Osteoporosis International

, Volume 21, Issue 1, pp 183–187

Bone recovery after zoledronate therapy in thalassemia-induced osteoporosis: a meta-analysis and systematic review

Short Communication

DOI: 10.1007/s00198-009-0875-4

Cite this article as:
Mamtani, M. & Kulkarni, H. Osteoporos Int (2010) 21: 183. doi:10.1007/s00198-009-0875-4

Abstract

Summary

Zoledronate is a promising bisphosphonate that improves the bone mineral density by 0.69 standard deviations in thalassemia-induced osteoporosis, but the entire range of its actions and side effects is currently not fully understood.

Introduction

Zoledronate is a promising bisphosphonate for the treatment of thalassemia-induced osteoporosis; however, a quantitative summary of its beneficial effect and its effects on the markers of bone turnover are not established.

Methods

We conducted a meta-analysis of the published randomized controlled trials using standardized mean difference and a random effects model for improvement in bone mineral density (BMD). We also conducted a systematic review for the influence of zoledronate on markers of bone turnover and bone pain.

Results

We found that zoledronate improves the baseline BMD by 0.69 (95% confidence interval 0.47–0.90) standard deviations—an effect that was more pronounced when BMD was measured at the lumbar spine. However, the mechanistic interpretations of the effects on the markers of bone turnover are not completely clear.

Conclusion

Sufficient evidence exists to demonstrate that 4 mg zoledronate given every 3 months markedly improves the BMD; however, more qualitative and quantitative evidence is required to understand the mechanisms of its action and the potential side effects.

Keywords

Osteoclasts Thalassemia Zoledronate 

Introduction

The advent of and the advances in the transfusional and iron-chelation therapies have radically improved the life-span of patients suffering from thalassemia major (TM), but this prolongation of life has uncovered a range of other co-morbidities that continue to pose daunting therapeutic challenges. A common group of morbidities associated with TM includes the skeletal system disorders, of which osteoporosis is the most common consequent to a substantial expansion of the bone marrow [1, 2, 3, 4]. Thalassemia-induced osteoporosis (TIO) has been observed in 30–50% of the TM patients in spite of adequate transfusion and iron chelation and can lead to substantially compromised quality of life in the thalassemic patients [5, 6, 7]. It is therefore imperative that efficacious treatments be evaluated and employed in treating the TIO.

Emergence of the bisphosphonate group of drugs has heralded a unique opportunity to surmount the difficulties in treating patients of TIO. This is because in patients of TIO, there is an increased bone resorption attributable to an enhanced osteoclastic function [4, 8], and bisphosphonates are potent inhibitors of osteoclastic function [9, 10, 11]. In several previous studies, alendronate, clodronate, pamidronate, and zoledronate have all been examined for their potential use in this regard [12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23], and zoledronate has been identified as the most promising candidate bisphosphonate for an additional reason that its dosages can be timed in such a way as to coincide with the transfusion sessions [12]. Yet, the United States Food and Drug Administration have currently placed a safety alert [24, 25] on zoledronate due to two possible adverse effects associated with its use: severe musculoskeletal pain and atrial fibrillation [26, 27]. These adverse effects are especially important in the context of TIO since the severe musculoskeletal pain can further limit the quality of life in TIO patients [28, 29], while the atrial fibrillation may further jeopardize an already compromised myocardium in these patients [30, 31, 32].

In this regard, although recent reviews [4, 10] suggest that zoledronate can be efficacious in increasing the bone mineral density (BMD), a quantitative summary of the degree of this effect is not available at present. Additionally, from a mechanistic standpoint, the possible effects of zoledronate on the markers of bone turnover are not firmly established. For example, it is believed that the receptor activator of nuclear factor κ B (RANK) and RANK ligand (RANKL) and its decoy receptor osteoprotegenerin (OPG) play a cardinal role in the pathogenesis of TIO [33, 34, 35]. Yet, the clinical evidence in this regard [18, 19] is inconclusive. Summarily, there exist knowledge gaps in the understanding of the effectiveness of zoledronate in the management of TIO. We therefore undertook a meta-analysis and a systematic review of the published randomized controlled clinical trials of zoledronate for the treatment of TIO.

