Osteoporosis International

, Volume 22, Issue 3, pp 781–787

Prevalent vertebral fractures predict subsequent radiographic vertebral fractures in postmenopausal Korean women receiving antiresorptive agent

Authors

  • S. H. Kim
    • Division of Endocrinology, Department of Internal MedicineKwandong University College of Medicine, Myongji Hospital
  • H. S. Choi
    • Division of Endocrinology, Department of Internal MedicineDongguk University Ilsan Hospital
  • Y. Rhee
    • Division of Endocrinology and Metabolism, Department of Internal MedicineYonsei University College of Medicine
  • K. J. Kim
    • Division of Endocrinology and Metabolism, Department of Internal MedicineYonsei University College of Medicine
    • Division of Endocrinology and Metabolism, Department of Internal MedicineYonsei University College of Medicine
    • Brain Korea 21 Project for Medical SciencesYonsei University
    • Institute of Endocrine ResearchYonsei University College of Medicine
Original Article

DOI: 10.1007/s00198-010-1298-y

Cite this article as:
Kim, S.H., Choi, H.S., Rhee, Y. et al. Osteoporos Int (2011) 22: 781. doi:10.1007/s00198-010-1298-y

Abstract

Summary

The relationship between prevalent vertebral fractures and new vertebral fractures in Korean women has not been previously studied. We found that prevalent vertebral fracture is a strong risk factor for subsequent radiographic vertebral fracture, independent of age and spine bone mineral density (BMD) in postmenopausal Korean women receiving antiresorptive agents.

Introduction

The presence of prevalent vertebral fractures increases the risk of subsequent vertebral fractures. This observational study examined whether prevalent vertebral fractures influenced future incident vertebral fracture in postmenopausal women receiving antiresorptive treatment.

Methods

Using the medical records, we retrospectively assessed 1,200 postmenopausal women who had visited the osteoporosis clinic. Among them, we selected patients whose BMD was measured at least once a year for 3 years. We excluded patients whose lateral spine X-ray film at baseline or follow-up period was missing, which is the key assessment. In the end, we analyzed 666 postmenopausal women. The mean duration of follow-up period was 3.2 years.

Results

The majority of patients (83%) received bisphosphonates or raloxifene during the mean duration of 3.2 years. Fifty-five of the 666 women had new incident radiographic vertebral fractures during the follow-up period. Prevalent vertebral fractures were associated with a five-fold increased risk (odd ratio 5.7, 95% CI 3.09–10.74) of incident vertebral fractures after adjusting for age. These associations remained significant after the adjustment for multiple confounding factors (odd ratio 4.4, 95% CI 1.97–9.75). The risk of incident vertebral fracture increased with the number of prevalent vertebral fractures at baseline: 3.4 (95% CI 1.54–7.70) for those with a single fracture and 7.4 (95% CI 3.10–17.54) for those with two or more after adjustment for age and spine BMD.

Conclusions

We confirmed that prevalent vertebral fracture is a strong risk factor for new vertebral fractures, independent of age and spine BMD in postmenopausal Korean women receiving antiresorptive agents.

Keywords

AlendronateBone densityOsteoporosisRaloxifeneVertebral fracture

Introduction

Vertebral fracture is the most common osteoporotic fracture, and it is a well-recognized and serious consequence of postmenopausal osteoporosis [1]. All vertebral fractures, whether symptomatic or radiographically identified, are associated with increased mortality and morbidity [2]. It is well established that a prior osteoporotic fracture increases the risk of future fractures [37]. Prevalent vertebral fractures have been shown to be strong predictors of incident vertebral fractures, independent of bone mineral density (BMD) [710]. Moreover, prevalent vertebral deformities increase the risk of subsequent hip fractures [8, 11]. Many published guidelines recommend that pharmacologic therapy, in order to reduce fracture risk, be considered for postmenopausal women with radiographic vertebral fracture, even in the absence of osteoporosis by BMD criteria [12, 13].

Fracture risk is strongly affected by ethnicity [14]; therefore, fracture risk factors should be evaluated according to each ethnic and population group. Moreover, the association of prevalent vertebral fractures and new vertebral fractures in patients receiving antiresorptive might be different when compared with those without osteoporosis medication in epidemiologic studies. Previously, the relationship between prevalent vertebral fractures and new vertebral fractures, especially in Korean women taking osteoporosis medication, has not been studied. We therefore retrospectively observed the effects of prevalent vertebral fractures on the risk of new vertebral fractures in postmenopausal Korean women receiving antiresorptive agents.

