• E-mail
• Print
• Comment
• Font Size
• Digg
• del.icio.us
• Discuss article

Efficacy of Risedronate Against Hip Fracture in Patients With Neurological Diseases: a Meta-Analysis of Randomized Controlled Trials

Posted on: Thursday, 26 June 2008, 06:02 CDT

By Iwamoto, Jun Matsumoto, Hideo; Takeda, Tsuyoshi

Key words: Alzheimer's disease - Hip fracture - Parkinson's disease - Risedronate - Stroke ABSTRACT

Objective: Neurological diseases, including Alzheimer's disease, stroke, and Parkinson's disease have been reported to increase the risk for fractures. The purpose of the present study was to clarify the efficacy of risedronate against hip fracture in patients with neurological diseases.

Methods: The literature was searched with PubMed from 1995 to the present, with respect to strictly conducted randomized controlled trials (RCTs) with narrow confidence intervals (CIs), and a meta- analysis was conducted.

Results: Four RCTs met the criteria; one RCT for Alzheimer's disease (n = 461, mean age = 78 years), two RCTs for stroke (n = 267, mean age = 76 years for men; n = 345, mean age = 71 years for women), and one RCT for Parkinson's disease (n = 223, mean age = 71 years). According to the results of RCTs, the relative risks (95% CI) for hip fracture with risedronate treatment compared with placebo treatment were 0.26 (0.10, 0.69) for Alzheimer's disease, 0.20 (0.04, 0.89) for stroke in men, 0.14 (0.02, 1.16) for stroke in women, and 0.34 (0.09, 1.21) for Parkinson's disease. Overall, the relative risk (95% CI) for hip fracture with risedronate treatment was 0.25 (0.13, 0.48), suggesting 75% of risk reduction rate with risedronate treatment in patients with one of the three neurological diseases (heterogeneity: 0.58, p = 0.9016 and overall effect: 17.36, p < 0.0001). No severe adverse events were reported in the risedronate and placebo groups.

Conclusion: The results of a meta-analysis of strictly conducted RCTs suggest that there is efficacy against hip fracture and safety with risedronate treatment in patients with neurological diseases including Alzheimer's disease, stroke, and Parkinson's disease.

Introduction

The potent anti-resorptive drugs, bisphosphonates including etidronate, alendronate, and risedronate have widely been used for the treatment of osteoporosis. In particular, alendronate and risedronate have been used as first-line drugs in the treatment of postmenopausal osteoporosis1,2. However, because of the lower quality of the trials on etidronate, indicated by the inappropriate intention-to-treat, drop-out rate, duration of treatment, and choice of vertebral fracture ascertainment method, the results of randomized controlled trials (RCTs) and meta-analyses of RCTs of etidronate appear to be flawed1. Thus, etidronate is considered as the second-line drug in the treatment of postmenopausal osteoporosis. A systematic review and meta-analyses have established the efficacy of alendronate and risedronate against vertebral, nonvertebral, and hip fractures in postmenopausal women with osteoporosis1,2. Furthermore, the long-term skeletal effects and safety of these drugs have also been confirmed1,2.

It is well known that the risk for fractures is high in elderly patients with neurological diseases including Alzheimer's disease, stroke, Parkinson's disease, and amyotrophic lateral sclerosis (ALS)3-8. Other neurological diseases have rarely been studied, probably because of the small number of subjects. In particular, hip fractures in patients with those neurological diseases, who are prone to fall, could lead to impaired mobility and increased mortality. Therefore, a strategy for preventing hip fracture should be established in elderly disabled patients with neurological diseases.

Strictly conducted RCTs with narrow confidence intervals (CIs) have shown the efficacy of bisphosphonates against hip fracture in patients with neurological diseases including Alzheimer's disease, stroke, Parkinson's disease, and ALS3-8. In particular, evidence on the anti-fracture efficacy of risedronate has been accumulated in patients with such neurological diseases3-6. However, there are no reports on systematic reviews and meta-analyses of RCTs regarding the efficacy of risedronate against hip fracture in patients with neurological diseases. Thus, the present study was conducted as a meta-analysis of RCTs with risedronate to establish the efficacy of risedronate against hip fracture in patients with neurological diseases.

Methods

The efficacy of risedronate against hip fracture for neurological diseases was investigated by searching the literature for strictly conducted RCTs with narrow CIs. The literature search was conducted through PubMed, using the following terms; risedronate, hip fracture, Alzheimer's disease, stroke, Parkinson's disease, and amyotrophic lateral sclerosis or ALS. The literature search was conducted for strictly conducted RCTs published from 1995 to the present. Non-English papers were excluded.

