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At least 19 recordsLinked to original sources

PubMed2000

Effect of pamidronate on skeletal morbidity in myelomatosis. Part 1. The results of the first 12 months of pamidronate therapy.

BACKGROUND: Osteolytic bone destruction caused by increase of osteolytic activity is a major manifestation of multiple myeloma (MM). Pamidronate (3-amino-1-hydroxypropylidene)-1,1-bisphosphonate) inhibits osteoclastic activity and reduces bone resorption. METHODS: Since October 1995 the efficacy of pamidronate is evaluated in MM patients all receiving anti-myeloma chemotherapy acc. to VMCP/VBAP alternating regimen. 46 patients with stage III myeloma and osteolytic lesions were randomized to receive either pamidronate (Aredia; Novartis) 60 mg i.v. in 4-hour infusion monthly (n = 23) or chemotherapy alone (control group n = 23). Estimation of performance status, quality of life, pain score, analgesic consumption, serum calcium concentration and twenty four-hours Calcium excretion, urine Calcium/creatinine ratio is done at least once a month (before pamidronate administration) while X-ray skeletal survey--before treatment and then every six months. RESULTS: In the first months of treatment apparent reduction of bone pain occurred. Hypercalcaemia was revealed in 6 patients at entry into the study. In 5 of these patients pamidronate restored and maintained normocalcaemia for a median 6 months. In 3 patients an aggressive plasma cell proliferation was accompanied by reoccurrence of hypercalcaemia. At skeletal X-ray examination performed after 6 and 12 cycles of pamidronate and by comparing each of consecutive imaging with previous one the progression of osteolysis was respectively found in 67% and 39% of patients. In the control group corresponding figures were: 79% and 70%. The mean number of skeletal events (pathologic fracture, radiation to bone and spinal cord compression) per year was lower in the pamidronate group (1.82) than in control-patients (2.72), p < 0.013. The proportion of patients who developed skeletal event (excluding vertebral fractures) was lower in the pamidronate group -34% v 52%. Adverse events of pamidronate: hypocalcaemia (< 2 mmol/l) observed in 7 patients occurred in particular patients beginning from 2 to 7 days after drug administration. In 2 patients hypocalcaemia that appeared in 24 hours after drug infusion was accompanied by blood pressure decrease; in one case systolic blood pressure dropped up to 60 mmHg, in the other one--to 90 mmHg. Muscular pain and fever up to 39 degrees C (transient and self-limiting "influenza like syndrom") occurred in 5 patients, in two patients after several hours and in three other--after some dozens of hours from drug administration. In one case hypertransaminasaemia was observed. CONCLUSIONS: In the first year of treatment monthly intravenous pamidronate administration as an adjunct to chemotherapy in patients with advanced multiple myeloma with osteolysis is an efficient approach in prevention and treatment of hyperacalcaemia, hypercalciuria and bone pain. It also shows some preventive effect on bone lesion occurrence.

Adult↗

PubMed2003

Three-year effectiveness of intravenous pamidronate versus pamidronate plus slow-release sodium fluoride for postmenopausal osteoporosis.

All currently available and approved therapies for osteoporosis inhibit bone resorption. But, despite their great value, antiresorptive agents are generally not associated with dramatic increases in bone mass. In light of these data, the aim of our prospective, placebo-controlled, randomized clinical trial, with a 3-year follow up, was to examine the effects of cyclic intravenous pamidronate and fluoride in combination, versus pamidronate alone, on bone mineral density (BMD) at vertebral and femoral levels, biochemical markers of bone turnover, IGF-1 serum levels, and safety and tolerability in 40 postmenopausal women with osteoporosis. During the treatment period, pamidronate alone reduced both markers of bone formation and bone resorption, resulting in an increase of BMD, after 3 years, of 7.07% at the lumbar level and of 6.76% at the femoral level. In the group treated with pamidronate and fluoride, markers of bone turnover had a different trend: after 3 years, there was a lower reduction of bone resorption and an increase of bone formation markers, with a concomitant increase in IGF-1 levels. This resulted, after 3 years of treatment, in a marked variation of BMD at the lumbar level (+12.74%) and a reduced, but still significant, increase at the femoral level (3.89%). Spine radiography and clinical evaluation did not reveal any vertebral fractures in either treatment group. In conclusion, the combined use of pamidronate and fluoride produced somewhat larger, continuous increases in BMD, at the lumbar level, than pamidronate alone.

Alkaline Phosphatase↗

PubMed1998

Randomized trial of pamidronate in patients with thyroid cancer: bone density is not reduced by suppressive doses of thyroxine, but is increased by cyclic intravenous pamidronate.

