Urine N-telopeptide excretion in dogs with appendicular osteosarcoma

Canine appendicular osteosarcoma (OSA) is a commonly diagnosed cancer that is capable of inducing pathologic bone remodeling. Investigating surrogate indices of bone metabolism may contribute to the diagnostic and therapeutic management of bone malignancies in companion animals. This study evaluated the excretion of N-terminal telopeptide (NTx), a marker of bone resorption that is detected in urine. Sixty-three dogs with appendicular OSA were compared with 29 age-matched healthy dogs. Dogs with appendicular OSA had significantly higher baseline urine NTx excretion than healthy controls (P < .0001). In 17 dogs with OSA treated with either amputation or standardized palliative therapies, significant reductions in urine NTx excretion were observed, suggesting that excessive bone resorption in dogs with OSA may be linked with focal skeletal osteolysis or its consequences. To identify any relationship between indicators of pathologic bone turnover, baseline urine NTx excretion was correlated with serum bone alkaline phosphatase (bALP) or radiographic tumor lengths at diagnosis. No significant correlations were identified between baseline urine NTx excretion and either bALP or tumor length. The findings from this study suggest that high urinary NTx excretion may support the diagnosis of focal skeletal osteolysis in dogs, and reductions in urine NTx excretion after treatment may reflect elimination or minimization of pathologic bone resorption.     

Double-Blind Placebo-Controlled Trial of Adjuvant Pamidronate with Palliative Radiotherapy and Intravenous Doxorubicin for Canine Appendicular Osteosarcoma Bone Pain

Background: Canine osteosarcoma (OSA) causes focal malignant osteolysis leading to severe pain. Despite the documented efficacy of radiotherapy or IV aminobisphosphonates for managing cancer bone pain, their potential combined therapeutic value has not been reported in OSA-bearing dogs.
Hypothesis: Pamidronate combined with standardized palliative therapy will improve pain control and bone biologic effects in OSA-bearing dogs.
Animals: Fifty dogs with appendicular OSA treated with standardized palliative therapy and either pamidronate or sterile saline.
Methods: Randomized, prospective, double-blinded, placebo-controlled study. Treatment responses for dogs receiving standardized palliative therapy with (n = 26) or without (n = 24) adjuvant pamidronate were serially evaluated for changes in subjective pain scores, urine N-telopeptide (NTx) excretion, primary tumor relative bone mineral density ( r BMD), and computerized pressure platform gait analysis.
Results: Median duration of subjective pain relief for dogs treated with adjuvant pamidronate or placebo was 76 and 75 days, respectively ( P = .39). Forty percent (20/50; pamidronate [11/26] and placebo [9/24]) of dogs experienced durable analgesia, defined by pain alleviation ≥112 days. For patients achieving durable pain control, dogs treated with pamidronate achieved greater reductions in NTx excretion and larger increases in r BMD compared with placebo controls. Changes in peak vertical force assessed by computerized pressure platform gait analysis correlated with pain alleviation in OSA-bearing dogs.
Conclusions and Clinical Importance: Combining pamidronate with standardized palliative therapy is safe, but does not clearly improve pain alleviation. However, in dogs achieving durable pain control, adjuvant pamidronate appears to decrease focal bone resorption in the local tumor microenvironment.     

Evaluation of intravenous pamidronate administration in 33 cancer-bearing dogs with primary or secondary bone involvement

The purpose of this study was to evaluate the clinical safety of pamidronate when administered at a mean dosage of 1.0 mg/kg IV q28d in 33 tumor-bearing dogs. Biochemical tests of renal function were evaluated before each successive pamidronate treatment. Of 33 dogs treated with pamidronate, 1 dog had clinically relevant increases in serum creatinine and blood urea nitrogen concentrations. The biologic activity of IV pamidronate was assessed prospectively in 10 dogs with appendicular osteosarcoma and was assessed on reductions in urine N-telopeptide excretion (P = .042) and enhanced bone mineral density of the primary tumor measured with dual-energy x-ray absorptiometry (P = .024). Additionally, in these 10 dogs, pamidronate's therapeutic activity was supported by subjective improvement in pain control in 4 of the 10 dogs treated. IV pamidronate appears clinically safe in tumor-bearing dogs and may possess modest biologic activity for managing neoplastic complications associated with pathologic bone resorption.     