Materials and methods

We first searched MEDLINE®, EMBASE®, and CINAHL® databases with the strategy “(zoledronic OR zoledronate) AND thalassemia”, which resulted in 11 publications. Of these, there was one review article, one comment on a trial, one case report, four randomized controlled trials, and four reports that used data from these four original trials. We therefore selected the four original trials [12, 14, 18, 19] for the purpose of this meta-analysis. All the trials recruited thalassemic patients and defined osteoporosis on the basis of low BMD for at least one of the studied bone sites. These trials represented five patient groups (Table 1) who received zoledronic acid 4 mg every 3 or 6 months for 1 year and the primary endpoint for our meta-analysis was the change from baseline BMD. The mean baseline BMD at the lumbar spine (which was studied in all the trials) and the co-interventions were similar across trials.
Table 1

Characteristics of the studies included in the meta-analysis

Study

Country

BMD sites studied

Follow-up (months)

Frequency (months)

Samples

Age (years)

Males N (%)

Baseline BMDa at LS

Co-intervention

Perifanis et al. [18]

Greece

LS

12

3

29

27.2 (7.3)

13 (44.8%)

−2.87

Ca, Vit D

Voskaridou et al. [19]

Greece

LS, FN, W

12

6

23

44.1 (11.7)

6 (26.1%)

−3.30

HRT

Voskaridou et al. [19]

Greece

LS, FN, W

12

3

21

42.6 (10.7)

9 (42.9%)

−2.90

HRT

Otrock et al. [14]

Lebanon

LS, FN, TH, T

9

3

18

22.72 (5.85)

12 (66.7%)

−2.77

HRT, Ca, Vit D

Gilfillan et al. [12]

Greece

LS, FN, TH, WB

12

3

12

27.8 (18.2–40.4)

8 (66.7%)

−2.86

Ca, Vit D

BMD bone mineral density, LS lumbar spine, FN femur neck, W wrist, TH total hip, T trochanter, WB whole body, Ca calcium supplementation, Vit D vitamin D supplementation, HRT hormone replacement therapy

aExpressed as T scores

To meta-analytically synthesize the primary endpoint, we used the standardized mean difference (SMD) after Hedges's g transformation under the scenario of a random effects model. The latter transformation was necessary since the BMD has been reported using different units as T scores, z scores, or g/cm2. Heterogeneity across studies was examined using the I2 statistic and an I2 value above 56% was considered significant. We then examined whether there existed any significant publication bias—graphically using a funnel plot and statistically using Egger's test. Finally, we also summarized the reported evidence on the potential beneficial effects on markers of bone turnover and the reported adverse effects of zoledronate therapy in TIO. All statistical analyses were conducted using Stata 10.0 (College Station, TX, USA) software package.

Results

The included trials represented evidence from 103 patients of TIO who were treated with zoledronate. All the trial groups included in this meta-analysis had assessed BMD at the lumbar spine, four trial groups had studied it at the femur neck, while the number of studies assessing BMD at other sites (for example, wrist, hip, trochanter, and whole body) was very few. For this reason, we restricted our meta-analysis to the studies assessing BMD at the lumbar spine and the femur neck. Our results (Fig. 1a) showed that across all sites of BMD assessment, the improvement in SMD was 0.69 at the end of the first year of follow-up. This translates to a clinical improvement of 24.5% [95% confidence interval (CI) 18.1%–31.6%] in BMD. Maximal clinical improvement in BMD was observed at lumbar spine (SMD 0.91) and femur neck (SMD 0.41). The study groups reporting BMD at other sites did not find a significant improvement in BMD at the respective sites (data not shown). Only one trial group [19] had used zoledronate therapy every 6 months. Therefore, we also conducted a subgroup meta-analysis, which included only those trial groups that had received zoledronate every 3 months. We observed that when zoledronate was given every 3 months, its benefit was even more (SMD 0.74, 95% CI 0.50–0.97).
Fig. 1