Patients taking suppressive doses of T4 are thought to have accelerated bone loss and increased risk of osteoporosis. We therefore randomize 55 patients taking suppressive doses of T4 to treatment with pamidronate (APD) 30 mg i.v. every 3 months for 2 yr (APD/T4), or placebo (placebo/T4). Patients had measurements of bone mineral density (BMD) of the spine, hip, radius, and total body every 6 months for 2 yr. There was no significant bone loss at any site in the placebo/T4 group. Ninety five percent confidence intervals excluded a rate of bone loss > 0.89%/yr for the spine and > 0.31%/yr at the total hip. When men were excluded from the analysis, there still was no significant bone loss for the placebo/T4 group, and confidence intervals did not change. The APD/T4 group showed increases in spine (4.3%, P = 0.0001), total hip (1.4%, P < 0.05), and trochanteric (3.0%, P = 0.0001) BMDs. In conclusion, premenopausal women and men on suppressive therapy with T4 do not lose bone rapidly, and are not at increased risk of developing osteoporosis. A regimen of 30 mg APD given every 3 months for 2 yr causes significant suppression of bone resorption and increases in BMD, and may be an acceptable alternative treatment for osteoporosis in patients who cannot tolerate oral bisphosphonates.

Adult↗

PubMed2001

The impact of pamidronate on inpatient and outpatient services among metastatic breast cancer patients.

Our goal was to evaluate the impact of pamidronate therapy on medical resource utilization for treatment of bone metastases among patients with breast cancer. In this 12-center retrospective study, inpatient and outpatient resource utilization was abstracted from the medical charts of 295 patients with breast cancer who were diagnosed with bone metastases between July 1996 and April 1999. Data were abstracted from the time of bone metastasis diagnosis (baseline) to the present. The analysis compared non-pamidronate patients against pamidronate patients, who were stratified on the basis of whether their pamidronate therapy had been initiated within 3 months (early pamidronate group) or more than 3 months (late pamidronate group) after diagnosis. Resource utilization was compared among groups using multivariate regression analyses. A total of 101 early pamidronate, 72 late pamidronate, and 122 non-pamidronate patients were included in the analysis. The results showed that the early pamidronate group was roughly one-half as likely to have unplanned office visits attributable to bone metastases as the late pamidronate and non-pamidronate groups. The groups had a similar likelihood of ever being hospitalized for bone-related conditions; however, among those hospitalized, there were roughly one-half as many bone-related hospitalizations in the late pamidronate group as in the non-pamidronate group. Also, the mean length of stay was approximately 50% shorter in both pamidronate groups than in the non-pamidronate group. We conclude that pamidronate therapy may be associated with less medical resource utilization, particularly among patients hospitalized for bone-related conditions.

Aged↗

PubMed2005

Effects of intravenous pamidronate treatment in infants with osteogenesis imperfecta: clinical and histomorphometric outcome.

UNLABELLED: Clinical and histomorphometric outcome was compared between children with OI who had received pamidronate since infancy and age-matched patients who had never received pamidronate. Pamidronate was associated with improved vertebral shape and mass, higher cortical width, increased cancellous bone volume, and suppressed bone turnover. INTRODUCTION: Observations in small patient series indicate that infants with severe osteogenesis imperfecta (OI) benefit from treatment with cyclical intravenous pamidronate. However, detailed analyses of outcome are lacking for this age group. MATERIALS AND METHODS: Clinical outcome was evaluated in 29 children with OI types I (n = 3), III (n = 14), or IV (n = 12) who started pamidronate therapy before 2 years of age (age at treatment onset: median, 6 months; range, 2 weeks to 23 months) and who had completed 3 years of treatment (total annual pamidronate dose, 9 mg/kg). They were compared with a historical control group of 29 untreated children with severe OI who were matched for OI type and age at the 3-year treatment time-point. In addition, iliac bone histomorphometry was compared between 24 pamidronate-treated patients and 24 age-matched OI patients who had not received pamidronate. RESULTS: Morphometric evaluation of lumbar vertebrae (L(1)-L(4)) showed that the shape of vertebral bodies was better preserved in pamidronate-treated patients. This was accompanied by significantly higher lumbar spine areal and volumetric BMD (+110 and +96%, respectively) and a larger vertebral bone volume (+26%) on densitometry. Regarding mobility function, the Pediatric Evaluation of Disability Inventory gross motor score was 50% greater in the pamidronate group (p < 0.001). Iliac bone histomorphometry showed 61% higher cortical width and 89% higher cancellous bone volume in pamidronate-treated patients. Bone formation rate per bone surface in the pamidronate group was only 17% that of untreated patients. CONCLUSIONS: In conclusion, this study suggests that cyclical pamidronate treatment started in infancy leads to improved bone strength and better gross motor function but also suppresses bone turnover markedly. It is therefore prudent to reserve pamidronate treatment to infant OI patients who present with a moderate to severe phenotype.

