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Fracture Prevention with Zoledronate in Older Women with Osteopenia + Editorial
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Download the PDF here
Download the PDF here
Download the PDF here
Editorial
Clifford J. Rosen, M.D.
Low bone mineral density (i.e., a T score below -2.5) is the current operational definition of osteoporosis. However, low bone mineral density is actually a risk factor for fracture, not a disease marker. Notwithstanding, nearly all osteoporosis treatment algorithms are based on bone mineral density, frequently combined with the clinical risk factors of age and prevalent fractures. Given the high prevalence of low bone mineral density with advanced age, a review of the history underlying determination of risk and the concept of osteopenia is worthwhile.
When measurement of bone density was first introduced 25 years ago, absolute bone mineral density (g per square centimeter) was considered as too onerous for clinicians to understand. At that time, several population studies had shown that bone mineral density was a complex trait with a Gaussian distribution. Hence, a measurement of bone mineral density could easily be represented by the number of standard deviations by which the bone mineral density of an individual patient differed from the mean, termed a T score. Given that approximately 68% of the population should have a bone mineral density within 1 standard deviation from the mean, persons whose measurement fell at or below 2.5 standard deviations from the mean (2.5% of the population) were considered to be at highest risk for fractures.1 Thus, clinicians tended to recommend treatment to women who had a T score below -2.5. However, it was clear that there was an intermediate, yet substantial, group of patients with a T score between -1 and -2.5 who were subsequently described as having osteopenia and were at risk for fractures, based statistically on the continuous nature of the bone mineral density distribution. The National Osteoporosis Risk Assessment study, a longitudinal examination involving more than 150,000 postmenopausal women, confirmed that the vast majority of fractures occurred in women with osteopenia.2 Similar findings were also noted in a study involving more than 14,000 women from the Netherlands, known as the Rotterdam study.3 Still, it was disappointing that in the Fracture Intervention Trial, a study that examined the effect of alendronate treatment on new fractures in 4432 women, treatment with alendronate did not reduce the risk of fractures among women who had bone mineral density in the osteopenic range.4 Those data, coupled with a growing recognition of atypical femoral fractures as a very rare but devastating side effect of antiresorptive therapy, particularly among women with osteopenia, led to a rapid decrease in new prescriptions for osteoporosis, as well as less adherence to treatment among previously treated women.5,6 Ultimately, these events led to a treatment gap in patients who had strong clinical risk factors for an osteoporotic fracture (particularly age) but had T scores in the osteopenic range.
Reid et al.7 now report in the Journal the results of a 6-year, randomized, double-blind, placebo-controlled trial of zoledronate at a dose of 5 mg, administered intravenously at 18-month intervals, in 2000 postmenopausal women 65 years of age or older who had osteopenia. Three elements of this trial are unique as compared with earlier studies that showed that annual administration of zoledronate reduced the risk of fractures in older postmenopausal women.8,9 First, the current trial showed, with sufficient statistical power, that zoledronate administered less frequently than once a year was associated with not only a greater increase in bone mass than that observed in the placebo group but also a significantly lower risk of vertebral and nonvertebral fractures. The duration of the current trial was twice that of registration trials of newer therapies.4,8,9 Second, in contrast to the Fracture Intervention Trial of oral alendronate in women who did not have prevalent fractures but had osteopenia, treatment with intravenous zoledronate was effective in preventing fractures among women with an average T score of -1.27 at the total hip and -1.64 at the femoral neck. The reasons for this difference are not clear, although zoledronate is a more potent antiresorptive agent than alendronate, and at least one third of the participants in the current trial had clinical risk factors that placed them at higher risk for fracture (i.e., a baseline 10-year risk of hip fracture of more than 3% or a baseline 10-year risk of any osteoporotic fracture of more than 20%), even though the bone mineral density was considered to indicate osteopenia. Also, the average age of the participants in the current trial was approximately 3.5 years older than that in the Fracture Intervention Trial. Owing to the interaction between age and bone mineral density, the results of the current trial should not be extrapolated to younger postmenopausal women (50 to 64 years of age) with osteopenia. Third, 6 years of intermittent treatment with zoledronate resulted in relatively few adverse events, although the current trial was not powered to assess more rare side effects, such as osteonecrosis of the jaw and atypical femoral fractures.
Taken together, the results of the trial by Reid et al. should have an effect on clinical practice. Given the effectiveness of infrequent administration of zoledronate in reducing the risk of fragility fracture, this treatment can certainly be added to our armamentarium for treating osteoporosis, and it would represent an approach that would not be hindered by adherence issues. But just as importantly, this trial reminds us that risk assessment and treatment decisions go well beyond bone mineral density and should focus particularly on age and a history of previous fractures.
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Fracture Prevention with Zoledronate in Older Women with Osteopenia
"Bisphosphonates prevent fractures in patients with osteoporosis, but their efficacy in women with osteopenia is unknown. Most fractures in postmenopausal women occur in those with osteopenia, so therapies that are effective in women with osteopenia are needed.
