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Abstract
Background Incidence of a fracture, particularly in the hip joint, is high in Parkinson's disease (PD), owing to the immobilisation-induced bone resorption and vitamin D deficiency with reduced bone mineral density (BMD). The authors previously demonstrated the lowered incidence of hip fractures in PD by daily administration of risedronate and vitamin D.
Methods This randomised, double-blind, placebo-controlled study was conducted to determine the efficacy of 17.5 mg once-weekly risedronate in the prevention of hip fracture in women with PD. Patients were randomly assigned to 17.5 mg risedronate once a week (n=136) or a placebo (n=136) combined with daily 1000 IU of ergocalciferol. Incidence of hip fractures was compared between the two groups during the 2-year follow-up.
Results Hip fractures occurred in 15 patients in the placebo group and 3 patients in the risedronate group. The RR for hip fractures in the risedronate group as compared with the placebo group was 0.20 (95% CI 0.06 to 0.66). In the risedronate group, serum calcium levels decreased during the follow-up, while the levels in the placebo group increased. BMD increased by 3.4% in the risedronate group and decreased by 3.2% in the placebo group (p<0.01).
Conclusions Treatment with once-weekly risedronate and ergocalciferol prevents hip fractures in older women with PD.
- Hip fracture
- osteoporosis
- Parkinson's disease
- risedronate
- rehabilitation
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Introduction
Recent advances in treatment have prolonged survival of patients with Parkinson's disease (PD), and the patients' physical state has become increasingly important in the management of PD. Previous studies1 2 have demonstrated a high incidence of hip fractures in PD patients, and the decreased bone mineral density (BMD) of the hip joint,3 or second metacarpal,4 has been documented. We previously showed that 25-hydroxyvitamin D (25-OHD) deficiency due to sunlight deprivation induces compensatory hyperparathyroidism,4 which enhances bone resorption and BMD loss resulting in fractures in PD patients.5
We have demonstrated that alfacalcidol, menatetrenone6 and ergocalciferol (vitamin D2) plus alendronate or risedronate7 8 prevent BMD decrease in older PD patients.
Risedronate reduces bone resorption by inhibiting osteoclastic activity7 and decreases fracture risk in postmenopausal women with osteoporosis.9 Risedronate may be potentially beneficial in reducing the bone resorption in older women with PD.5 Recent studies outside Japan have shown the effectiveness of once-weekly risedronate 35 mg in women with postmenopausal osteoporosis.10 A weekly dosage of 17.5 mg risedronate is now approved by the Japanese insurance system and may have better compliance than a daily dosage.11
We conducted a double-blind trial to evaluate the efficacy of once-weekly risedronate and ergocalciferol in older women with PD in reducing hip fractures.
Materials and methods
We selected 272 female outpatients (mean age 74 years, range 65–86) who had been examined at the Mitate Hospital. Patients with impairment of renal, hepatic, cardiac or thyroid function or those who had known causes of osteoporosis were excluded. Patients were excluded if they had been treated with corticosteroids, oestrogens, calcitonin, bisphosphonate, calcium or vitamins D and K for 3 months or more during the 12 months preceding the study, and those who had been administered these agents for even a brief period during the preceding 2 months were also excluded. We assessed Hoehn and Yahr stages and patients at stage 5 were excluded, because their disability predicted minimum chance of a fracture.
The study was approved by the local ethics committee and written informed consent was obtained from all subjects.
Sunlight exposure in the preceding year was assessed by the patients or family members and graded as almost none, <15 min per week or longer. Falls were defined as incidents where the subject fell due to an unexpected loss of balance. The number of falls per subject was recorded during the follow-up by the patients and/or family members who were instructed to complete the protocol (date, time and circumstance).
Each patient was assigned to one study group by computer-generated random numbering. A random allocation sequence was implemented using numbered containers and the sequence was concealed until interventions were assigned. Patients received once a week 17.5 mg risedronate (n=136) or a placebo (n=136) plus a daily dose of 1000 IU ergocalciferol. The patients were blinded to assignment, which was confirmed by a questionnaire filled by patients at the end of the study. Patients were randomised using a permuted block size of four. Follow-up assessment of patients' condition was performed by a physician (YS) who did not participate in the initial randomisation. No dose adjustments were made during the study. Patients were prohibited from taking other drugs that could affect bone and calcium metabolism.
A general medical evaluation was carried out and laboratory values were assessed upon entry into the study to obtain baseline values and again repeated after 2 years.
The data for BMD, at the start, 1 and 2 years later, of the patients who completed the cohort were analysed. BMD of the second metacarpal in both hands was measured by personnel blind to the assignment using a computed x-ray densitometer.12
At the entry and at the end of the study, fasting blood and urine samples were obtained. Blood samples were analysed for ionised calcium, intact parathyroid hormone (PTH), 25-OHD and 1,25-[OH]2D. Urinary deoxypyridinoline (D-Pyr) was expressed relative to creatinine concentration (D-Pyr/creat). The normal ranges of the BMD and biochemical indices in older women are given in table 1.13 14
Baseline clinical characteristics of the female patients with Parkinson's disease at study entry
In addition to overall clinical status, careful evaluation for a radiographically diagnosed hip fracture was performed every 4 weeks. To assess adverse events, each patient underwent physical examination. Blood haematological and biochemical tests were performed.