Bone and Bones↗

PubMed1998

Pamidronate. A review of its use in the management of osteolytic bone metastases, tumour-induced hypercalcaemia and Paget's disease of bone.

Pamidronate (APD) is a potent inhibitor of bone resorption that is useful in the management of patients with osteolytic bone metastases from breast cancer or multiple myeloma, tumour-induced hypercalcaemia or Paget's disease of bone. After intravenous administration, the drug is extensively taken up in bone, where it binds with hydroxyapatite crystals in the bone matrix. Matrix-bound pamidronate inhibits osteoclast activity by a variety of mechanisms, the most important of which appears to be prevention of the attachment of osteoclast precursor cells to bone. In patients with osteolytic bone metastases associated with either breast cancer or multiple myeloma, administration of pamidronate together with systemic antitumour therapy reduces and delays skeletal events, including pathological fracture, hypercalcaemia and the requirement for radiation treatment or surgery to bone. Pamidronate generally improves pain control. Quality-of-life and performance status scores in pamidronate recipients were generally as good as, or better than, those in patients who did not receive the drug. Overall survival does not appear to be affected by pamidronate therapy. Tumour-induced hypercalcaemia also responds well to pamidronate therapy: 70 to 100% of patients achieve normocalcaemia, generally 3 to 5 days after treatment. Response durations vary, but are commonly 3 weeks or longer, In comparative studies, pamidronate produced higher rates of normocalcaemia and longer normocalcaemic durations than other available osteoclast inhibitors, including intravenous etidronate, clodronate and plicamycin (mithramycin). In most patients with Paget's disease of bone, intravenous pamidronate reduces bone pain and produces biochemical response. Serum alkaline phosphatase levels generally fall 50 to 70% from baseline 3 to 4 months after pamidronate treatment. Biochemical response may be prolonged. Pamidronate is well tolerated by most patients. Transient febrile reactions, sometimes accompanied by myalgias and lymphopenia, occur commonly after the first infusion of pamidronate. Other reported adverse events include transient neutropenia, mild thrombophlebitis, asymptomatic hypocalcaemia and, rarely, ocular complications (uveitis and scleritis). Pamidronate should be considered for routine use together with systemic hormonal or cytotoxic therapy in patients with breast cancer or multiple myeloma and osteolytic metastases. At present, pamidronate is the drug of choice for first-line use in the management of patients with tumour-induced hypercalcaemia. It is an effective treatment for Paget's disease and is the treatment of choice where oral bisphosphonates are not an option.

Antineoplastic Agents↗

PubMed2003

Efficacy and safety of ibandronate in the treatment of hypercalcemia of malignancy: a randomized multicentric comparison to pamidronate.

GOALS: To compare the efficacy and safety of ibandronate and pamidronate in patients with hypercalcemia of malignancy (HCM). PATIENTS AND METHODS: Seventy-two patients with HCM [albumin-corrected serum calcium (CSC) >2.7 mmol/l] were treated with a single infusion of ibandronate (2 or 4 mg) or pamidronate (15, 30, 60, or 90 mg) on day 0. The dose was dependent on the severity of hypercalcemia (baseline CSC level). CSC was assessed daily until day 4, then at intervals until day 28. The primary endpoint was lowering of CSC at day 4. Secondary endpoints included the number of patients responding and time to re-increase following response. MAIN RESULTS: Using the CSC baseline approach, the most frequently administered doses were 4 mg ibandronate (78.4%) and 60 mg pamidronate (50.0%). Mean lowering of CSC at day 4 was 0.6 mmol/l for ibandronate and 0.41 mmol/l for pamidronate. The 95% confidence interval for the difference ibandronate pamidronate had a lower limit of 0.05 mmol/l, indicating that ibandronate was as effective as pamidronate. The number of patients responding to the two agents was also similar; 76.5% of ibandronate patients and 75.8% of pamidronate patients were rated as responders after the first dose of study medication. The median time to re-increase after response was longer for ibandronate (14 days) than pamidronate (4 days) ( P=0.0303). In the subgroup of 17 patients with high baseline CSC (>3.5 mmol/l), ibandronate appeared to be more effective than pamidronate. The safety profile of both agents was similar. CONCLUSIONS: Ibandronate is at least as effective as pamidronate in the treatment of HCM. Furthermore, in patients with higher baseline CSC ibandronate appears to be more effective than pamidronate. The duration of response is significantly longer with ibandronate than pamidronate.

