Risk Of Clinical Vertebral Fractures Research Articles

Ankylosing spondylitis and the risk of fracture: results from a large primary care-based nested case-control study

Background and aims:Ankylosing spondylitis (AS) is associated with bone loss in the vertebrae and an increased prevalence of vertebral fractures, but literature about the magnitude of the risk of fracturing...

Effects of Raloxifene on Fracture Risk in Postmenopausal Women: The Raloxifene Use for The Heart Trial

Using data from a randomized placebo-controlled trial of 10,101 postmenopausal women not selected on the basis of osteoporosis, we examined whether the effect of raloxifene treatment on fractures was consistent across categories of fracture risk. Treatment with raloxifene for 5 yr reduced the risk of clinical vertebral fractures, but not nonvertebral fractures, irrespective of the presence or absence of risk factors for fracture. In The Raloxifene Use for The Heart (RUTH) trial, women assigned to raloxifene had a lower risk of clinical vertebral fractures but not nonvertebral fractures. However, it is uncertain whether the effect of raloxifene on fractures in this population not selected for low BMD differs according to risk factors for fractures. We randomly assigned 10,101 postmenopausal women >or=55 yr of age with documented coronary heart disease or at high risk for coronary events to 60 mg raloxifene daily or placebo and followed them for a median of 5.6 yr. Fractures (nonvertebral and clinical vertebral) were prespecified secondary endpoints that were reported at semiannual visits. Fractures were adjudicated and confirmed using X-ray reports or medical records. There was no difference between raloxifene and placebo groups in risk of nonvertebral fractures (428 versus 438 events; hazard ratio [HR], 0.96; 95% CI, 0.84-1.10), including hip/femur (89 versus 103 events; HR, 0.85; 95% CI, 0.64-1.13) and wrist (107 versus 111 events; HR, 0.95; 95% CI, 0.73-1.24) fractures. Women treated with raloxifene had a lower risk of clinical vertebral fractures (64 versus 97 events; HR, 0.65; 95% CI, 0.47-0.89). The effect of treatment with raloxifene on risk of nonvertebral and clinical vertebral fractures was consistent across fracture risk categories defined at baseline by age, smoking status, physical activity level, prior history of fracture, family history of hip fracture, diabetes mellitus, previous use of hormone therapy, thyroid hormone use, statin use, weight loss, body mass index, or fracture specific summary risk score. In older women with or at high risk of coronary heart disease not selected on the basis of osteoporosis or increased fracture risk, treatment with raloxifene for 5 yr reduced the risk of clinical vertebral fractures, but not nonvertebral fractures, irrespective of presence or absence of risk factors for fracture.

Effects of Continuing or Stopping Alendronate After 5 Years of Treatment. The Fracture Intervention Trial Long-term Extension (FLEX): A Randomized Trial

Pharmacokinetic studies have shown that bisphosphonates remain in the bone matrix for many years and are gradually released as bone is resorbed. The terminal half-life of one of these drugs, alendronate, exceeds 10 years, raising the possibility that some of its skeletal effects may continue for years after treatment ceases. In the Fracture Intervention Trial, a randomized, double-blind, placebo-controlled trial conducted at 10 clinical centers in the US, 1,099 postmenopausal women who had taken alendronate for an average of 5 years were randomly assigned to take alendronate in a dose of 5 or 10 mg daily or placebo for 5 years longer. All participants had low bone mineral density (BMD) at the femoral neck at the outset. Follow-up for clinical fractures averaged 4.2 years. Adding 5 years of alendronate therapy in a daily dose of 5 or 10 mg maintained total hip BMD compared with placebo. The mean total hip BMD declined 1% in women taking the medication and 3.4% in placebo recipients. Similar changes were found for the femoral neck and trochanter when analyzed separately. Lumbar spine BMD increased by 5.3% in the alendronate group and 1.5% in placebo patients. Comparable differences were found for total-body and forearm BMD. At each site, the gain in BMD after 10 years on alendronate was significantly greater than when treatment was limited to 5 years. Markers of bone turnover remained close to baseline during continued alendronate therapy but increased gradually in women taking placebo. Despite a lack of significant differences between treatment groups for all clinical fractures or nonvertebral fractures, the risk of clinical vertebral fracture was significantly lower for women who continued on alendronate (2.4% versus 5.3% in placebo recipients). The relative risk was 0.45, with a 95% confidence interval of 0.24-0.85. Loss of height did not differ significantly. No histomorphometric differences were found when 18 iliac crest biopsies were examined. Women in the two groups had similar numbers of serious adverse effects, and there were no significant group differences in rates of withdrawal because of adverse events or in mortality rates. Continuing alendronate therapy for as long as 10 years maintains bone mass, reduces bone remodeling, and does not increase the risk of fracture. Maintaining active treatment may be especially beneficial for women who are at high risk of clinical vertebral fracture as evidenced by a history of fracture or very low BMD.