RCTs showing the efficacy of risedronate against hip fracture were identified, and the efficacy of risedronate against hip fracture was analyzed using the data from RCTs. Relative risks and 95% CIs were calculated for individual trials. For pooled data analysis, no heterogeneity was found between the risedronate and placebo groups. The statistical significance was evaluated by calculating integration relative risk and 95% CI using the fixed effect model. Funnel plots and Macaskill and Egger tests were used to evaluate publication bias. Macaskill and Egger tests assessed publication bias by using precision (the sample size and the inverse of the standard error, respectively). The statistical analyses were performed using PC SAS v8.2.

Results

Identified RCTs

Four studies met the criteria for strictly conducted RCTs on the efficacy of risedronate against hip fracture in patients with neurological diseases including Alzheimer's disease, stroke, and Parkinson's disease3-6. Table 1 shows the detail of the identified four RCTs; one RCT for Alzheimer's disease (n = 461, mean age = 78 years), two RCTs for stroke (n = 267, mean age = 76 years for men; n = 345, mean age = 71 years for women), and one RCT for Parkinson's disease (n = 223, mean age = 71 years). The RCTs reflect studies in the elderly population. The respective durations of the illnesses for RCTs were 4.4 years (chronic), 90 days (subacute), 3 days (acute), and 4.9 years (chronic). The respective periods of the studies were 18 months, 18 months, 12 months, and 24 months. All of the RCTs were performed in Japan, and daily dosing regimen with risedronate (2.5 mg/day) was used for these RCTs. The dose of risedronate was reported to be effective to prevent vertebral fractures in Japanese postmenopausal women with osteoporosis9,10, and was, therefore, approved by the Health, Labor and Welfare Ministry in Japan. Because the average life span of the Japanese is the longest in the world, there might be a number of disabled elderly patients with neurological diseases who suffer from hip fracture. So, Japanese physicians have noticed the necessity of preventing hip fracture in such patients. Therefore, studies might have aggressively been conducted by Japanese physicians to test the efficacy of interventions against hip fracture in patients with neurological diseases. Calcium and vitamin D supplementation were provided in one RCT of patients with chronic Alzheimer's disease, vitamin D supplementation was provided in one RCT of patients with chronic Parkinson's disease, and neither calcium nor vitamin D supplementation was provided in two RCTs of patients with acute or subacute stroke.

Meta-analysis

The four RCTs were processed for a meta-analysis. Figure 1 shows the results of a meta-analysis. According to the results of RCTs, the relative risks (95% CI) for hip fracture with risedronate treatment compared with placebo treatment were 0.26 (0.10, 0.69) for Alzheimer's disease, 0.20 (0.04, 0.89) for stroke in men, 0.14 (0.02, 1.16) for stroke in women, and 0.34 (0.09, 1.21) for Parkinson's disease. Overall, the relative risk (95% CI) of hip fracture with risedronate treatment was 0.25 (0.13, 0.48), suggesting 75% of the risk reduction rate with risedronate treatment in patients with one of the three neurological diseases (heterogeneity: 0.58, p = 0.9016 and overall effect: 17.36, p < 0.0001).

Table 1. Identified randomized controller trials

Figure 2 shows that the funnel plots were asymmetrical and that publication bias was not identified by the Macaskill [p = 0.8677 for the sample size) and Egger (p = 0.3059 for the inverse of the standard error) tests.

Adverse events

Among all the subjects (n = 648 for each group) in the four RCTs, eleven patients experienced abdominal pain, seven had esophagitis, and three experienced leucopenia in the risedronate group, while six patients experienced abdominal pain or discomfort or gastrointestinal symptoms such as epigastric discomfort and nausea in the placebo group. All of them were resolved with appropriate therapy without discontinuation of risedronate or placebo treatment.

Serious adverse events including death, overdose, and any other events that were life-threatening or permanently disabling or that required intervention to prevent permanent impairment were not observed in either the risedronate or placebo group in any RCTs.