Single-agent pamidronate for palliative therapy of canine appendicular osteosarcoma bone pain

BACKGROUND: Canine appendicular osteosarcoma (OSA) causes focal bone destruction, leading to chronic pain and reduced quality-of-life scores. Drugs that inhibit pathologic osteolysis might provide additional treatment options for managing cancer-induced bone pain. Aminobisphosphonates induce osteoclast apoptosis, thereby reducing pain associated with malignant osteolysis in human patients with cancer. HYPOTHESIS: Treatment of dogs with pamidronate administered intravenously will alleviate bone pain and reduce pathologic bone turnover associated with appendicular OSA in dogs. ANIMALS: Forty-three dogs with naturally occurring appendicular OSA administered pamidronate intravenously. METHODS: Prospective study. Therapeutic responses in dogs treated with pamidronate administered intravenously and nonsteroidal anti-inflammatory drugs (NSAID) were evaluated by using a numerical cumulative pain index score (CPIS), and by quantifying urine N-telopeptide (NTx) excretion and relative primary tumor bone mineral density (rBMD) assessed with dual energy x-ray absorptiometry. In addition, variables, including pamidronate dose, skeletal mass, baseline and change for CPIS, urine NTx and rBMD during treatment, and baseline tumor volume and radiographic pattern were compared between dogs clinically responsive and nonresponsive to pamidronate therapy. RESULTS: Twelve of 43 dogs (28%) had pain alleviation for >4 months, lasting a median of 231 days. Changes in CPIS and rBMD during treatment were statistically different between responders and nonresponders (P = .046 and .03, respectively). CONCLUSIONS AND CLINICAL IMPORTANCE: Substantiated by reductions in CPIS and increases in rBMD, single-agent pamidronate administered intravenously with NSAID therapy relieves pain and diminishes pathologic bone turnover associated with appendicular OSA in a subset of dogs.     

The bone biologic effects of zoledronate in healthy dogs and dogs with malignant osteolysis

BACKGROUND: Malignant osteolysis is a process whereby cancer cells in concert with osteoclasts erode bone matrix. Aminobisphosphonates (NBPs) such as zoledronate induce osteoclast apoptosis and thereby decrease malignant skeletal destruction, severity of bone pain, and frequency of pathologic fracture. HYPOTHESIS: IV-administered zoledronate will reduce homeostatic bone turnover in healthy dogs and pathologic bone resorption in dogs diagnosed with primary and secondary bone tumors. ANIMALS: Six healthy dogs and 20 dogs with naturally occurring primary or metastatic bone tumors were administered zoledronate IV. METHODS: Prospective study: In all dogs, healthy (n = 6) and with malignant osteolysis (n = 20), the bone biologic effects of zoledronate were evaluated by quantifying changes in serum C-telopeptide (CTx) or urine N-telopeptide (NTx) concentrations or both. In dogs with osteosarcoma (OSA) (n = 10), serial changes in tumor relative bone mineral density (rBMD) assessed by dual-energy x-ray absorptiometry were used to characterize zoledronate's antiresorptive effects within the immediate tumor microenvironment. Additionally, the biochemical tolerability of zoledronate was assessed in 9 dogs receiving multiple (> or =2) consecutive treatments. RESULTS: All dogs had significant reductions in serum CTx or urine NTx concentrations or both after zoledronate administration. In a subset of dogs with appendicular OSA, reduced urine NTx concentrations and increased primary tumor rBMD coincided with improved limb usage as reported by pet owners in dogs treated with zoledronate and concurrent oral analgesics. Multiple zoledronate infusions were not associated with biochemical evidence of toxicosis. CONCLUSIONS AND CLINICAL IMPORTANCE: In dogs with skeletal neoplasms, IV-administered zoledronate exerts bone biologic effects, appears safe, and can provide pain relief.     

