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  • As with any open label

    2019-05-08

    As with any open-label study, it is possible that a placebo effect may have contributed to patients analgesia after initiation of the therapy. A randomized placebo-controlled trial would be required to finally prove the high analgesic effect of the loading-dose treatment with Ibandronate in metastatic bone disease. However, our results are consistent with previous reports. Two randomized, double-blind, placebo-controlled multicenter studies examined the efficiency of oral Ibandronate in bone pain relief. These studies were conducted with near-identical protocols, allowing data to be pooled [15–17]. 564 patients with metastatic bone disease due to breast cancer were randomised to receive oral Ibandronate 50mg (n=287) or placebo (n=277) once daily. In endothelin receptor antagonists to placebo, Ibandronate rapidly reduced bone-pain scores. With placebo, bone-pain scores did not change for 36 weeks and then steadily increased over the next 60 weeks. After 60 weeks the difference in bone-pain score was significant comparing both groups (p=0.001). Mean analgesic use increased in both groups, but this increase was significantly less in the Ibandronate group (p=0.019) [16,17]. In a small open-label pilot study of 18 patients with severe bone pain due to metastatic bone disease, short-term and intensive treatment with Ibandronate intravenously showed to have a high analgetic effect. Ibandronate 4mg was infused for 2h for 4 consecutive days. Within 7 days bone pain scores were significantly reduced, pain reduction was sustained over the whole study period of 6 weeks. Furthermore, improvements were seen in patients quality of life, patient functioning and performance status [2]. Altundag et al. observed in their phase II study of loading-dose Ibandronate treatment in patients with painful metastatic bone disease due to breast cancer a significant analgetic effect of the infused Ibandronate. 13 women with breast cancer, bone metastases and moderate/severe pain received 6mg Ibandronate intravenously over 15min over 3 consecutive days. During the follow-up period of 14 days pain level and analgesic use decreased significantly. Karnofsky performance index as a marker of functional impairment increased from day (77.7) to day 14 (80.8). No renal safety concerns or other serious adverse effects were reported [12]. In 11 Austrian breast cancer patients with severe pain, insufficiently controlled by standard analgetics, an infusion of 6mg Ibandronate i.v. for 3 consecutive days led to a significant decrease of pain (VAS<5) in all patients. Analgetic use was reduced within 3 days, and the WHO performance score was improved [18]. The reduction of bone pain under Ibandronate treatment has previously been observed in a phase III randomized trial of patients with bone metastases and breast cancer receiving 6mg Ibandronte i.v every 3–4 weeks. A significant reduction in bone pain score was observed within 4 weeks after the first infusion with Ibandronate 6mg compared to a placebo. The Ibandronate-receiving patients remained on decreased pain levels throughout the 2-year study period [13]. Currently, there are no head-to head trials comparing the efficacy of high intense loading-dose Ibandronate i.v. therapy regimen for metastatic bone pain versus other bsiphosphonates [12]. Barrett-Lee et al. compared the efficacy of oral ibandronic acid versus intravenous zoledronic endothelin receptor antagonists acid in the treatment of bone metastases from breast cancer in their open label, non-inferiority phase III trial. 705 patients received oral ibandronic acid 50mg daily, 699 patients were treated with intravenous zoledronic acid at 4mg every 3–4 weeks. Their results suggest that both drugs have acceptable side-effects and are options to prevent skeletal-related events caused by bone metastases. Pain scores showed a reduction in both study groups from baseline at 12 weeks, this reduction seemed to be maintained throughout the whole follow-up period of 96 weeks [18]. Compared to these results our data suggests that using a loading-dose treatment of Ibandronate in metastatic bone disease is associated with a faster reduction in bone pain compared to the standard therapeutic regimen. The intensive loading-dose regimen was not associated with any strong adverse effects. One patient experienced a flu-like syndrome (fever, myalgia) that lasted for 48h. No renal or gastrointestinal side effects were noted. Parameters as hemotology, blood chemistry, urine analyses and renal function stayed in physiological levels for the whole follow-up period. These results are in line with former studies, where i.v. Ibandronate 6mg has been shown not to be associated with attenuation in renal function [19]. Opioid-resistent bone pain is difficult to manage, fast and relieving therapeutical options are scarce but needed. Therefore, the loading-dose therapy with 6mg Ibandronate i.v. may offer a promising new therapeutic modality for patients with severe metastatic bone pain. In the current study, we were able to demonstrate fast and safe analgetic effects of intensive Ibandronate therapy. The rapid improvement in patients pain level should improve these patients quality of life. The positive effects of loading-dose Ibandronate therapy seen in this study, needs further investigation in controlled clinical trials of opioid-resistent pain due to metastatic bone disease.