Severity of prevalent vertebral fractures and the risk of subsequent vertebral and nonvertebral fractures: results from the MORE trial

Abstract

Prevalent vertebral fractures and baseline bone mineral density (BMD) predict subsequent fracture risk. The objective of this analysis is to examine whether baseline vertebral fracture severity can predict new vertebral and nonvertebral fracture risk. In the randomized, double-blind 3-year Multiple Outcomes of Raloxifene Evaluation (MORE) trial, 7705 postmenopausal women with osteoporosis (low BMD or prevalent vertebral fractures) were randomly assigned to placebo, raloxifene 60 mg/day, or raloxifene 120 mg/day. Post hoc analyses studied the association between baseline fracture severity and new fracture risk in the placebo group and the effects of placebo, raloxifene 60 mg/day, and raloxifene 120 mg/day on new fracture risk in women with the most severe prevalent vertebral fractures (n = 614). Vertebral fracture severity was visually assessed using semiquantitative analysis of radiographs and categorized by estimated decreases in vertebral heights. Reported new nonvertebral fractures were radiographically confirmed. Baseline vertebral fracture severity predicted vertebral and nonvertebral fracture risk at 3 years. In women without prevalent vertebral fractures, 4.3 and 5.5% had new vertebral and nonvertebral fractures, respectively. In women with mild, moderate, and severe prevalent vertebral fractures, 10.5, 23.6, and 38.1% respectively had new vertebral fractures, whereas 7.2, 7.7, and 13.8% respectively experienced new nonvertebral fractures. Number of prevalent vertebral fractures and baseline BMD also predicted vertebral fracture risk, but the severity of prevalent vertebral fractures was the only predictor of nonvertebral fracture risk and remained a significant predictor after adjustment for baseline characteristics, including baseline BMD. In patients with severe baseline vertebral fractures, raloxifene 60 mg/day decreased the risks of new vertebral [RR 0.74 (95% Cl 0.54, 0.99); P = 0.048] and nonvertebral (clavicle, humerus, wrist, pelvis, hip, and leg) fractures [RH 0.53 (95% CI 0.29, 0.99); P = 0.046] at 3 years. To prevent one new fracture at 3 years in women with severe baseline vertebral fractures with raloxifene 60 mg/day, the number needed to treat (NNT) was 10 for vertebral and 18 for nonvertebral fractures. Similar results were observed in women receiving raloxifene 120 mg/day. In summary, baseline vertebral fracture severity was the best independent predictor for new vertebral and nonvertebral fracture risk. Raloxifene decreased new vertebral and nonvertebral fracture risk in the subgroup of women with severe vertebral fractures at baseline. These fractures may reflect architectural deterioration, independent of BMD, leading to increased skeletal fragility.

Introduction

Patients with osteoporosis are susceptible to fractures due to multifactorial changes in bone quality and/or quantity, which together contribute to bone strength [1]. Additional risk factors for osteoporotic fractures include age, previous osteoporotic fractures, genetic predisposition, and falls [2]. Acceleration of bone turnover with aging leads to bone loss, which is manifest as decreased bone mineral density (BMD) [3] and disruption of trabecular architecture [4], which in turn results in impaired bone strength and increased fracture risk [5].

Baseline BMD and prevalent radiographic vertebral fractures are independent predictors of subsequent vertebral and nonvertebral fractures [6], [7], [8]. Observational case-control studies have found that patients with existing vertebral fractures have an increased risk of new vertebral and nonvertebral fractures [9], [10], [11], [12]. In randomized prospective clinical trials, women with radiographic vertebral fractures at baseline have a higher incidence of new vertebral fractures at endpoint, compared to women without baseline vertebral fractures, irrespective of therapeutic intervention [13], [14], [15]. The number of prevalent radiographic vertebral fractures also predicts the risk of subsequent vertebral and nonvertebral fractures [16], [11], [10], [17]. Furthermore, the occurrence of a new vertebral fracture increases the risk of subsequent vertebral fractures within the following year, and this increased risk is exacerbated by the number of prevalent vertebral fractures [17]. Patients with more severe degrees of vertebral deformities, measured as a relative decrease in vertebral height, have an increased risk of subsequent vertebral and nonvertebral fractures [11].

Although several lines of evidence indicate that baseline BMD, the presence and number of vertebral fractures at baseline, and the severity of prevalent vertebral fractures all contribute to decreased bone strength and increased fracture risk, no study to date has directly compared each of these contributing factors on their ability to predict subsequent fracture risk. All of these factors were assessed in the 3-year Multiple Outcomes of Raloxifene Evaluation (MORE) clinical trial in which vertebral fracture severity was determined by semiquantitative (SQ) assessment. The analysis of fracture incidence in the placebo group of MORE provided the opportunity to determine the relationships between each of these contributing osteoporosis risk factors and subsequent fracture risk.

The present analyses examined the relationship between the severity of baseline vertebral fractures and the risk of subsequent vertebral and nonvertebral fractures and compared the prediction of new fracture risk by baseline vertebral fracture severity to other baseline osteoporosis risk factors in the placebo group of the MORE trial. Because women with severe baseline vertebral fractures were found to have the greatest risk of subsequent fracture, further analyses examined the efficacy of raloxifene in reducing the risk of new fractures in this subgroup.