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BACKGROUND: Accelerated bone loss in patients with cancer is a frequent problem that may result from invasion of the cancer to bone, paraneoplastic tumor proteins, and/or hormonal therapies utilized for cancer treatment. Patients with osteolytic bone disease from multiple myeloma and bone metastases from solid tumors may develop a vicious cycle of bone destruction involving both osteolytic and osteoblastic effects. Consequently, a variety of skeletal-related events (SREs) may occur, including pathological fractures, hypercalcemia, spinal cord compression, and the need for surgical intervention and radiation therapy. METHODS: This article reviews the results of trials that investigated the safety and efficacy of pharmacologic agents, including bisphosphonates and denosumab, for treatment of bone metastases. This analysis is derived from an assessment of the medical literature. RESULTS: Beneficial systemic therapies for bone metastases have been developed to decrease SREs. Possible antitumor effects of the bisphosphonates are explored. In addition, the utility of markers of bone turnover in relation to response to therapy and survival, the safety and toxicity of bone-targeted therapies, treatment guidelines, and economic considerations are also discussed. CONCLUSIONS: Effective systemic therapies for metastatic bone disease are available. Ongoing and future research projects in this field are also presented.

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BACKGROUND: Topiramate was approved for the treatment of epilepsy in 1999 and has since been approved for the prevention of migraine headache. It is structurally different from the majority of antiepileptic medications and is pharmacodynamically unique in its ability to inhibit the enzyme carbonic anhydrase. Postmarketing reports of topiramate-associated hypothermia have occurred but this adverse event has not been well characterized. Data mining of an adverse event database was used to assist in the identification of hypothermia. OBJECTIVE: We sought to explore a possible association between the concomitant use of topiramate and valproic acid and the induction of hypothermia. METHODS: This was a pharmacovigilance case series survey of spontaneous hypothermia, a reported adverse event in patients treated with topiramate and valproic acid, alone and in combination. The U.S. Food and Drug Administration's Adverse Events Reporting System (AERS) database was searched for reports of hypothermia in association with the use of topiramate. A data mining algorithm was used on the AERS to identify scores for hypothermia associated with antiepileptic drugs. RESULTS: We identified 22 unduplicated reports of hypothermia in patients exposed to topiramate. Three of the 22 were confounded by patient overdoses with multiple drugs and not considered. Use of more than one antiepileptic drug was reported in most of the remaining 19 reports. Of these 19 reports, valproic acid was mentioned in 7. Two of the 19 reports mentioned topiramate only. Eleven of the 19 patients were men. The median age of the 19 patients was 40 years (range, 3(1/2)-82 years). Body temperatures ranged from 29.5 degrees C (moderate hypothermia) to 35 degrees C (mild hypothermia) with a median of 34 degrees C. Eleven of 18 reports of hypothermia occurred during the cooler months (one report did not indicate the time of year in which hypothermia occurred). Comorbid conditions included hypothyroidism in six reports, five in patients who received valproic acid concomitantly with topiramate and five reports of hyperammonemia in similarly treated patients. Data mining scores (empirical Bayes geometric mean) for antiepileptic drugs ranged from a high of 5.845 for phenobarbital to 2.956 for gabapentin. Hypothermia was reported 4.7 times more frequently when topiramate was used than was statistically expected. CONCLUSION: We have found hypothermia, defined as an unintentional drop in body core temperature to <35 degrees C, to be associated with concomitant administration of topiramate (a carbonic anhydrase inhibitor) and valproic acid in patients who have tolerated either drug alone. Data mining analysis for topiramate showed a signal of hypothermia. Topiramate was reported 4.72 times more frequently in the database than would be statistically expected when considering all other drugs. Topiramate may act pharmacodynamically to potentiate the effects of valproic acid as a result of its ability to decrease blood HCO(3) (-) and increase blood ammonia levels.

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The absorption of oral digoxin and of desmethyldiazepam, from its precursor clorazepate, was studied in seven patients who had received abdominal and/or pelvic radiation therapy for neoplastic disease. All patients were in remission and had normal renal function and no evidence of malabsorption. Single 0.5-mg doses of digoxin tablets and 15-mg doses of clorazepate were administered in the fasting state. Concentrations of digoxin (by radioimmunoassay) and desmethyldiazepam (by gas chromatography) were determined in multiple plasma samples and all urine collected during 24 hours after dosage. The mean (+/- S.E.) weight-normalized area under the 24-hour plasma digoxin concentration curve (WtN-AUC-24) in the patients (722 +/- 40 ng/ml-hr-kg) was similar to that in five normal controls (713 +/- 57 ng/ml-hr-kg), but 24-hour urinary excretion of digoxin in patients (54.5 +/- 4.4 microgram) was significantly less (P less than 0.025) than in controls (83.4 +/- 11.4 microgram). Neither age, sex, nor renal function explained the difference. In the clorazepate study, WtN-AUC-24 for desmethyldiazepam in the patients (187 +/- 19 microgram/ml-hr-kg) was significantly less (P less than 0.01) than in 15 normal control subjects (230 +/- 5 microgram/ml-hr-kg). Age and sex did not explain the difference. Thus, radiation therapy, or the underlying disease, is associated with malabsorption of these two drugs, possibly because of damage to gastric acid-secreting cells.

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The case records of 81 patients over the age of 60 were reviewed with respect to complications following lymphangiography. Adverse prognostic factors and complications were studied. Of the 81 patients, 48 were 60-69 years old and 33 were 70 or older; 19 patients had mild risk factors and 16 had severe risk factors. There were only six complications secondary to lymphangiography--two moderate and four mild. No severe complications were noted. This study suggests that age in itself is not a contraindication to lymphangiography.

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Biotransformation of chlordiazepoxide was studied in mice following a single 1000-rad dose of hepatic irradiation. Meabolic N-demethylation of chlordiazepoxide in irradiated mice was impaired when tested 3 days after irradiation. No such effect was observed in mice tested 3 weeks or 6 weeks after irradiation. Thus, hepatic irradiation appeared to produce short-lived, reversible impairment of drug-metabolizing function. The effect was small and of uncertain biological significance.

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