Discussion

Treatment of osteoporosis is conducted in accordance with the principles of evidence-based medicine (EBM). EBM incorporates information derived from the highestquality investigations with clinical judgment and patient values, to allow optimal clinical management. Available clinical evidence has been classified hierarchically into various levels, with strictly conducted systematic reviews with homogeneity representing the highest level, followed by strictly conducted RCTs with narrow CIs or meta- analyses with homogeneity of RCTs, which have long been considered as the 'gold standard' in the context of clinical investigations". Thus, the results of meta-analyses with homogeneity of RCTs could play an important role in establishing the efficacy of risedronate against hip fracture in patients with neurological diseases. The bisphosphonate, risedronate, inhibits osteoclastmediated bone resorption. Loss of osteoclast function and apoptosis is the consequence of loss of function of one or more important signaling protein12. This drug is not metabolized but can inhibit enzymes of the mevalonate pathway, thereby preventing the biosynthesis of isoprenoid compounds that are essential for the post-translational modification of small GTPases12. Because risedronate strongly suppresses bone resorption, leading to an improvement of bone quality as well as BMD13, it was considered potentially effective to prevent fractures in patients with Alzheimer's disease, stroke, and Parkinson's disease which cause an increase in bone resorption3-6.

Figure 1. Effect of nsedronate on the inddence of hip fracture. The relative risks (95%CIs) of the four RCTs are shown. Overall, the relative risk (95% CI) of hip fracture with nsedronate treatment was 0.25 (0.13, 0.48), suggesting 75% of the risk reduction rate with nsedronate treatment in patients with one of the three neurological diseases (heterogeneity: 0.58, p = 0.9016 and overall effect: 17.36, p < 0.0001). RCT: randomized controlled trial, CI: confidence interval

Figure 2. Funnel plots. The funnel plots and Macaskill and Egger tests were used to evaluate publication bias. The Macaskill and Egger tests assessed publication bias by using precision (the sample size and the inverse of the standard error, respectively). The funnel plots were asymmetrical and publication bias was not identified by the Macaskill (p = 0.8677 for the sample size) and Egger (p = 0.3059 for the inverse of the standard error) tests. RR: relative risk, SE: standard error

The efficacy of risedronate against hip fracture has been established in postmenopausal women with osteoporosis14,15. A RCT (HIP study) conducted by McClung et al.14, using the incidence of hip fracture as a primary end-point, demonstrated that the rate of reduction in hip fracture following risedronate treatment was 30%. A meta-analysis by Liberman et al.15 has demonstrated that risedronate reduces the risk for hip fracture by 27%. In the present study, however, there was a 75% risk reduction with risedronate treatment in patients with one of the neurological diseases including Alzheimer's disease, stroke, and Parkinson's disease. Furthermore, the heterogeneity was 0.58 (p = 0.9016), suggesting the moderate consistency of the results of the four RCTs. Thus, the evidence derived from the literature, based on the results of a meta- analysis of strictly conducted RCTs with narrow CIs, suggests that risedronate could be a first-line drug in preventing hip fracture in patients with neurological diseases including Alzheimer's disease, stroke, and Parkinson's disease.

Risedronate appears to be quite effective in reducing the incidence of hip fracture in elderly disabled patients who are prone to falls due to neurological diseases. It is known that anti- resorptive therapies that produce larger decreases in bone turnover markers together with larger increases in BMD are associated with greater reductions in nonvertebral fracture risk, especially at sites primarily composed of cortical bone16. In the four RCTs in patients with neurological diseases, BMD of the metacarpus that is composed of cortical bone markedly increased with treatment differences between 5.0% and 6.4%3-6. On the other hand, in the two RCTs (the North America and Multinational Vertebral Efficacy with Risedronate Therapy Studies) in postmenopausal women with osteoporosis1718, treatment differences in changes in BMD were 2.8 % and 3.1% at the femoral neck, respectively and 1.6% and 2.1% at the midshaft of the radius, respectively. Thus, greater increases in BMD at sites primarily composed of cortical bone in the four RCTs might contribute to the greater efficacy against hip fracture in patients with neurological diseases. However, further studies may be needed to clarify the mechanism other than BMD increase for the greater anti-fracture efficacy of risedronate in patients with neurological diseases, because other factors such as cortical thickness, cortical porosity, and mean mineralization of bone might play a role in determining quality of cortical bone19.