Use of pamidronate to reverse vitamin D3-induced toxicosis in dogs.

OBJECTIVES: To determine whether pamidronate disodium can reduce vitamin D3-induced hypercalcemia in dogs and whether combination treatment with calcitonin is more effective than treatment with pamidronate alone. ANIMALS: 20 clinically normal male Beagles. PROCEDURE: All dogs were given 8 mg of cholecalciferol (CCF)/kg of body weight once orally, then were assigned randomly to 4 groups of 5 dogs each. Dogs were given 0.9% NaCl solution IV (group 1), calcitonin SC and 0.9% NaCl solution IV (group 2), pamidronate and 0.9% NaCl solution IV (group 3), or a combination of all 3 agents (group 4). Dogs were observed for 28 days, and serial blood and urine samples were collected for determination of serum biochemical, electrolyte, and 25(OH)D3 values, CBC, and urine mineral excretion. Samples of kidney, stomach, lung, aorta, liver, duodenum, and brain were evaluated by light microscopy and quantitative mineral analysis. RESULTS: Two dogs in group 1 were euthanatized 4 days after CCF administration because of severe clinical signs of disease. Dogs in group 3 lost less weight and had significantly lower serum phosphorus, total and ionized calcium, and urinary zinc concentrations, compared with dogs in group 1. On day 4, serum urea nitrogen concentration was significantly lower in dogs of groups 3 and 4, compared with dogs in group 1. Mild to moderate mineralization of kidneys and stomach were observed in the 2 group-1 dogs euthanatized on day 4. CONCLUSIONS: Pamidronate administration effectively prevents CCF-induced hypercalcemia and mineralization of soft tissues. CLINICAL RELEVANCE: Pamidronate is a potentially useful antidote against CCF toxicosis in dogs.     

Bone metabolic effects of single-dose zoledronate in healthy dogs

Zoledronate, an aminobisphosphonate with potent antiresorptive activity in bone, has the potential for treatment of malignant osteolysis and hypercalcemia in dogs. The purpose of this study was to evaluate the bone metabolic effects of a single dose of zoledronate in healthy dogs. Four skeletally mature, male, intact dogs received a 15-minute i.v. infusion of zoledronate at a dosage of 0.25 mg/kg. Urine N-telopeptide of type I collagen (NTx) excretion decreased significantly from baseline by 76, 63, 77, and 73% on days 7, 14, 21, and 28, respectively (P < .0125). Serum bone-specific alkaline phosphatase (bALP) decreased significantly from baseline by 36 and 42% on days 21 and 28, respectively (P < .0125). No changes were detected in indices of calcium homeostasis (ionized calcium, intact PTH, or urine calcium excretion). Single-dose i.v. zoledronate at 0.25 mg/kg appears to inhibit homeostatic osteolytic activity in healthy, skeletally mature dogs. Prospective studies should assess repeated-dose safety and activity in healthy and diseased animals of various age groups.     

A comparison of five different bone resorption markers in osteosarcoma-bearing dogs, normal dogs, and dogs with orthopedic diseases

BACKGROUND: Various bone resorption markers in humans are useful for supporting the diagnosis of malignant skeletal pathology, with certain bone resorption markers appearing to be more discriminatory for detecting cancer-induced osteolysis than others. Canine osteosarcoma (OSA) is characterized by focal bone destruction, but a systematic investigation for determining which bone resorption marker best supports the diagnosis of OSA in dogs has not been reported. HYPOTHESIS: Dogs with OSA will have increased concentrations of bone resorption markers compared with healthy dogs and dogs with orthopedic disorders. Differences will exist among various bone resorption markers for their ability to support the diagnosis of malignant osteolysis in dogs with OSA. ANIMALS: Single time point, cross-sectional, cohort study including dogs with OSA (n = 20) or orthopedic disorders (n = 20) and healthy dogs (n = 22). METHODS: Basal concentrations of urine and serum N-telopeptide (NTx), urine and serum C-telopeptide (CTx), and urine deoxypyridinoline (DPD) were compared among all 3 groups. RESULTS: Compared with healthy dogs and dogs with orthopedic disorders, urine NTx, serum NTx, and serum CTx concentrations were significantly increased in dogs with OSA. For urine NTx and serum NTx, the calculated lower and upper 95% confidence limits in dogs with OSA did not overlap with dogs diagnosed with orthopedic disorders or healthy dogs. CONCLUSIONS AND CLINICAL IMPORTANCE: Of the markers evaluated in this study, urine NTx and serum NTx appear to be the most discriminatory resorption markers supporting the diagnosis of focal malignant osteolysis in dogs with OSA.     