Materials and methods

Study population

Using the medical records of Severance Hospital, we retrospectively assessed postmenopausal women who had visited the osteoporosis clinic for the first time between January 2000 and December 2004. We further reviewed medical records of 1,200 patients to select patients whose BMD was measured at least three times annually until December 2006. We excluded patients whose lateral spine X-ray film taken upon onset of osteoporosis or upon the final year of the follow-up period was missing. Patients were also excluded if (1) they were taking any osteoporosis medication (bisphosphonate, raloxifene, or calcitonin) at baseline or had a history of osteoporosis medication, (2) they had other diseases such as rheumatoid arthritis, malignancy, renal dysfunction (serum creatinine >1.4 mg/dL), and Paget's disease, or (3) they were taking glucocorticoid. We also excluded patients who stopped osteoporosis medication during the follow-up period. In the end, we selected and analyzed 666 postmenopausal women. The mean duration of follow-up period was 3.2 years.

BMD assessment

BMD of the lumbar spine and hip was assessed by a dual energy X-ray absorptiometry (DXA, Hologic QDR4500W, Bedford, MA) at baseline and annually thereafter. The coefficients of variation for the lumbar spine and hip were both less than 1%.

Confirmation of prevalent radiographic vertebral fractures and incident radiographic vertebral fractures

The vertebral fracture was assessed using the visual semiquantitative vertebral deformity (SQ) scoring system of Genant et al. [15] An SQ score of 0 was assigned to normal vertebra; mild grade 1 deformity was defined as a 20–25% reduction in anterior, middle, or posterior vertebral height; moderate grade 2 deformity was defined as a 25–40% reduction in any height; and severe grade 3 deformity was defined as a 40% reduction in any height. A prevalent vertebral fracture was defined as more than grade 1 deformity. A new incident fracture was defined as a vertebral fracture occurring in a vertebra that was not fractured at baseline. One radiologist read 50 randomly selected radiographs on two separate occasions to evaluate the intraobserver reproducibility of the SQ. The intraobserver agreement based on the dichotomous fracture/non-fracture decision was 94% (κ = 0.86; P value < 0.01).

Statistical analysis

Statistical analysis was carried out using SPSS for Windows (v 11.0, SPSS Inc., Chicago, IL, USA). Baseline characteristics of women with prevalent radiographic vertebral fractures were compared with those of women without vertebral fracture using t tests for continuous variables and χ2 statistics for categorical variables. Logistic regression analyses were performed to determine the association between prevalent radiographic vertebral fractures and incident vertebral fractures. The first model was adjusted for age only, and the second model for age and baseline spine BMD. Finally, we included covariates which were significant in univariate analyses (P < 0.1). Covariates included in the final regression model were age, baseline spine BMD, body mass index (BMI), and use of antiresorptive agents (bisphosphonate or raloxifene) during the follow-up period.

To examine whether the impact of prevalent vertebral fractures on the risk of incident radiographic vertebral fractures varies according to the level of BMD, we divided the patients into two groups defined by the level of spine BMD (T-score between −1.0 and −2.5, and T-score ≤ −2.5). For each group, logistic regression models were used to evaluate the risk of incident vertebral fractures attributable to baseline prevalent vertebral fractures.

Results

Characteristics of subjects with/without vertebral fracture at baseline

At baseline, 567 patients had no prevalent vertebral fracture, and 99 (15%) had at least one fracture. Sixty subjects had a single fracture, 27 had two, and 12 had three or more at baseline. Women with prevalent vertebral fractures were older, further from menopause, and had lower BMD than those without any fracture (Table 1). At baseline, 215 of 567 patients (38%) without prevalent vertebral fracture had osteoporosis and 352 (62%) had osteopenia. Meanwhile, 68 of 99 subjects (69%) with prevalent vertebral fractures had osteoporosis.
Table 1

Baseline characteristics of study subjects

Variable

Without prevalent vertebral fractures (n = 567)

With prevalent vertebral fractures (n = 99)

P value

Age (years)

62.1 ± 7.0

68.1 ± 7.6

<0.001

Years since menopause

11.0 ± 6.8

17.5 ± 9.1

<0.001

Height

155.0 ± 4.8

152.1 ± 5.5

<0.001

Body mass index (kg/m2)