New Interesting Findings in Bone Treatment Study- study find women with osteopenia - do not need to have osteoporosis - but only with osteopenia showed improvements with reduced fractures & there were reduced rates of death, cancers, CVD: MIs, stroke, , vascular events - see table immediately below
The current trial showed that administration of zoledronate every 18 months for 6 years reduced the risk of fragility fractures (both vertebral and nonvertebral) in older women with hip bone mineral density indicating osteopenia. The reduction in the risk of nonvertebral fracture was similar to that reported previously in patients with osteoporosis who were treated with zoledronate.8,9 Our findings were also consistent with those of trials of clodronate5 and estrogen14 that showed similar fracture prevention in women who did not necessarily have osteoporotic bone mineral density. Our results address an important knowledge gap identified in the recently published American College of Physicians guidelines on osteoporosis, which stated that "current evidence is limited for a treatment benefit for women aged 65 years or older with osteopenia." Consequently, those guidelines were equivocal in endorsing pharmaceutical treatment in this patient group.15 In contrast, the National Osteoporosis Foundation guidelines of 2014 did endorse pharmaceutical intervention in women with osteopenia who had a 10-year risk of hip fracture greater than 3%, although the guideline noted that "there are relatively few data confirming fracture risk reductions with pharmacotherapy in this group of patients."6 Our trial addressed this knowledge gap.
Prespecified adverse events of interest are shown in Table 3. The odds ratio for death was 0.65 (95% CI, 0.40 to 1.05) with zoledronate, and the odds ratio for cancer was 0.67 (95% CI, 0.50 to 0.89). Among the 68 deaths that occurred between randomization and year 6 of the trial, 41 were from neoplasms (25 in the placebo group and 16 in the zoledronate group), 8 were from strokes (7 in the placebo group and 1 in the zoledronate group [odds ratio with zoledronate, 0.14; 95% CI, 0.01 to 0.92]), and 7 were from cardiac events (3 in the placebo group and 4 in the zoledronate group). No atypical femoral fractures or cases of osteonecrosis of the jaw were reported in either group."
Abstract
Background
Bisphosphonates prevent fractures in patients with osteoporosis, but their efficacy in women with osteopenia is unknown. Most fractures in postmenopausal women occur in those with osteopenia, so therapies that are effective in women with osteopenia are needed.
Methods
We conducted a 6-year, double-blind trial involving 2000 women with osteopenia (defined by a T score of -1.0 to -2.5 at either the total hip or the femoral neck on either side) who were 65 years of age or older. Participants were randomly assigned to receive four infusions of either zoledronate at a dose of 5 mg (zoledronate group) or normal saline (placebo group) at 18-month intervals. A dietary calcium intake of 1 g per day was advised, but calcium supplements were not provided. Participants who were not already taking vitamin D supplements received cholecalciferol before the trial began (a single dose of 2.5 mg) and during the trial (1.25 mg per month). The primary end point was the time to first occurrence of a nonvertebral or vertebral fragility fracture.
Results
At baseline, the mean (±SD) age was 71±5 years, the T score at the femoral neck was -1.6±0.5, and the median 10-year risk of hip fracture was 2.3%. A fragility fracture occurred in 190 women in the placebo group and in 122 women in the zoledronate group (hazard ratio with zoledronate, 0.63 - reduced by 37%; 95% confidence interval, 0.50 to 0.79; P<0.001). The number of women that would need to be treated to prevent the occurrence of a fracture in 1 woman was 15.
As compared with the placebo group, women who received zoledronate had a lower risk of nonvertebral fragility fractures (hazard ratio, 0.66; P=0.001), symptomatic fractures (hazard ratio, 0.73; P=0.003), vertebral fractures (odds ratio, 0.45; P=0.002), and height loss (P<0.001).
Conclusions
The risk of nonvertebral or vertebral fragility fractures was significantly lower in women with osteopenia who received zoledronate than in women who received placebo. (Funded by the Health Research Council of New Zealand; Australian New Zealand Clinical Trials Registry number, ACTRN12609000593235.)
Bisphosphonates are the principal class of medications used in the management of postmenopausal osteoporosis and have been shown to prevent fractures.1 Prevention of fractures with bisphosphonates has been shown most clearly in patients with osteoporosis, which is defined either by a bone-density T score of less than -2.5 or by the presence of prevalent vertebral fractures; whether bisphosphonates are efficacious in patients with osteopenia alone is uncertain. However, treating only patients who have osteoporosis has only a limited capacity to decrease total numbers of fractures, since fractures tend to occur in the much larger group of women whose bone mineral density is in the osteopenic range.2 If interventions are to achieve a substantial decrease in the total numbers of fractures, therapies shown to be effective in women with osteopenia are needed.