Effect of spironolactone on diuresis and urine sodium and potassium excretion in healthy dogs

ObjectivesTo document the diuretic effect of different oral doses of spironolactone (SP) in healthy dogs.BackgroundSP is currently mentioned as a diuretic agent in the dog. However, the recommended doses were empirically defined and their corresponding diuretic effect has never been documented in dogs.Animals, materials and methodsEight adult Beagle dogs were used for two separate 2 * 2 cross-over designs. In the first cross-over, 4 dogs received SP orally for 8 days at 1 and 2 mg/kg per day. In the second cross-over the 4 other dogs received SP similarly, but at 4 and 8 mg/kg per day. Dogs were weighed on the first and last day of each period. Plasma SP and canrenone (the main active metabolite of SP) were assayed by high performance liquid chromatography (HPLC). Daily water consumption, urine weight, urine specific gravity, and urine excretion of sodium and potassium were measured during the SP treatment.ResultsTwo hours after SP administration, SP was metabolized into canrenone. A significant 14 and 22% decrease in urine potassium excretion was observed at 1 and 2 mg/kg, respectively, but not at the two other dose levels. Daily water consumption, urine weight, urine specific gravity, and urine excretion of sodium were not significantly altered by the SP treatment regardless of dose.ConclusionsRepeated oral administration of SP at 1, 2, 4 or 8 mg/kg for 8 days had no effect on water and sodium diuresis in healthy dogs.     

Pharmacokinetics and bioavailability of 2-mercaptopropionylglycine administered intravenously and orally in dogs

The pharmacokinetic disposition of 2-mercaptopropionylglycine (2-MPG) given as a single intravenous injection and/or as a single oral dose was studied in 9 normal and 13 cystinuric dogs. After intravenous injection of approximately 10 or 20 mg/kg body weight the pharmacokinetics were best described by a three-exponential function. The first phase involved a distribution process apparently including establishment of drug-plasma protein and drug-tissue binding. The second phase involved rapid renal elimination and 60% of the drug was excreted within 3 h of administration. There was also a slow terminal third phase with a long half-life after both intravenous (t1/2 = 23 h) and oral (t1/2 = 22 h) administration. No dose dependency was observed. A deep pool of reversibly tissue-bound 2-MPG was indicated by a Vss of 3.3 +/- 0.9 l/kg body weight and the long terminal elimination phase. Total clearance was estimated as 4.1 +/- 0.9 ml/min/kg body weight. 2-MPG was eliminated mainly by renal excretion, but there was a difference in recovery of dose between normal and cystinuric dogs. During the first 24 h after intravenous and oral administration, 69% and 54%, respectively, of the drug was recovered in the urine of normal dogs. The corresponding figures in cystinuric dogs were 44% and 29%, respectively. The absolute bioavailability (FAUC) was 88 +/- 20% in normal dogs.     

Outcome after repair of a sarcoma-related pathologic fracture in dogs: a Veterinary Society of Surgical Oncology Retrospective Study