23.2 ± 2.6

23.6 ± 3.3

NS

Serum calcium (mg/dL)

9.6 ± 0.4

9.6 ± 0.3

NS

Inorganic phosphate (mg/dL)

3.8 ± 0.4

3.9 ± 0.4

NS

iPTH (pg/ml)

34.7 ± 15.8

34.8 ± 18.8

NS

25(OH)D (ng/mL)

16.4 ± 6.6

17.7 ± 8.0

NS

Estrogen use

   

Past or current

47 (8%)

8 (8%)

NS

BMD (T-score)

   

L-spine (L1-4)

−2.0 ± 0.9

−2.8 ± 1.1

<0.001

Femur neck

−1.7 ± 0.7

−2.2 ± 0.9

<0.001

Total hip

−1.1 ± 0.8

−1.8 ± 0.9

<0.001

Values are mean ± SD

iPTH intact parathyroid hormone, 25(OH)D 25-hydroxyvitamin D

Prevalent vertebral fractures and the risk of incident radiographic vertebral fractures

During the follow-up period of 3.2 years, 370 (55.5%) received bisphosphonates (daily or weekly), and 142 (21%) received raloxifene. Forty-four subjects (6.6%) received bisphosphonate followed by raloxifene or raloxifene followed by bisphosphonate. Ninety-seven percent of patients with prevalent vertebral fractures and 80% of patients without fracture were treated with antiresorptive agents.

Of 666 patients, 55 (8.3%) had one or more incident vertebral fractures during the follow-up period. Among those who had no prevalent vertebral fractures, 28 women (4.9%) developed new incident vertebral fractures. The prevalence of incident vertebral fractures increased with the number of vertebral fractures at baseline: 20% for those with a single fracture and 38% for those with two or more. After adjusting for age, patients with prevalent vertebral fractures at baseline showed a 5.7-fold increase in risk of incident vertebral fractures (95% CI 3.09–10.74). After an additional adjustment for the lumbar spine BMD, the association of prevalent vertebral fractures with incident radiographic vertebral fractures was attenuated but remained significant (OR, 4.7; 95% CI 2.40–9.11). Further adjustment for potential confounders did not alter the association (OR, 4.4; 95% CI 1.97–9.75) (Table 2). The hazard ratio increased with the number of prevalent vertebral fractures at baseline, which was 3.4 (95% CI 1.54–7.70) for those with a single fracture and 7.4 (95% CI 3.10–17.54) for those with two or more after the adjustment for age and spine BMD (Fig. 1).
Table 2

Relative risk (OR) of incident vertebral fracture in subjects with or without prevalent vertebral fracture

Baseline predictor

Age-adjusted OR (95% CI)

Age- and BMD-adjusted OR (95% CI)

Multivariate-adjusted ORa (95% CI)

I. In all patients (n = 666)

Any prevalent vertebral fracture

5.7 (3.09–10.74)

4.7 (2.40–9.11)

4.4 (1.97–9.75)

One vertebral fracture

4.0 (1.90–8.75)

3.4 (1.54–7.70)

2.5 (0.91–6.98)

Two or more vertebral fractures

9.2 (4.16–20.61)

7.4 (3.10–17.54)

10.3 (3.68–28.91)

II. In patients with OP medication (n = 556)

Any prevalent vertebral fracture

5.2 (2.71–9.98)

3.9 (1.95–7.90)

3.7 (1.81–7.36)

One vertebral fracture

3.3 (1.47–7.64)

2.6 (1.07–6.17)

2.4 (1.01–5.82)

Two or more vertebral fractures

8.8 (3.90–19.82)

6.8 (2.80–16.35)

5.7 (2.54–14.9)

aAdjusted for age, baseline spine BMD, BMI, and use of antiresorptive agents (bisphosphonate or raloxifene)

https://static-content.springer.com/image/art%3A10.1007%2Fs00198-010-1298-y/MediaObjects/198_2010_1298_Fig1_HTML.gif
Fig. 1

The risk for incident vertebral fractures increased with the number of prevalent vertebral fractures at baseline, which was 3.4 (95% CI 1.54–7.70) for those with a single fracture and 7.4 (95% CI 3.10–17.54) for those with two or more after the adjustment for age and spine BMD

Additionally, we examined the effect of prevalent vertebral fractures on incident vertebral fractures in 556 patients who were taking osteoporosis medication during the follow-up period. The risk of incident vertebral fractures appeared to be attenuated compared to that of all patients. The ratio increased with the number of prevalent vertebral fractures at baseline, which was 2.6 (95% CI 1.07–6.17) for those with a single fracture and 6.8 (95% CI 2.80–16.35) for those with two or more after the adjustment for age and spine BMD (Table 2).