Administration, Oral↗

PubMed2006

Renal safety of 1-hour pamidronate infusion for breast cancer and multiple myeloma patients: comparison between clinical trials and population-based database.

PURPOSE: The American Society of Clinical Oncology recommends infusion of pamidronate over 2 hours to avoid renal deterioration, although there are data to suggest that 1-hour infusions may be safe. METHODS: Prevalence of renal deterioration with 1-hour pamidronate infusions from a population database was compared to renal deterioration with 2-hour pamidronate infusions, in randomised, controlled, trials. A cost-minimisation analysis, comparing the 1- and 2-hour pamidronate infusions, and the 15-minute infusion of zoledronic acid, was performed with a sensitivity analysis that varied the opportunity cost of time in the treatment room. RESULTS: Renal deterioration occurred in 7.7% of 169 patients with multiple myeloma and metastatic breast cancer. There is no evidence that this differs from the 10% reported in randomised, controlled, trials (one-tailed binomial test, P = 0.3874). A subgroup analysis showed that renal deterioration occurred in 15 and 1.1% of patients with multiple myeloma and metastatic breast cancer, respectively. The median increase in serum creatinine was 13 and 7% in the multiple myeloma and breast cancer groups, respectively. The respective costs/dose (drug/labour/supplies) of pamidronate and zoledronic acid are 325 dollars and 610 dollars. Cost neutrality occurs if the opportunity cost of chair time is 6.33 dollars/minute for pamidronate 1-hour versus zoledronic acid, and 2.71 dollars/minute for pamidronate 2-hour versus zoledronic acid. If a median 4 dollars/minute is used, the respective costs of pamidronate 1-hour, 2-hour, and zoledronic acid infusions are 685 dollars, 925 dollars, and 790 dollars/cycle. CONCLUSIONS: Prevalence of renal deterioration with 1-hour pamidronate infusions from a population database was not significantly different to 2-hour pamidronate infusions in clinical trials. Our findings suggest further support for the safety of 1-hour pamidronate infusions. Pamidronate via 1-hour infusion is less expensive than zoledronic acid.

Aged↗

PubMed2005

Costs and consequences of using pamidronate compared with zoledronic acid in the management of breast cancer patients in the UK.

OBJECTIVE: To estimate the costs and consequences of using pamidronate compared to zoledronic acid in the prophylactic management of skeletal morbidity among breast cancer patients in the UK. DESIGN AND SETTING: This was a modelling study performed from the perspective of the UK's National Health Service (NHS). METHODS: Published clinical outcomes from a comparative study were combined with resource utilisation estimates derived from a panel of clinicians. This enabled the construction of a decision model depicting the management of patients with breast cancer receiving antineoplastic therapy who are 18 years of age or above and who have at least one bone metastasis (lytic or mixed). There are no significant differences in outcome between using pamidronate and zoledronic acid in breast cancer patients. Therefore, a cost minimisation analysis was performed to identify the treatment strategy that achieves the same outcome for least cost. The expected time attributable to a pamidronate and zoledronic acid infusion was also estimated. MAIN OUTCOME MEASURES AND RESULTS: Starting treatment with pamidronate among patients receiving chemotherapy is expected to lead to a healthcare cost of 6046 pounds over 12 months compared to 6981 pounds with zoledronic acid. In comparison, for patients receiving hormonal therapy, starting treatment with pamidronate is expected to lead to a healthcare cost of 5401 pounds over 12 months compared to 6043 pounds with zoledronic acid. This cost difference is primarily due to the lower acquisition cost of pamidronate and fewer tests among pamidronate-treated patients. Accordingly, pamidronate affords a less expensive management modality. Multivariate analysis showed the expected time attributable to a pamidronate infusion to be 110 to 277 minutes compared with 136 to 296 minutes for a zoledronic acid infusion. CONCLUSION: Use of pamidronate instead of zoledronic acid affords an economic benefit to the NHS. Moreover, published clinical trials show no statistical difference between pamidronate and zoledronic acid at 1 year. Hence, within the limitations of our model and the published evidence, pamidronate is the preferred first-line intravenous bisphosphonate for use in breast cancer patients receiving antineoplastic therapy who are 18 years of age or above and who have at least one bone metastasis (lytic or mixed).

Adolescent↗

PubMed2000

Pamidronate prevents skeletal complications and is effective palliative treatment in women with breast carcinoma and osteolytic bone metastases: long term follow-up of two randomized, placebo-controlled trials.