Objective: To report outcome in dogs after internal fixation of a sarcoma‐related pathologic fracture of the appendicular skeleton. Study Design: Multi‐institutional case series. Animals: Dogs (n=16). Methods: Medical records of participating VSSO members were reviewed for dogs with pathologic fracture associated with a confirmed bone sarcoma of the appendicular skeleton repaired by external or internal fixation. Dogs were included if they had a histological diagnosis of osteosarcoma or sarcoma and excluded if they had radiation before fracture. Data collected were analyzed for signalment, fracture location, staging performed, method of fracture fixation, histopathology, adjunctive treatment and outcome. Results: Signalment and fracture location of 16 dogs that met the inclusion criteria was similar to dogs with appendicular OSA without fracture. One of 14 dogs had pulmonary metastasis and 3 of 5 dogs had bone metastasis. Bone plate or interlocking nail were used for repair in 12 dogs. Limb use immediately after surgery in 13 dogs was good (4), weight‐bearing but lame (7) and non‐weight bearing (2). Adjunctive therapy was administered in 5 dogs (chemotherapy, 3; radiation, 4; pamidronate, 3). Survival time ranged from 18 to 897 days; median survival was 166 days. Conclusions: Repair of pathologic fracture can result in palliation and prolonged survival.     

Proximal radial and distal humeral osteosarcoma in 12 dogs

Twelve dogs were diagnosed with osteosarcoma of the proximal radius or distal humerus from 1990 to 2002, representing 1.0% of all dogs diagnosed with appendicular osteosarcoma. The median body weight (29.8 kg) was significantly less than that of dogs with appendicular osteosarcoma at other sites. Ten dogs were treated with amputation and chemotherapy. These dogs had a metastatic rate of 60%, a median metastasis-free interval of 356 days, and a median survival time of 824 days. There were no significant differences in metastasis-free interval or survival time between dogs with osteosarcoma of the proximal radius or distal humerus and dogs with appendicular osteosarcoma at other sites.     

Cisplatin and doxorubicin toxicosis in dogs with osteosarcoma

Toxicosis associated with doxorubicin and cisplatin administration starting either 2 or 10 days after limb amputation for osteosarcoma was examined retrospectively in dogs. The purpose was to determine whether dosage and timing of chemotherapy affected rates of toxicosis after administration of the 1st treatment. Records of 100 dogs with appendicular osteosarcoma without evidence of metastases or concurrent disease were examined. Dogs received chemotherapy with doxorubicin and cisplatin every 3 weeks for 3 treatments starting 2 days (n = 51) or 10 days (n = 49) after amputation. The dosage of cisplatin was 60 mg/m2 and was given with 6-hour saline diuresis and butorphanol. Doxorubicin was given at 12.5-25 mg/ml during fluid administration. Hematologic data were collected before and weekly after treatment. Client interviews were conducted to assess gastrointestinal toxicosis during the interval between treatments. The reported toxicoses were graded on a scale of 0 to 4. Dogs receiving 25 mg/m2 of doxorubicin experienced greater rates of grade 4 toxicity (67%; n = 6) than dogs in groups receiving 12.5-20 mg/m2 of doxorubicin (< or = 25%; n = 94, P = .03). Dogs in the Day 2 group experienced greater rates (35%) of grade 4 toxicity than dogs in the Day 10 group (12%, P = .007). We concluded that chemotherapy administered 2 days after surgery produced an unacceptable level of toxicoses. except at greatly reduced dosages, and that even with a delay of treatment, 25 mg/m2 of doxorubicin, when given in combination with cisplatin at 60 mg/m2, was too toxic for routine use.     

Cisplatin and doxorubicin combination chemotherapy for the treatment of canine osteosarcoma: a pilot study

Sixteen dogs with histologically confirmed appendicular osteosarcoma were treated by amputation followed by cisplatin and doxorubicin chemotherapy. All dogs began chemotherapy within 24 hours of surgery. Cisplatin was administered at 50 mg/m2 intravenously (IV) concurrent with saline-induced diuresis. Doxorubicin was administered 24 hours later at 15 mg/m2 as a slow IV bolus. This protocol was given on a 21-day cycle for 4 cycles. No dose delays were required, but dose reduction of doxorubicin was required in 2 dogs because of neutropenia. Thoracic radiography was performed every 2 months after completion of therapy to monitor for metastatic disease. Two dogs were still alive and free from disease at the time of last contact (24 and 75 months, respectively). Postmortem examinations were performed on 13 of the 14 dogs that died. Eight of these dogs were euthanized because of metastatic osteosarcoma. Of the remaining 5 dogs, euthanasia was performed because of complications of idiopathic megaesophagus (n = 1), arthritis (n = 2), and hemangiosarcoma (n = 2). The median disease-free interval and survival times were 15.7 and 18 months, respectively. When compared to a historical group of 36 dogs with appendicular osteosarcoma treated with surgery and 4 doses of cisplatin. both disease-free interval and overall survival were significantly longer in the study population (P < .015 and P < .007, respectively).     