Hypovitaminosis D in elderly disabled patients increases the risk for falls and thus the risk for possible subsequent fractures20-22 and induces compensatory hyperparathyroidism, further contributing to reduction in BMD3. Consequently, vitamin D and calcium supplementation would be needed in patients with malnutrition and sunlight deprivation. In the present study, however, two RCTs for acute or subacute stroke did not supplement either calcium or vitamin D. Immobilization at the acute or subacute phase of the illness may induce hypercalcemie due to an immobilization-induced increase in bone resosption4,5. Hypercalcemia, in turn, may inhibit the compensatory hyperparathyroidism that otherwise could occur in response to hypovitaminosis D4,5. Since calcium and vitamin D supplementation might further have increased hypercalcemia, such treatment might have been avoided in patients with acute or subacute stroke. Risedronate was useful in improving immobilizationinduced hypercalcemia and resultant inhibition of parathyroid hormone secretion in patients with acute or subacute stroke. Theoretically, however, risedronate with calcium and vitamin D supplementation could be a suitable treatment in such patients with increased bone resorption and hypovitaminosis D, probably because the effect of risedronate on calcium metabolism would overwhelm that of calcium and vitamin D supplementation.

RCTs have demonstrated that abdominal pain, esophagitis, and leucopenia were observed in 21 (3.2%) patients of the risedronate group3-6. However, all of them were resolved with appropriate therapy without discontinuation of risedronate treatment3-6. No severe adverse events were experienced by patients treated with risedronate3-6. These results confirm the short-term safety of risedronate in patients with neurological diseases including Alzheimer's disease, stroke, and Parkinson's disease. In postmenopausal women with osteoporosis, there was no indication of any loss of efficacy against vertebral fracture even after 7 years of risedronate treatment23, suggesting the longterm efficacy of risedronate against vertebral fracture. However, because long-term treatment is needed to reduce the life time risk for hip fracture, the long-term anti-fracture efficacy and safety of risedronate remain to be established in elderly disabled patients with neurological diseases.

Once-weekly risedronate has safety and tolerance profiles similar to daily risedronate24,25. It has been reported that the once- weekly bisphosphonate is the preferred dosing regimen to once-daily bisphosphonate. It is considered to be more convenient, and is the regimen that most of the patients are more willing to take for a long period of time26. Thus, the once-weekly risedronate is expected to provide benefit in terms of better adherence (compliance and persistence) of patients to the treatment, as compared with daily risedronate. This may be true particularly in elderly disabled patients with difficulty in taking medicines daily. Thus, it would be of interest to study the efficacy of once-weekly risedronate as well possibly as intravenous bisphosphonates such as ibandronate and zoledronate, and subcutaneous denosumab against hip fracture in elderly patients with neurological diseases.

Conclusion

The evidence derived from the literature, based on the results of a meta-analysis of strictly conducted RCTs with narrow CIs, suggests that there is efficacy against hip fracture (75% of risk reduction rate) and safety with daily risedronate treatment in patients with neurological diseases including Alzheimer's disease, stroke, and Parkinson's disease.

Acknowledgments

Declaration of interest: The authors declare that there is no involvement of any pharmaceutical company with this study or with the preparation of this article. The authors have no relevant conflicts of interest.

References

1. Iwamoto J, Takeda T, Sato Y. Effects of antifracture drugs in postmenopausal, male and glucocorticoid-induced osteoporosis - usefulness of alendronate and risedronate. Expert Opin Pharmacother 2007;8:2743-56

2. Iwamoto J, Takeda T, Sato Y. Efficacy and safety of alendronate and risedronate for postmenopausal osteoporosis. Curr Med Res Opin 2006;22:919-28

3. Sato Y, Kanoko T, Satoh K, Iwamoto J. The prevention of hip fracture with risedronate and ergocalciferol plus calcium supplementation in elderly women with Alzheimer disease: a randomized controlled trial. Arch Intern Med 2005;165:1737-42

4. Sato Y, Iwamoto J, Kanoko T, Satoh K. Risedronate sodium therapy for prevention of hip fracture in men 65 years or older after stroke. Arch Intern Med 2005;165:1743-8

5. Sato Y, Iwamoto J, Kanoko T, Satoh K. Risedronate therapy for prevention of hip fracture after stroke in elderly women. Neurology 2005;64:811-6

6. Sato Y, Honda Y, Iwamoto J. Risedronate and ergocalciferol prevent hip fracture in elderly men with Parkinson disease. Neurology 2007;68:911-5

7. Sato Y, Iwamoto J, Kanoko T, Satoh K. Alendronate and vitamin D^sub 2^ for prevention of hip fracture in Parkinson's disease: a randomized controlled trial. Mov Disord 2006;21:924-9 8. Sato Y, Honda Y, Iwamoto J. Etidronate for fracture prevention in amyotrophic lateral sclerosis: a randomized controlled trial. Bone 2006;39:1080-6