Association between prevalent vertebral fractures and the risk of incident vertebral fractures according to the BMD level

In logistic regression analysis, spine BMD was an independent risk factor for new incident vertebral fractures along with prevalent vertebral fracture (Table 3). Furthermore, we examined whether the association between prevalent vertebral fractures and incident vertebral fractures changed according to the BMD level. Among osteopenic patients, a new vertebral fracture occurred in 22.5% of those with previous prevalent vertebral fractures and in 3.7% without prevalent vertebral fractures; 29.4% of osteoporotic patients with prevalent vertebral fractures and 6.9% of osteoporotic patients without fractures experienced new vertebral fractures. Baseline prevalent vertebral fractures were associated with a 6.5-fold increase (95% CI 2.09–19.90) of incident radiographic vertebral fractures in those with osteopenia after the adjustment for age and spine BMD. For those with osteoporosis, the relative risk for incident radiographic vertebral fractures was 3.7 (95% CI 1.66–8.48) (Table 4).
Table 3

Logistic regression analyses with new vertebral fractures as a dependent variable

Variable

Exp(B)

95% CI

P value

Age

1.05

0.99–1.10

NS

BMI

1.13

0.98–1.31

NS

Spine BMD

0.006

0.00–0.18

<0.01

Prevalent vertebral fracture

4.57

2.04–10.25

<0.01

Use of antiresorptive agents

2.21

0.65–7.52

NS

Age, BMI, spine BMD, prevalent vertebral fractures, and use of antiresorptive agents were entered into the binary logistic regression analysis

Table 4

Relative risk of age and BMD adjusted incident radiographic vertebral fracture in those with prevalent vertebral fractures according to BMD level

BMD level

Age and BMD-adjusted incident radiographic vertebral fracture [OR (95% CI)]

Prevalence of new incident radiographic vertebral fractures (number of new vertebral fractures)

Without prevalent vertebral fractures

With prevalent vertebral fractures

Osteopenia (n = 383) (T-score −1.0 to −2.5)

6.5 (2.09–19.90)

3.7% (13/352)

22.5% (7/31)

Osteoporosis (n = 283) (T-score ≤−2.5)

3.7 (1.66–8.48)

6.9% (15/215)

29.4% (20/68)

Discussion

In this observational study of 666 postmenopausal Korean women, we found that subjects with prevalent vertebral fractures were at a much higher risk of new incident vertebral fractures compared to those without them. Women with prevalent vertebral fractures have approximately four to five times higher risk of further vertebral fractures after the adjustment for age and spine BMD. Furthermore, the risk of new incident vertebral fractures increased with the number of previous vertebral fractures.

Previous studies have found that the prevalent vertebral fracture is a risk factor for an incident fracture. Black and colleagues [8] showed a five-fold increased risk of new vertebral fractures in elderly women with prevalent vertebral fractures after a mean of 3.7 years. Linsay and colleagues reported that almost 20% of postmenopausal women experience another fracture within 1 year of an incident vertebral fracture in a large clinical trial data analysis [4]. Moreover, a meta-analysis showed that women with preexisting vertebral fractures had an approximately a four times higher risk of subsequent vertebral fractures than those without prior fractures [16].

The relationship between prevalent vertebral fractures and new vertebral fractures in Korean women has not been previously studied. In the present study, we retrospectively observed the effect of prevalent vertebral fracture on the risk of new vertebral fractures in postmenopausal Korean women receiving antiresorptive agents. Many randomized clinical trials have shown that these antiresorptive agents reduced the incidence of vertebral fractures by up to 40–50% when compared with placebo in postmenopausal osteoporotic women [1719]. In our study, 83% of patients took oral bisphosphonate or raloxifene during the mean of 3.2 years, and more patients with prevalent vertebral fractures received either bisphosphonate or raloxifene compared to those without the fractures (97% vs. 80%). Nonetheless, the risk of incident vertebral fractures was 4.4 times higher in patients with prevalent vertebral fractures than those without fractures, even after the adjustment for multiple confounding factors. When the effect of prevalent vertebral fractures in patients who were taking antiresorptive agents was assessed exclusively, the risk of new vertebral fractures seemed attenuated but remained significant (2.6 for those with a single fracture and 6.8 for those with two or more).