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Effects of Continuing or Stopping Alendronate After 5 Years of Treatment

The optimal duration of treatment of women with postmenopausal osteoporosis is uncertain. To compare the effects of discontinuing alendronate treatment after 5 years vs continuing for 10 years. Randomized, double-blind trial conducted at 10 US clinical centers that participated in the Fracture Intervention Trial (FIT). One thousand ninety-nine postmenopausal women who had been randomized to alendronate in FIT, with a mean of 5 years of prior alendronate treatment. Randomization to alendronate, 5 mg/d (n = 329) or 10 mg/d (n = 333), or placebo (n = 437) for 5 years (1998-2003). The primary outcome measure was total hip bone mineral density (BMD); secondary measures were BMD at other sites and biochemical markers of bone remodeling. An exploratory outcome measure was fracture incidence. Compared with continuing alendronate, switching to placebo for 5 years resulted in declines in BMD at the total hip (-2.4%; 95% confidence interval [CI], -2.9% to -1.8%; P<.001) and spine (-3.7%; 95% CI, -4.5% to -3.0%; P<.001), but mean levels remained at or above pretreatment levels 10 years earlier. Similarly, those discontinuing alendronate had increased serum markers of bone turnover compared with continuing alendronate: 55.6% (P<.001) for C-telopeptide of type 1 collagen, 59.5% (P < .001) for serum n = propeptide of type 1 collagen, and 28.1% (P<.001) for bone-specific alkaline phosphatase, but after 5 years without therapy, bone marker levels remained somewhat below pretreatment levels 10 years earlier. After 5 years, the cumulative risk of nonvertebral fractures (RR, 1.00; 95% CI, 0.76-1.32) was not significantly different between those continuing (19%) and discontinuing (18.9%) alendronate. Among those who continued, there was a significantly lower risk of clinically recognized vertebral fractures (5.3% for placebo and 2.4% for alendronate; RR, 0.45; 95% CI, 0.24-0.85) but no significant reduction in morphometric vertebral fractures (11.3% for placebo and 9.8% for alendronate; RR, 0.86; 95% CI, 0.60-1.22). A small sample of 18 transilial bone biopsies did not show any qualitative abnormalities, with bone turnover (double labeling) seen in all specimens. Women who discontinued alendronate after 5 years showed a moderate decline in BMD and a gradual rise in biochemical markers but no higher fracture risk other than for clinical vertebral fractures compared with those who continued alendronate. These results suggest that for many women, discontinuation of alendronate for up to 5 years does not appear to significantly increase fracture risk. However, women at very high risk of clinical vertebral fractures may benefit by continuing beyond 5 years. clinicaltrials.gov Identifier: NCT 00398931.

