Overall Study Question
This phase 2 randomized, multicentre, double blind, placebo-controlled trial was designed to determine the effects of 5 dosing regimens of intravenous zoledronic acid, the most potent bisphosphonate available to date, on bone mineral density (BMD) and bone turnover in postmenopausal women with low BMD.
This trial included 351 postmenopausal women, aged 45 to 80 years. The onset of menopause was defined as the date of oophorectomy if applicable, or 12 months after the cessation of menses in women over 50 years of age, and 18 months after the cessation in menses in women between 45 and 49 years of age. Women were eligible for this study if they had a BMD at the lumbar spine that was at least 2.0 standard deviations (SD) below the mean value for young adults (this corresponds to a T score lower than –2), and had no more than one vertebral fracture at screening.
Exclusion criteria were as follows: systemic estrogen treatment within the past 3 months; evidence of secondary osteoporosis (e.g. steroid-induced osteoporosis); clinical or laboratory evidence of hepatic or renal disease; disorders of the parathyroid or thyroid glands; a serum 25-hydroxyvitamin D concentration £15 ng/mL; a history of cancer; previous treatment with bisphosphonates or fluoride; or current therapy with any other drug known to affect the skeleton.
Patients were randomized to receive placebo or zoledronic acid. All patients received calcium supplementation (1 g/day). The duration of the study period was 12 months.
BMD of the lumbar spine, the non-dominant proximal femur and forearm, and the total body were measured by dual-energy-x-ray-absorptiometry (DEXA) at baseline, 6, 9, and 12 months. Biochemical markers of bone turnover were also evaluated at baseline and every 3 months for most patients. Markers of bone formation included serum bone-specific alkaline phosphatase and serum osteocalcin. Markers of bone resorption included serum type I collagen C-telopeptide and urinary type I collagen cross-linked N-telopeptide. The primary study endpoint was BMD of the lumbar spine at 12 months.
Are the Results of the Study Valid?
1. Was assignment of patients randomized?
Yes. Patients were randomized to receive one of the following:
(2) zoledronic acid 0.25 mg IV every 3 months;
(3) zoledronic acid 0.5 mg IV every 3 months;
(4) zoledronic acid 1 mg IV every 3 months;
(5) zoledronic acid 2 mg IV every 6 months;
(6) zoledronic acid 4 mg IV x 1 dose.
2. Were all patients who entered the trial properly accounted for and attributed at its conclusion?
Yes. This trial included 351 post-menopausal women. During the study, 35 patients withdrew (15 because of personal reasons; 14 withdrew due to adverse effects). Dropout rates appeared to be similar across all treatment arms. Thus, 316 women completed the study. Data were analyzed for 351 women according to the intention-to-treat principle.
3. Were patients, their clinicians, and study personnel ‘blind’ to treatment?
Yes. This was a double-blind trial. In order to maintain blinding, all women received an intravenous infusion of either zoledronic acid or placebo every 3 months. All infusions were 20 mL in volume and were infused over 5 minutes. Infusions were prepared at each center by a pharmacist who had no contact with the patients.
4. Were the groups similar at the start of the trial?
Yes. The groups appeared to be similar at baseline.
5. Aside from the experimental intervention, were the groups treated equally?
Yes. Study procedures appeared to be identical for both groups, with follow-up at 3, 6, 9 and 12 months. All patients received 1 gram elemental calcium PO daily.
What were the Results?
1. How large was the treatment effect?
For the primary endpoint, there was a progressive increase in BMD of the lumbar spine over 12 months that was similar for all zoledronic acid groups, with values that were significantly higher (4.3 to 5.1%) than placebo (p<0.001).
BMD values for the femoral neck were 3.1 to 3.5% higher for zoledronic acid compared to placebo (p<0.001). Distal radius BMD was significantly higher (0.8 to 1.6%) compared to placebo for most of the zoledronic acid groups (p£0.05), with the exception of the 0.25 mg 4-dose regimen. Total body BMD was higher (0.9 to 1.3%) compared to placebo for most of the zoledronic acid groups (p<0.03), with the exception of the 0.5 mg 4-dose regimen.
The authors reported that biochemical markers of bone resorption reached a nadir at 1 month with zoledronic acid treatment (median decreases of 65 to 83% in serum C-telopeptide and 50 to 69% in the urinary N-telopeptide: creatinine ratio), whereas there were no significant changes in the placebo group. However, given that most samples were obtained every 3 months, it is difficult to know the exact time to maximal suppression of biochemical markers. The decrease in markers of resorption tended to be dose-dependent. Suppression of biochemical markers of bone resorption was maintained at 12 months with zoledronic acid. All zoledronic acid groups had values for these markers that were significantly different from those in the placebo group (p<0.01 for all comparisons), but there were no significant differences among the zoledronic acid groups. Biochemical markers of bone formation, such as serum osteocalcin and bone-specific alkaline phosphatase) showed no sharp decrease apparent at 1 month, but suppression persisted at 12 months with all doses (p<0.001).
The authors also reported that during the study period there were no vertebral fractures, and 5 non-vertebral fractures in patients taking zoledronic acid, compared to 1 patient taking placebo.
