The Journal of Informed Pharmacotherapy 2002;11:201.
Reviewer: Suzanne I. Singh,
Reviewer’s e-mail address: email@example.com
Reviewer's profession/specialty: Pharmacist/PharmD student (University of Toronto)
Reid IR, Brown JP, Burckhardt P et al. Intravenous zoledronic acid in postmenopausal women with low bone mineral density. N Engl J Med 2002; 346: 653-61. PubMed Citation
Thisphase 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 receiveplacebo 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.
1. Was assignment of patients randomized?
Yes. Patients were randomized to receive one of the following: (1) placebo; (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.
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.
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
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.
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).
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.
. (4) 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. (2,3) 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.
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
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
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
Mild myalgia, pain, nausea and fever also occurred more frequently in patients receiving zoledronic acid.
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
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
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 bisphosphonates2,3.
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.
PD, Treatment of postmenopausal osteoporosis, Lancet
2002 Jun 8; 359(9322): 2018-26
SR, Melton LJ, Epidemiology and outcomes of
osteoporotic fractures, Lancet 2002 May 18;
Copyright © 2002 by the Journal of Informed Pharmacotherapy. All rights reserved.