Consistent evidence to show that fracture prevention is possible in patients with osteopenia is lacking. The results of a trial reported by Cummings et al. did not show a significantly lower risk of clinical fractures with alendronate than with placebo among women with osteopenia, although prevention of fractures among women with osteoporosis was observed.3 In contrast, pooled results from trials of risedronate suggested fracture prevention among patients who had osteopenia,4 and treatment with clodronate was found to reduce the incidence of total fractures among community-dwelling women older than 75 years of age whose participation in the trial was not based on the presence or absence of osteoporosis.5 The need to establish treatment efficacy in osteopenia has become more pressing, given the clinical trend to base intervention decisions on absolute fracture risk.6 Many patients at high risk for fracture do not have T scores of less than -2.5 but rather have osteopenia in combination with other risk factors, such as age. Intervention in such patients currently lacks an adequate evidence base.
Zoledronate (also known as zoledronic acid) has characteristics that make it attractive for use in women who have osteopenia. It is administered by intravenous injection at intervals of 1 year or longer, it is preferred over oral bisphosphonates by a majority of patients,7 and it has had a satisfactory safety profile.8,9 The current trial assesses the effects of zoledronate on fracture in postmenopausal women with hip bone mineral density that is characterized as osteopenia.
Discussion
The current trial showed that administration of zoledronate every 18 months for 6 years reduced the risk of fragility fractures (both vertebral and nonvertebral) in older women with hip bone mineral density indicating osteopenia. The reduction in the risk of nonvertebral fracture was similar to that reported previously in patients with osteoporosis who were treated with zoledronate.8,9 Our findings were also consistent with those of trials of clodronate5 and estrogen14 that showed similar fracture prevention in women who did not necessarily have osteoporotic bone mineral density. Our results address an important knowledge gap identified in the recently published American College of Physicians guidelines on osteoporosis, which stated that "current evidence is limited for a treatment benefit for women aged 65 years or older with osteopenia." Consequently, those guidelines were equivocal in endorsing pharmaceutical treatment in this patient group.15 In contrast, the National Osteoporosis Foundation guidelines of 2014 did endorse pharmaceutical intervention in women with osteopenia who had a 10-year risk of hip fracture greater than 3%, although the guideline noted that "there are relatively few data confirming fracture risk reductions with pharmacotherapy in this group of patients."6 Our trial addressed this knowledge gap.
The current trial differs from the two phase 3 trials of zoledronate8,9 in that dosing in our trial was at 18-month intervals, and the use of calcium supplementation was very low (approximately 2%). Zoledronate has a sustained duration of action, with bone-turnover markers still suppressed by almost half 5 years after a single infusion.16 McClung et al. found that annual administration of zoledronate for 2 years had effects on bone mineral density and bone-turnover markers that were almost equal to the effect of a single baseline dose.17 The reduction in the risk of fractures observed in the current trial suggests that annual administration may be unnecessary for maximal efficacy in the prevention of fractures and that even longer intervals between doses should be considered. Calcium supplements act as weak antiresorptive agents in the management of osteoporosis, and this effect is likely to be trivial when combined with zoledronate, which exhibits effects that are much more potent.
The adverse-event data from the current trial are not completely consistent with data from other trials, and confirmation of our results is warranted. Imbalances between the groups in the incidence of cancer, coronary heart disease, and death were observed in our trial. Previously, a meta-analysis of bisphosphonate trials showed that treatment with bisphosphonate reduced the risk of mortality,18 and similar results were also observed in one of the phase 3 trials of zoledronate.9,19 The reason that the other phase 3 trial of zoledronate8 did not reproduce that finding remains unclear, although the women who were enrolled in the trial had lower bone mineral density and were geographically more diverse than those who participated in the trial by Lyles et al.9 or in the current trial. The results of some20 but not all21 trials of breast cancer suggest that bisphosphonates have antitumor effects. There is also evidence from trials that suggests that bisphosphonates reduce the risk of vascular disease,18,22-25 and observational studies of myocardial infarction support this possibility.26-28 The possible vascular and cancer benefits in the current trial justify additional trials of zoledronate in which these conditions are the primary end points. The current findings may appear to be reassuring with respect to atypical femoral fractures and osteonecrosis of the jaw, but the trial is underpowered to definitively assess such rare events.
The strengths of the current trial are that it was well powered for the primary end point, it was of long duration, and the rate of participant retention was high. In the placebo group, treatment with bisphosphonates was initiated in 11.5% of participants (as compared with 3.3% of participants in the zoledronate group), so the estimates of benefit are conservative. The duration of the trial indicated that the intervention can be sustained on a long-term basis in clinical practice. We did not formally adjust for the number of secondary and exploratory end points, so some positive findings should be considered in that light. Of the 22 prespecified secondary and exploratory end points in the trial, approximately 1 might be expected on the basis of chance alone. Our trial involved only women who were 65 years of age or older and had hip bone mineral density that was characterized as osteopenia, so our findings should not be extrapolated to younger women, men, or persons who have normal bone mineral density.
The current trial showed that treatment with zoledronate every 18 months, with minimal use of calcium supplements, reduced the risk of fragility fractures (vertebral and nonvertebral) over the course of 6 years in older women with hip bone mineral density characterized as osteopenia.
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