral fractures were excluded from the analysis, prior fractures and/or high bone turnover were still associated with an increased risk of fracture (data not shown).

Women at high risk of fracture may benefit from therapeutic intervention if risk factors are amenable to bone-specific agents. Indeed, some BMD-independent risk factors such as risk of falls are important predictors, especially for hip fracture, but may not be modified by pharmacological intervention. For example, risedronate did not reduce the risk of hip fracture in elderly women enrolled in the presence of fall-related risk factors, whereas it did so in osteoporotic women. (44) Alendronate did not reduce the risk of clinical fractures in women with a T score < −1.6, but it did so in those that also had a prevalent vertebral fracture. (45, 46) Finally, a greater reduction in fracture risk among women with high pretreatment levels of bone turnover has been shown with ibandronate(47) and alendronate. (48) Thus, osteopenic women with previous fractures or high BTM levels are likely to respond to antiresorptive agents, although this should be tested prospectively.

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. Moreover, we analyzed the most specific and sensitive biochemical markers of bone turnover. Our study was limited by a relatively small number of osteopenic women who sustained incident fracture(s), which precluded the identification of risk factors specific for a given type of fracture and by the lack of power to analyze separately the various combinations of the three risk factors. Although we found that 85% of osteopenic women with incident fracture (s) had one or more of the three identified risk factors for fracture, this number should be interpreted cautiously and should be assessed in large cohort with more incident fractures. In addition, women were community-dwelling white volunteers, and our findings may not be generalized to other populations. Overall, our results need to be confirmed in larger longitudinal studies.

We conclude that, in postmenopausal women with BMD values in the osteopenic range, a low BMD, an increased level of BTMs, and history of prior fracture predict the risk of vertebral and nonvertebral fractures up to 10 years later. Their assessment may play an important role in identifying women at high risk of fracture who could not be adequately detected by BMD measurement alone and who may benefit from therapeutic intervention.

Acknowledgements

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. Acknowledgements
  8. References

The authors thank A Bourgeaud, O Borel, B Vey-Marty, and D Oury for excellent technical assistance. This work was supported by a contract from INSERM-MSD-Chibret (OFELY Study).

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  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. Acknowledgements
  8. References
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