2. How precise was the estimate of the treatment effect?
This trial was designed to detect a difference of at least 4% in the degree of change from baseline to 12 months in primary endpoint (lumbar spine BMD). The authors did not report confidence intervals for any of the study endpoints.
Will the Results Help Me in Caring for My Patients?
1. Can the results be applied to my patient care?
Yes. The methodology of this trial was fair, and the results can be considered valid. The results can be applied to patients that would fit in to the inclusion criteria of this study. It is important to note that the patient population in this trial may be considered a low-risk population for fractures. Post-menopausal women were eligible for this study if they had a BMD at the lumbar spine that was at least 2.0 standard deviations (SD) below the mean value for young adults (this corresponds to a T score lower than –2). This BMD classifies the patient as being osteopenic, while a T score lower than 2.5 confers a diagnosis of osteoporosis.
2. Were all clinically important outcomes considered?
Ideally, it is desirable to look at the effects of treatment of the incidence of fractures, particularly hip fractures, which are associated with significant morbidity and mortality. The investigators evaluated the impact of treatment on BMD, which may be considered an acceptable surrogate endpoint in this trial for several reasons. Firstly, the patients included in this trial were a low risk osteoporosis population who had a low baseline risk of fractures. Thus, the sample size or duration of follow-up would need to be increased in order to detect whether treatment would impact the fracture rate in this patient population. Secondly, there seems to be a good correlation between BMD and incidence of fractures based on existing data for bisphosphonates. Assessing BMD of the lumbar spine is appropriate as a primary outcome measure since the lumbar spine is most useful for assessing therapeutic response since changes are of the earliest and greatest magnitude because of the high rate of remodeling.
Other endpoints that were evaluated in this trial include biochemical markers of bone turnover. These surrogate endpoints are of interest because they may be important predictors in determining response to therapy. Clinically relevant adverse effects such as hypersensitivity and infusion site reactions, acute renal insufficiency and hypocalcemia were also considered in this trial.
3. Are the likely treatment benefits worth the potential harms and costs?
Acute renal insufficiency and hypocalcemia are two important short-term effects that have previously been reported with the administration of intravenous bisphosphonates. In this trial, while there were no episodes of acute renal insufficiency noted, mean serum calcium concentrations in the zoledronic acid groups declined significantly, by approximately 0.08 mmol/L between baseline and one month (p<0.05 for all comparisons). From 3 months onwards, calcium concentrations were similar between the zoledronic acid and placebo groups.
In the past, there have been concerns about a potential negative impact of intravenous bisphosphonates on bone mineralization. Preliminary findings from a limited number of bone biopsy samples taken during this study indicated no change in cortical bone thickness, cancellous bone volume, trabecular thickness, separation or number, and no evidence of osteomalacia in patients receiving zoledronic acid. Further study is required in order to determine the impact of intravenous zoledronic acid on bone mineralization.
Mild myalgia, pain, nausea and fever also occurred more frequently in patients receiving zoledronic acid. The annual cost of zoledronic acid is estimated to be approximately $600 CDN. Comparatively, the annual costs of etidronate, alendronate and risedronate are estimated to be approximately $200, $500-800, and $750 CDN, respectively.
Although zoledronic acid is currently only indicated for the treatment of hypercalcemia of malignancy in Canada, its use in osteoporosis is appealing since its high potency may allow use of smaller doses with extended dosing intervals, thus possibly leading to reduced adverse effects and improved patient compliance. This trial, sponsored and designed by the manufacturer of zoledronic acid, suggests that the drug may be potentially useful in the management of post-menopausal osteoporosis.
Some of the limitations of this studied must be highlighted. Firstly, the women who participated in this trial did not necessarily meet the diagnostic criterion for osteoporosis, and in fact could be considered a low risk population for fractures. As such, the authors used this as justification for the use of a placebo comparator arm. Secondly, this trial does not provide a direct comparison with oral bisphosphonates. And finally, even though the use of surrogate endpoints may have been acceptable in this trial, this study did not demonstrate the effect of zoledronic acid on the most clinically relevant endpoint, namely fracture rates.
The effects of zoledronic acid on BMD noted in this trial are consistent with what has been observed with oral bisphosphonates in previous trials. When given either daily or intermittently (e.g. once-weekly alendronate), oral bisphosphonates tend to increase BMD of the lumbar spine by approximately 3 to 6% in one year, with less of an effect on hip BMD. Thus, based on an indirect comparison, the effects of zoledronic acid on BMD may be considered comparable to that of oral bisphosphonates.
In general, zoledronic acid appeared to be well-tolerated in this trial, with the most common adverse effects being decreased calcium concentrations, myalgia and pyrexia associated with its administration. Thus, zoledronic acid may be an attractive option for treating osteoporosis as once-yearly dosing has the potential to dramatically increase patient compliance and possibly minimize the risk of adverse effects compared to current oral bisphosphonate therapy. While the annual cost of zoledronic acid seems comparable to that of other bisphosphonates on the market, data on the cost-effectiveness of this intervention is needed. Thus, one may consider zoledronic acid to be “worth the shot” in certain patients, for example, those who have not tolerated daily or intermittent dosing of oral bisphosphonates without contraindications to therapy. Nevertheless, the long-term efficacy and safety of zoledronic acid in post-menopausal women with low BMD are unknown, and its role in therapy needs to be further defined.