Whenever a patient dropped out of the study or died, the results were analysed only for their active treatment time. The primary end point was defined as the incidence of a hip fracture. Spearman's rank correlation coefficients were calculated to determine the relationship among BMD, Hoehn and Yahr stages, PTH concentrations and each variable. The paired t test was used to assess the difference in variables between baseline and after 2 years. The two groups were compared with respect to the BMD by the Wilcoxon rank-sum test. All statistical analyses were performed using the Statview J 5.0 software package. p Values <5% were considered significant.
Results
Baseline characteristics of study subjects
Patients were recruited from January 2007 to June 2007, and 272 subjects were randomised into the two groups (figure 1). Ten patients in the treatment group and 12 in the placebo group dropped out due to non-compliance, loss to follow-up, intercurrent illness or death; 250 patients completed the trial.
Flow of participants through the study.
Of the baseline clinical features (table 2), there were no significant differences between the two groups in Hoehn and Yahr stages, dietary vitamin D intake, BMD, serum indices of bone metabolism and so on. The values of metacarpal BMD in the two groups were lower than the reference range of normal Japanese population.13 14 The values of serum 25-OHD and 1,25-[OH]2D in the two groups were lower, while serum ionised calcium and urinary D-Pyr higher than the reference range.13 14
Biochemical indices of bone metabolism before and after the 2-year period in the 250 subjects who completed the study
When the two groups were analysed together, BMD correlated positively with 25-OHD (r=0.209, p<0.001) and negatively with calcium (r=−0.173, p<0.01) or D-Pyr (r=−0.315, p<0.001). Hoehn and Yahr stages correlated with serum ionised calcium (r=0.349, p<0.001), 25-OHD (r=−0.387, p<0.001), urinary D-Pyr (r=0.305, p<0.001) or BMD (r=−0.192, p<0.01).
Changes in biochemical markers
During the 2-year period, Hoehn and Yahr stages deteriorated in both groups. Serum ionised calcium and urinary D-Pyr decreased in the risedronate group and increased in the placebo group. Serum PTH and 1,25-[OH]2D were reduced in the placebo group, but there was a trend of increase in the risedronate group (table 2).
Bone changes
BMD was enhanced by 3.4±0.4% in the risedronate group and decreased by 3.2±0.2% in the placebo group (p<0.001).
Hip fracture incidence
Hip fractures occurred in 15 placebo group patients during the 2-year period. Three hip fractures were observed in the risedronate group. The RR in the risedronate group as compared with the placebo group for hip fractures was 0.20 (95% CI 0.06 to 0.66). The number of hip fracture per 1000 patient-years was 11 and 55 for the risedronate and placebo groups, respectively. There was no significant difference between the two groups in the number of falls.
The blinding of the group assignment was confirmed in all subjects by a questionnaire at the end of the study.
Adverse effects
Serious adverse events that required hospitalisation or intervention to prevent permanent impairment were not observed. In the risedronate group, two patients had oesophagitis and four had diarrhoea, which eventually healed without discontinuation of treatment. In the placebo group, one patient experienced abdominal pain.
Discussion
We have previously found that second metacarpal BMD is correlated with the risk of hip fracture in PD patients5 and that reduced second metacarpal BMD may reflect a decrease throughout the appendicular skeleton.
The number of hip fractures in the risedronate group was lower than in the placebo group by 80%. Serum levels of 25-OHD and calcium, urinary D-Pyr and Hoehn and Yahr stages correlated with BMD in PD patients. In both groups, immobilisation-induced bone resorption may explain increased serum calcium and urinary D-Pyr. Since serum calcium correlated negatively with PTH, hypercalcaemia may have inhibited PTH secretion that otherwise might be induced by hypovitaminosis D. The lowered PTH secretion would have decreased 1,25-[OH]2D production.
The rate of hip fracture in the older population between 70 and 79 years is reported to be 6.6 per 1000 patient-years.15 The fracture rate in the present series was higher, which may be attributable to osteoporosis due to 25-OHD insufficiency, increased bone resorption and inhibition of renal 1,25-[OH]2D synthesis. Hip fractures in PD patients may be reduced by inhibiting the immobilisation-induced bone resorption.
Loss of BMD in untreated older women with PD is reported to be 4.3% over 1 year.6 In the present study, BMD decreased by 3.2% in the placebo group and increased by 3.4% in the risedronate group over 2 years. The hip fracture rate in older women with PD without treatment for osteoporosis is reported to be 148 per 1000 patient-years,6 and the fracture rate in the placebo group was far low, which is explained by the effect of ergocalciferol.
We previously showed that daily dosage of risedronate7 or alendronate8 plus ergocalciferol reduced a hip fracture. The present study confirmed that treatment with 17.5 mg risedronate once a week plus ergocalciferol is well tolerated and highly effective in reducing a fracture in PD patients.
References
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Footnotes
Funding This study was partially supported by the Mitate Hospital, Tagawa, Japan.
Competing interests None.
Patient consent Obtained.
Ethics approval This study was conducted with the approval of the local ethics committee of Mitate Hospital.
Provenance and peer review Not commissioned; not externally peer reviewed.
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