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    • Introduction Tumor metastases of the

    2019-06-20

    Introduction Tumor metastases of the skeleton occur in up to 80% of patients in progressed stages of cancer, most commonly in cases of breast, lung, prostate, kydney and thyroid tumors [1,2]. Bone metastases are often associated with pathologic fractures, hypercalcemia and spinal cord compression, as well as severe bone pain [3]. Orthopedic surgeons are challenged with patients presenting with newly diagnosed bone metastases and severe and disabling pain. Skeletal pain is commonly divided in 3 groups: ongoing pain, incident breakthrough pain and movement-evoked breakthrough pain [4,5]. Initially bone cancer patients most frequently suffer from ongoing pain, hurting as a dull, constant throbbing pain that intensifies with time [6]. In advanced stages of bone cancer extreme pain can occur spontaneously, or after weight-bearing or movement of the affected extremity [7]. Breakthrough pain is difficult to control, often high doses of opioids and non-steroidal drugs are required, accompanied by adverse effects like somnolence, cognitive impairment and constipation [4,6]. Metastatic bone disease is a consequence of a tumorinduced imbalance of the activities of JNJ-10198409 and osteoblasts. Bisphosphonates have been shown to be a real alternative by reducing bone pain from metastases, probably by inhibiting the underlying processes of osteoclast-mediated bone resorption [1]. First- and second-generation bisphosphonates like clodronate or pamidronate, showed significant analgesic effects in patients with metastatic bone pain [8,9]. In the need for rapid relief of severe metastatic bone pain, especially for breakthrough and opioid-resistent pain, without the negative side effects of opioids, the third generation bisphosphonate Ibandronate has been examined as a possible treatment option for patients suffering from metastatic breast cancer [2,10–12]. A large multicenter study of patients with metastatic breast cancer evaluated the impact of intravenous Ibandronate on skeletal-related events and bone pain. Patients treated with 6mg Ibandronate intravenously every 4 weeks for 2 years experienced significant reduction in bone pain compared to a control group [13]. Mancini et al. showed in 18 patients with metastatic bone disease, receiving a nonstandard treatment with 4mg Ibandronate intravenously for 4 consecutive days significantly reduced bone pain scores within 7 days [2]. Patients attending orthopedic departments with newly diagnosed bone metastatic disease are in need of rapid pain relief before being transferred to further treatment modalities. Therefore, the purpose of this current study was to evaluate the short-term efficacy and safety of loading dose Ibandronate (6mg intravenously administered for 3 consecutive days by a 1h infusion) in patients with newly diagnosed metastatic bone disease of different primary tumors, suffering from severe bone pain.
    Patients and methods Thirty-three patients with symptomatic skeletal metastases from different tumor origins were treated with intravenous Ibandronate in an open, prospective, non-randomized study. The median age of patients was 59 years (33–78 yrs) (Table 1). All patients had radiologically confirmed bone metastases and were experiencing opioid resistant pain in site of the skeletal metastases. 23 patients described vertebral bone pain due to vertebral metastases, 3 patients complained about hip pain, 7 patients described all body pain. All of the patients were admitted due to the bone pain, for none of the patients an orthopedic operation was scheduled. None of the patients had received bone radiotherapy or bisphosphonate therapy previously. Furthermore, patients were excluded if endodermis had moderate or severe hypercalcaemia (serum calcium >12mg/dL), impaired renal function (serum creatinine >1.5mg/dL), a change to their hormonal treatment or chemotherapy during 2 months before study entry. During the study the patients received only Ibandronate plus opioids and non-steroidal antiphlogistic drugs. Patients were withdrawn from the study if they received other interventions that could have affected their level of pain. Ibandronate 6mg was infused intravenously for 1h on days 1, 2, 3 of the study. All patients were followed up until day 7 of the study. Physical examinations and assessments of vital signs were conducted on day 1 and every 2nd day thereafter. Efficacy variables included pain, and the use of analgesic. Bone pain was assessed using a visual analog scale from 0 (no pain) to 10 (worst pain imaginable) [14]. Changes in pain severity during treatment were rated as improvement when the sum of decreases in pain scored between visits outweighed the sum of increases [10]. Indirect measurement of pain was received by using the Morphine Equivalent Daily Dose (MEDD) index of opioid consumption. The MEDD is calculated as the daily morphine dose (in milligrams) multiplied by an MEDD factor of three for intravenous treatment, two for subcutaneous therapy or one for oral treatment [14]. Adverse events were monitored throughout the study (total of 7 days) and for 4 weeks after. Laboratory parameters reflecting renal function and serum calcium levels (Normal values, 8.5 to 10.3mg/dl) were evaluated every day throughout study time.