Effects of Raloxifene on Cardiovascular Events and Breast Cancer in Postmenopausal Women

The effect of raloxifene, a selective estrogen-receptor modulator, on coronary heart disease (CHD) and breast cancer is not established. We randomly assigned 10,101 postmenopausal women (mean age, 67.5 years) with CHD or multiple risk factors for CHD to 60 mg of raloxifene daily or placebo and followed them for a median of 5.6 years. The two primary outcomes were coronary events (i.e., death from coronary causes, myocardial infarction, or hospitalization for an acute coronary syndrome) and invasive breast cancer. As compared with placebo, raloxifene had no significant effect on the risk of primary coronary events (533 vs. 553 events; hazard ratio, 0.95; 95 percent confidence interval, 0.84 to 1.07), and it reduced the risk of invasive breast cancer (40 vs. 70 events; hazard ratio, 0.56; 95 percent confidence interval, 0.38 to 0.83; absolute risk reduction, 1.2 invasive breast cancers per 1000 women treated for one year); the benefit was primarily due to a reduced risk of estrogen-receptor-positive invasive breast cancers. There was no significant difference in the rates of death from any cause or total stroke according to group assignment, but raloxifene was associated with an increased risk of fatal stroke (59 vs. 39 events; hazard ratio, 1.49; 95 percent confidence interval, 1.00 to 2.24; absolute risk increase, 0.7 per 1000 woman-years) and venous thromboembolism (103 vs. 71 events; hazard ratio, 1.44; 95 percent confidence interval, 1.06 to 1.95; absolute risk increase, 1.2 per 1000 woman-years). Raloxifene reduced the risk of clinical vertebral fractures (64 vs. 97 events; hazard ratio, 0.65; 95 percent confidence interval, 0.47 to 0.89; absolute risk reduction, 1.3 per 1000). Raloxifene did not significantly affect the risk of CHD. The benefits of raloxifene in reducing the risks of invasive breast cancer and vertebral fracture should be weighed against the increased risks of venous thromboembolism and fatal stroke. (ClinicalTrials.gov number, NCT00190593 [ClinicalTrials.gov].).

Strontium ranelate: An increased bone quality leading to vertebral antifracture efficacy at all stages

Strontium ranelate is a new antiosteoporotic treatment with a dual mode of action, both increasing bone formation and decreasing bone resorption, which rebalances bone turnover in favor of bone formation and increases bone strength. The antifracture efficacy of strontium ranelate, 2 g per day orally, in the treatment of postmenopausal osteoporosis has been investigated in a large-scale, international, multicenter, phase 3 program in which more than 7000 patients were recruited. This article deals with the vertebral antifracture efficacy of strontium ranelate in postmenopausal women with osteoporosis. A significant early (after 1 year) and sustained (over 3 years) antifracture efficacy of strontium ranelate, compared with placebo, was demonstrated in patients with prevalent vertebral fracture with reductions in risk of new vertebral fracture of 49% after 1 year ( P < 0.001) and 41% over 3 years ( P < 0.001). In addition, the relative risk of clinical vertebral fracture was significantly reduced by 52% ( P = 0.003) after 1 year and by 38% ( P < 0.001) over 3 years in the strontium ranelate group compared with placebo. Strontium ranelate was also demonstrated to significantly decrease the relative risk of vertebral fractures by 45% ( P < 0.001) in patients without prevalent vertebral fracture over 3 years, vs. placebo. Bone mineral density was linearly increased during 3 years of treatment with strontium ranelate in comparison with placebo. Strontium ranelate was well tolerated throughout the entire duration of the clinical trials. Thus, strontium ranelate, 2 g per day orally, is a new, effective, and safe treatment for postmenopausal patients with osteoporosis, to reduce the vertebral fracture risk in patients with or without a history of vertebral fracture.