a Forest plot of the trials included in meta-analysis. Dark squares indicate the point estimates of the standardized mean difference (SMD) and the error bars represent the 95% confidence intervals, while the hollow diamonds indicate the summary effect. b Funnel plot of the published randomized controlled trials for zoledronate use in TIO. The statistical significance of the potential bias is shown as Egger's P. c A summary of the systematic review of the influence of zoledronate on the markers of bone turnover. Downward arrows indicate a reduction in the levels, plus/minus signs indicate conflicting results, and dashes indicate no significant effect. CTX C-telopeptide of collagen type I, TRACP-5b 5b isoenzyme of tartrate resistant acid phosphatase, tALP total alkaline phosphatase, bALP bone alkaline phosphatase, OC osteocalcin, CICP C-telopeptide of procollagen type I, sRANKL soluble receptor activator nuclear factor k B ligand, OPG osteoprotegerin, OPN osteopontin, IGF-1 insulin-like growth factor-1, PTH parathyroid hormone, DPD deoxypyridinoline, P [18], O [14], G [12], V1 and V2 groups A and B from [19], respectively

However, the I2 parameter indicated that there remained a substantial amount of unexplained heterogeneity. The value of I2 was even higher for the subgroup analysis of BMD at the lumbar spine primarily owing to a significantly high benefit observed in the study by Perifanis et al. [18]. Indeed, when we excluded this study from the meta-analysis, we observed that the I2 became 0 (p = 0.560). Interestingly, even without this trial, the summary effect size (SMD) was 0.60 (95% CI 0.27–0.93). The funnel plot and the Egger's P test results (Fig. 1b) demonstrated that there was no significant publication bias in the trials included in this meta-analysis.

The influence of zoledronate on markers of bone turnover was however not very clear and could not be meta-analytically combined due to small number of trials available for each marker (Fig. 1c). Nevertheless, existing evidence strongly suggests that levels of alkaline phosphatase (in bone or in plasma) and osteocalcin are significantly reduced but surprisingly evidence for effects of zoledronate on the markers of osteoclastic function including levels of OPG is inclonclusive. Mechanistically, this would favor the view that a suppression of C-telopeptide of collagen type I (CTX), a marker of bone resorption, might proffer an explanation in support of the beneficial effect of zoledronate in the context of TIO. Evidence also supports a reduction in the levels of parathyroid hormone and deoxypyridinoline post-zoledronate treatment.

Two trials [14, 19] have specifically studied the effects of zoledronate therapy on bone pain. In one study [19], on a visual analog scale, there was a reduction from a baseline mean score of 4.6–4.8 to a score of 0.3–0.8 at the end of 1 year, while in another study [14], brief pain inventory scores dropped from 2.0 at baseline to 0.78 at 9 months. Neither study observed any fracture events during follow-up. Together, these results indicated that the overall bone pain improved after zoledronate therapy. None of the studies have reported any events of atrial fibrillation although an acute cardiac death was reported by Voskaridou et al. [19].

Discussion

Our results indicate that published randomized controlled trials strongly support the use of zoledronic acid for the treatment of TIO in terms of the improved BMD although how exactly zoledronate is mechanistically able to achieve this beneficial effect is unclear. However, Fig. 1c suggests that classical markers of bone resorption and formation diminish after treatment, implying that a possible explanation for this beneficial effect could be a reduction in the bone turnover. More importantly, it appears that the side effects of zoledronate in the scenario of TIO are limited if any and that it may actually help alleviate—rather than cause—the bone pain. Additionally, it has been shown that zoledronic acid therapy can also augment erythropoetic activity [20] and that even after cessation of zoledronate therapy there continues to be a long-term improvement in BMD [21]. The latter finding is especially important in the light of other observations [36, 37], which suggest that it may be possible to reduce the cost of zoledronate therapy by reducing the number of zoledronate doses. Recent data also suggest that the efficacy of zoledronate therapy might depend on the other genotypes like that in the genes encoding the vitamin D receptor [15] and bone type I collagen [23]. While all these factors may ultimately influence the efficacy of zoledronate, its use in the management of TIO to improve BMD appears highly promising but larger studies with longer follow-up are needed to more fully understand its possible adverse effects.

Conflicts of interest

None.

Copyright information

© International Osteoporosis Foundation and National Osteoporosis Foundation 2009

Authors and Affiliations

  1. 1.Lata Medical Research FoundationNagpurIndia
  2. 2.San AntonioUSA

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