In the Fracture Intervention Trial (FIT) among subjects with vertebral fracture at baseline, 15% of those in the placebo group and 8% of those in the alendronate group had experienced a new morphometric vertebral fracture [20]. In subjects without an initial vertebral fracture, new vertebral fractures had occurred in 4% in the placebo group and 2% in the alendronate group after 4.2 years [17]. Although there were some differences in age and baseline characteristics, subjects with baseline vertebral fractures seemed to have a four-fold increased risk of new vertebral fractures compared to those without baseline fractures in both group (15% vs. 4% in the placebo group, 8% vs. 2% in the alendronate group, respectively). In the Multiple Outcomes Raloxifene Evaluation (MORE) study, the risk of incident vertebral fracture was higher in patients with baseline vertebral fractures compared with those without fractures (21.2% vs. 4.5% in the placebo group, 14.7% vs. 2.3% in the raloxifene group) [21]. These results could be consistent with our study where women with prevalent vertebral fractures have a four times higher risk of further vertebral fractures after the adjustment for multiple factors. Moreover, these results could be consistent with a concept that the presence of previous vertebral fractures reflects the failure of bone quality regardless of BMD. Therefore, in addition to low BMD, a failure of bone quality may affect the occurrence of incidence vertebral fracture.

Recently, Lee et al. [22] identified clinical risk factors for osteoporotic fracture in Korean men and women. They reported that age, BMI, and history of previous fractures were independent risk factors of osteoporotic fracture in both sexes. Also, subjects with prior fractures had a higher risk of a clinical osteoporotic fracture (RR = 1.80 in women). The risk of subsequent fractures is not as great as that identified in our study. The discrepancy might be attributed to the fact that they included fracture events at several sites (hip, wrist, humerus, rib and pelvis, and vertebra). Vertebral fracture is commonly related to low BMD, while other sites of fractures are associated more with bone-related risk factors such as previous fracture history or parent's fracture history or fall-related risk factors than low BMD. Moreover, fractures at any particular site are most predictive of future fractures at that site. Other possible reasons for the discrepancy may be related to differences in the populations studied. In our study, the subjects were selected from the osteoporosis clinic at Severance Hospital which is a tertiary medical center. Subjects in our study were older (63.1 vs. 52.2 years) and more likely to have coexisting morbidity that might have increase the risk of fractures.

Low BMD is a well-known independent risk factor for new vertebral fractures. As expected, our study also showed that spine BMD as along with prevalent vertebral fractures was an independent risk factor for new vertebral fractures. In our study, prevalent vertebral fracture was associated with a greater risk of new vertebral fractures in patients with osteopenia compared to those with osteoporosis (6.5-fold vs. 3.7-fold). It was very hard for us to explain these results. Among patients without prevalent vertebral fracture, 3.7% of patients with osteopenia and 6.9% of osteoporosis patients developed new vertebral fractures. This result was consistent with the concept that low BMD was an important factor for new vertebral fracture. Meanwhile, among patients with prevalent vertebral fracture, the difference of new vertebral fracture incidence between the both groups was smaller than those without prevalent fracture (22.5% vs. 29.4%). These results suggest that prevalent vertebral fracture was another risk factor for new vertebral fractures regardless of BMD.

Our study has several limitations. First, as with all observational studies, systematic errors (e.g., selection bias) have been included in the observed results [23]. Observational errors may arise from differences in antiresorptive agents used during the follow-up period in our study. Second, we did not examine the effect of prevalent fracture severity on the risk of new vertebral fractures. Previous studies have shown that prevalent fracture severity, in addition to the number of fracture, was a valuable predictor of new vertebral fractures [24]. Third, we have no data on patients' compliance with osteoporosis treatment. However, we selected postmenopausal women whose BMD was measured at least three times. Thus, we consider the women in our study had a relatively good compliance.

In conclusion, within this observational study of women receiving antiresorptive agents, subjects with prevalent vertebral fractures had a much higher rate of new incident vertebral fractures than those without. We have reconfirmed that prevalent vertebral fractures increase the risk of further vertebral fractures in postmenopausal Korean women.

Conflicts of interest

None.

Copyright information

© International Osteoporosis Foundation and National Osteoporosis Foundation 2010