Efficacy of risedronate on clinical vertebral fractures within six months

SUMMARYObjective: Postmenopausal osteoporotic women with pre-existing or new incident vertebral fractures are at high risk for future fracture, so prompt treatment is warranted. Risedronate has been shown to reduce the incidence of radiographically-defined vertebral fractures by approximately two-thirds within 1 year.Research design: This study examined the effects of risedronate treatment on the time course of the reduction in the risk of clinical vertebral fractures (i.e., symptomatic fractures), on the risk of moderate-to-severe radiographic vertebral fractures, and on height.Results: In 2442 postmenopausal women with prevalent vertebral fractures from the Vertebral Efficacy with Risedronate Therapy (VERT) studies who received either risedronate 5 mg or placebo, daily risedronate reduced the risk of clinical vertebral fractures within 6 months (RR = 0.08, 95% CI 0.01-0.63), and by 69% at 1 year (RR = 0.31, 95% CI 0.12, 0.78). At 1 year, risedronate also reduced the risk of moderate-to-severe radiographically-defined vertebral fractures by 71% (RR = 0.29 95% CI 0.16, 0.54). Height loss was attenuated with treatment, most notably in patients who experienced new vertebral fractures, with a median difference of 0.73 cm compared with subjects receiving placebo ( p = 0.005).Conclusion: Risedronate reduces the risk of clinical vertebral fractures in postmenopausal women with osteoporosis within 6 months of commencing treatment.

Aging bone and osteoporosis: strategies for preventing fractures in the elderly.

As the older population increases, the incidence of osteoporotic fractures is expected to dramatically rise during the next few decades. Older patients are much more susceptible to fracture at any given bone mineral density (BMD) than are younger patients because of various factors, including the quality of aging bone, which involves more than BMD. Suppression of increased bone turnover by antiresorptive therapies, even with only small changes in BMD, can reduce fracture risk, especially in the lumbar spine. Bisphosphonate treatment can significantly reduce vertebral and nonvertebral fractures, including hip fractures, even in the very elderly. Prospective analyses show that risedronate therapy consistently and significantly reduces the risk of new morphometric vertebral fractures after 1 year in postmenopausal women. Post hoc analyses report significant reductions in the risk of 1 new clinical vertebral fracture after 6 months of risedronate therapy and after 1 year of alendronate therapy. Oral raloxifene therapy and salmon calcitonin nasal spray therapy have been shown to reduce the risk of vertebral fracture after 3 and 5 years, respectively, and post hoc data show a significant reduction in clinical vertebral fracture risk at 1 year with raloxifene use. However, neither raloxifene therapy nor calcitonin therapy reduce the risk of nonvertebral and hip fractures at currently approved doses. Bisphosphonates have been shown to be safe and efficacious with 7 years' risedronate sodium and 10 years' alendronate sodium data published, and bisphosphonates reduce bone turnover and increase BMD to a greater degree than raloxifene and calcitonin, which may partly account for their nonvertebral and hip fracture reduction effect. Therefore, bisphosphonate therapy with risedronate or alendronate should be considered in patients with low BMD at the hip and in older patients with osteoporosis and osteopenia, particularly those with an existing fracture.

Analysis of 1-year vertebral fracture risk reduction data in treatments for osteoporosis.

One-year vertebral fracture risk reduction from clinical trials in adults with postmenopausal or glucocorticoid-induced osteoporosis is reviewed. Data were obtained by conducting a literature search of osteoporosis medications using the MEDLINE database, bibliographies of selected citations, and recent meeting abstracts. The methodologic quality of the trials was assessed using recently published criteria for ranking evidence. In prospective analyses, the 1-year risk of new morphometric vertebral fractures was reduced by risedronate 5 mg/d in two 3-year studies in postmenopausal women with prevalent vertebral fracture, and in two 1-year studies in patients with or at risk for glucocorticoid-induced osteoporosis. The 1-year risk of clinical vertebral fractures was reduced by alendronate and raloxifene in post hoc analyses. Reduction of morphometrically identified vertebral fracture risk is a more stringent therapeutic goal than clinical vertebral fracture risk. Therefore, more weight should be given to data from studies that use the morphometry to assess vertebral fracture incidence.