9. Fujita T, Orimo H, Inoue T, et al. Clinical effect of bisphosphonate and vitamin D on osteoporosis: reappraisal of a multicenter double-blind clinical trial comparing etidronate and alfacalcidol. J Bone Miner Metab 2007;25:130-7

10. Kushida K, Fukunaga M, Kishimoto H, et al. A comparison of incidences of vertebral fracture in Japanese patients with involutional osteoporosis treated with risedronate and etidronate: a randomized, double-masked trial. J Bone Miner Metab 2004;22:469-78

11. Centre for Evidence-Based Medicine. Oxford-Centre Evidence Based Medicine. Levels of evidence and grades of recommendation. http://www.cebm.net/levels_of_evidence.asp

12. Rogers MJ, Frith JC, Luckman SP, et al. Molecular mechanism of action of bisphosphonate. Bone 1999;24(Suppl 5):73S-79S

13. Epstein S. The roles of bone mineral density, bone turnover, and other properties in reducing fracture risk during antiresorptive therapy. Mayo Clin Proc 2005;80:379-88

14. McClung MR, Geusens P, Miller PD, et al. Effect of risedronate on the risk of hip fracture in elderly women. New Engl J Med 2001;344:333-40

15. Liberman UA, Hochberg MC, Geusens P, et al. Hip and nonspine fracture risk reductions differ among antiresorptive agents: Evidence from randomised controlled trials. Int J Clin Pract 2006;60:1394-400

16. Hochberg MC, Greenspan S, Wasnich RD, et al. Changes in bone density and turnover explain the reductions in incidence of nonvertebral fractures that occur during treatment with antiresorptive agents. J Clin Endocrinol Metab 2002;87:1586-92

17. Harris ST, Watts NB, Genant HK, et al. Effects of risedronate treatment on vertebral and nonvertebral fractures in women with postmenopausal osteoporosis: a randomized controlled trial. J Am Med Assoc 1999;282:1344-52

18. Reginster J, Minne HW, Sorensen OH, et al. Randomized trial of the effects of risedronate on vertebral fractures in women with established postmenopausal osteoporosis. Osteoporosis Int 2000;11:83- 91

19. Epstein S. Is cortical bone hip? What determines cortical bone properties? Bone 2007;41(Suppl 1):S3-S8

20. Sato Y, Inose M, Higuchi I, et al. Changes in the supporting muscles of the fractured hip in elderly women. Bone 2002;30:325-30

21. Bischoff-Ferrari HA, Dawson-Hughes B, Willett WC, et al.. Effect of vitamin D on falls: a meta-analysis. J Am Med Assoc 2004;291:1999-2006

22. Bischoff-Ferrari HA, Willett WC, Wong JB, et al. Fracture prevention with vitamin D supplementation: a metaanalysis of randomized controlled trials. J Am Med Assoc 2005;293:2257-64

23. Mellstrom DD, Sorensen OH, Goemaere S, et al. Seven years of treatment with risedronate in women with postmenopausal osteoporosis. Calcif Tissue Int 2004;75:462-8

24. Emkey R. Alendronate and risedronate for the treatment of postmenopausal osteoporosis: clinical profiles of the once-weekly and once-daily dosing formulations. Med Gen Med 2004;6:6

25. Kishimoto H, Fukunaga M, Kushida K, et al. Efficacy and tolerability of once-weekly administration of 17.5 mg risedronate in Japanese patients with involutional osteoporosis: a comparison with 2.5-mg once-daily dosage regimen. J Bone Miner Metab 2006;24:405-13

26. Kendler D, Kung AW, Fuleihan Gel-H, et al. Patients with osteoporosis prefer once weekly to once daily dosing with alendronate. Maturitas 2004 48:243-51

CrossRef links are available in the online published version of this article: http://www.cmrojournal.com

Paper CMRO-4427_4, 10:39-23.04.08

Accepted for publication: 13 March 2008

Published Online: Ol April 2008

doi: 10.1185/030079908X297321

Jun Iwamoto, Hideo Matsumoto and Tsuyoshi Takeda

Department of Sports Medicine, Keio University School of Medicine, Tokyo, Japan

Address for correspondence: Dr. Jun Iwamoto, Department of Sports Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan. Tel.:+81 33353 1211; Fax: +81 3 3352 9467; jiwamoto@sc.itc.keio.ac.jp

Copyright Librapharm May 2008

(c) 2008 Current Medical Research and Opinion. Provided by ProQuest Information and Learning. All rights Reserved.

Source: Current Medical Research and Opinion

More News in this Category