Auranofin improves overall survival when combined with standard of care in a pilot study involving dogs with osteosarcoma

Osteosarcoma is the most common paediatric primary bone malignancy. The major cause of death in osteosarcoma is drug‐resistant pulmonary metastasis. Previous studies have shown that thioredoxin reductase 2 is a driver of metastasis in osteosarcoma and can be inhibited by auranofin (AF). Moreover, studies have shown that AF significantly reduces pulmonary metastases in xenotransplant models. Here, we describe a phase I/II study of AF in canine osteosarcoma, a well‐recognized spontaneous model of human osteosarcoma. We performed a single‐arm multicentre pilot study of AF in combination with standard of care (SOC) (amputation + carboplatin). We recruited 40 dogs to the trial and used a historical SOC‐only control group (n = 26). Dogs >15 kg received 9 mg AF q3d PO and dogs <15 kg received 6 mg q3d. Follow‐up occurred over at least a 3‐year period. Auranofin plus SOC improved overall survival (OS) (P = .036) in all dogs treated. The improved outcome was attributable entirely to improved OS in male dogs (P = .009). At the time of writing, 10 dogs (25%) survive without measurable disease in the treatment group with survival times ranging between 806 and 1525 days. Our study shows that AF improves OS in male dogs when combined with SOC. Our findings have translational relevance for the management of canine and human osteosarcoma. Our data justify a larger multicentre phase 2 trial in dogs and a phase I/II trial in human patients with refractory disease at the time of initial surgery.     

Effects of chlorothiazide on urinary excretion of calcium in clinically normal dogs.

Administration of thiazide diuretics has been recommended to prevent calcium oxalate urolith development in dogs. To evaluate the effects of thiazide diuretics in dogs, 24-hour urine excretion of calcium was measured in 6 clinically normal Beagles after administration of chlorothiazide (CTZ) for 2 weeks, administration of CTZ for 10 weeks, and administration of calcium carbonate and CTZ for 2 weeks. Compared with baseline values, 24-hour urine calcium excretion did not decrease after CTZ administration. When CTZ was given at a high dosage (130 mg/kg of body weight), urinary calcium excretion was significantly (P < 0.04) higher than baseline values. Based on these observations, we do not recommend CTZ for treatment or prevention of canine calcium oxalate urolithiasis.     

Samarium Sm 153 lexidronam for the palliative treatment of dogs with primary bone tumors: 35 cases (1999-2005)

OBJECTIVE: To evaluate survival times and palliative effects associated with the use of samarium Sm 153 lexidronam in dogs with primary bone tumors. DESIGN: Retrospective case series. ANIMALS: 35 dogs with primary appendicular (n = 32) or axial (3) bone tumors. PROCEDURES: 1 to 4 doses of samarium Sm 153 lexidronam were administered at a rate of 37 MBq/kg (16.8 MBq/lb), IV. Response to treatment, measured by lameness improvement, and survival time were determined. RESULTS: Of the 32 dogs with appendicular tumors, 20 (63%) had an improvement in the severity of lameness 2 weeks after administration of the first dose of radioactive samarium, 8 (25%) had no change in the severity of lameness, and 4 (12%) had a worsening. Overall median survival time was 100 days, with 3 dogs (8.6%) alive after 1 year. Median survival time for the 32 dogs with appendicular tumors was 93 days, with 3 (9.4%) alive after 1 year. This was not significantly different from the median survival time of 134 days for a historical cohort of 162 dogs with appendicular osteosarcoma that underwent amputation as the only treatment. CONCLUSIONS AND CLINICAL RELEVANCE: Results suggest that samarium Sm 153 lexidronam may be useful in the palliation of pain in dogs with primary bone tumors that are not candidates for curative-intent treatment.     

Differentiating effect of pamidronate on canine osteo‐sarcoma cell lines in vitro

Introduction: Pamidronate has been traditionally used to manage pathologic osteoclastic disorders. In addition to its effects on osteoclasts, pamidronate has also been demonstrated to promote phenotypic maturation and inhibition of proliferation in osteoblasts. Canine osteosarcoma (OSA) consists of malignant, undifferentiated osteoblasts. The objective of this study was to determine if micromolar concentrations of pamidronate could induce malignant osteoblastic differentiation as evaluated by an increase in alkaline phosphatase (ALP) activity and/or osteocalcin (OC) production, two specific markers of normal osteoblastic activity. Methods: Two canine OSA cell lines (HMPOS and COS 31) were used for all experiments. Cells were incubated for 48 or 72 hours with various pamidronate concentrations (0, 0.1, 1, 5, 10, and 20 μM). After incubation, the supernatants were sampled and the relative amounts of viable cells were determined with a cell proliferation assay (Cell Titer 96^® AQ_uous, Promega). An ALP detection kit (Starbright^®, Sigma^®) was used to measure the ALP activity and an ELISA (Osteocalcin EIA kit, Biomedical Technologies) was used to determine the concentration of osteocalcin in the supernatants. The ALP and osteocalcin values were corrected for the amount of viable cells. Results: Pamidronate induced a dose‐dependent reduction in the number of viable COS 31 and HMPOS cells at both 48 and 72 hours. A dose‐dependent elevation in ALP activity from baseline was observed. At 20 μM, a 2.3‐fold increase was observed for HMPOS at 72 hours, while a 1.43‐fold increase was observed for COS 31 at 72 hours. Very low level (less than 2 ng/ml) of osteocalcin pre‐ and post‐pamidronate treatment was detected for both COS 31 and HMPOS. Conclusion: The data suggests that pamidronate increases alkaline phosphatase activity in canine OSA cells in a dose‐dependent manner. However, cytotoxic assays are needed in order to accurately characterize any concurrent decrease in the number of viable cells. The potential differentiating effect of pamidronate on malignant osteoblasts provides an additional argument for its use in the palliative treatment of OSA.     

Effect of administration of nonsteroidal anti-inflammatory drugs before surgery on renal function in clinically normal dogs

OBJECTIVES: To investigate renal function in clinically normal dogs undergoing general anesthesia for ovariohysterectomies that received nonsteriodal antiinflammatory drugs (NSAID) before surgery. ANIMALS: 40 clinically normal dogs. PROCEDURE: After induction of anesthesia, dogs were given an analgesic. Renal function was assessed before surgery and 24 and 48 hours after surgery by means of serum urea and creatinine concentrations, fractional clearance of sodium (FC(Na)), urine gamma-glutamyltransferase (GGT) and alkaline phosphatase (ALP) activities, and urine analysis. Ten dogs in each of 4 groups received ketorolac tromethamine (0.5 mg/kg of body weight), ketoprofen (1 mg/kg), carprofen (4 mg/kg), or morphine (0.1 mg/kg; control group). RESULTS: Duration of general anesthesia ranged from 1.75 to 5 hours, with a mean of 3 hours. Two ketorolac- and 2 ketoprofen-treated dogs had transient azotemia. A significant decrease in the FC(Na) between before surgery and 24 hours after surgery, and between before surgery and 48 hours after surgery, was found in ketoprofen- and carprofen-treated dogs. Ketorolac-, ketoprofen-, and morphine-treated dogs had a decrease in urine specific gravity. Two ketorolac, 1 ketoprofen-, 1 carprofen-, and 4 morphine-treated dogs had increases in renal tubular epithelial cells on urine sediment examination 24 hours after surgery. CONCLUSIONS AND CLINICAL RELEVANCE: In clinically normal dogs undergoing general anesthesia and elective surgery, the use of NSAID as analgesics is not contraindicated. Compared with ketorolac or ketoprofen, carprofen had the least effect on renal function and integrity.