BACKGROUND: Pamidronate therapy previously has been shown to reduce skeletal complications effectively for up to 12 months in breast carcinoma patients with bone metastases. The current study data provide further follow-up results regarding the effects of long term (up to 24 months) pamidronate treatment in women with breast carcinoma and osteolytic metastases. METHODS: Follow-up results from two prospective, multicenter, randomized, double-blind, placebo-controlled intervention trials conducted at academic and community oncology centers were combined to provide a large data set with which to evaluate the long term efficacy and safety of pamidronate therapy. Seven hundred fifty-four women with Stage IV breast carcinoma and osteolytic metastases were randomized to the 2 treatment arms of the trial. Three patients were excluded from the intent-to-treat population for the analysis. A total of 751 evaluable patients were randomized to receive either a 90-mg intravenous pamidronate infusion (367 patients) or a placebo infusion (384 patients) every 3-4 weeks. The primary outcome measures were skeletal morbidity rate (events/year), proportion of patients developing a skeletal complication, and time to first skeletal complication. RESULTS: Of the 367 women receiving pamidronate, 115 (31.3%) completed the trial and 81 (22.1%) discontinued the study due to adverse events. Of the 384 women who received placebo, 100 (26.0%) completed the study and 76 (19.8%) discontinued the study due to adverse events. The skeletal morbidity rate was 2.4 in the pamidronate group and 3.7 in the placebo group (P < 0.001). In the pamidronate group, 186 of the 367 patients (51%) had skeletal complications compared with 246 of the 384 patients in the placebo group (64%) (P < 0.001). The median time to first skeletal complication was 12.7 months in the pamidronate group and 7 months in the placebo group (P < 0.001). Six patients treated with pamidronate discontinued treatment due to drug-related adverse events. Pain and analgesic scores were significantly worse in the placebo group compared with those patients in the pamidronate group. CONCLUSIONS: In the current study, monthly infusions of 90 mg of pamidronate as a supplement to antineoplastic therapy were found to be well tolerated and superior to antineoplastic therapy alone in preventing skeletal complications and palliating symptoms for at least 24 months in breast carcinoma patients with osteolytic bone metastases.

Aged↗

PubMed2003

Better late than never? Experience with intravenous pamidronate treatment in patients with low bone mass or fractures following cardiac or liver transplantation.

Organ transplantation is associated with a high turnover of bone metabolism, and an increased loss of bone mass and incidence of osteoporotic fractures. Established therapies for osteoporosis after organ transplantation are still lacking, however. We report on an intravenous bisphosphonate therapy initiated in transplant patients because of a high rate of bone loss or incident osteoporotic fractures. Twenty-one patients after liver transplantation and 13 patients after heart transplantation received 30 mg pamidronate intravenously every 3 months, combined with 1000 mg calcium and 1000 IU vitamin D per day. The median time interval between transplantation and start of pamidronate treatment was 1.9 years in cardiac patients and 2.3 years in liver patients. Lumbar spine bone mineral density (LS BMD) and femoral neck BMD (FN BMD) were measured before and every 6 months after pamidronate therapy was initiated. Spinal radiographs were performed annually. Biochemical markers of bone metabolism were determined every 3 months, immediately before pamidronate administration. From a previous observational study, 58 patients treated only with calcium and vitamin D were matched for age, sex, pretransplantation LS BMD and time interval between transplantation and the first pamidronate treatment. In the pamidronate-treated patients, the mean increase in LS BMD adjusted for baseline values amounted to 0.080 +/- 0.038 g/cm(2) (8.6 +/- 4.0 %) after 1 year and 0.091 +/- 0.058 g/cm(2) (10.4 +/- 6.1%) after 2 years compared with 0.001 +/- 0.037 g/cm(2) (0.26 +/- 4.0%) after 1 year and 0.015 +/- 0.057 g/cm(2) (1.8 +/- 6.0%) after 2 years in the historical control group (absolute LS BMD changes pamidronate group vs historical group p < 0.0001 after 1 and 2 years). The changes of FN BMD were 0.024 +/- 0.043 g/cm(2) (3.2 +/- 6.1%) after 1 year and 0.046 +/- 0.052 g/cm(2) (7.0 +/- 6.1%) after 2 years in the pamidronate group compared with -0.012 +/- 0.043 g/cm(2) (-1.6 +/- 6.1%) after 1 year and -0.013 +/- 0.052 g/cm(2) (-1.1 +/- 6.1%) after 2 years in the historical control group (absolute FN BMD changes pamidronate group vs historical group p = 0.003 after 1 year and p = 0.001 after 2 years). From a total of 287 application cycles of pamidronate treatment, no severe side effects were observed and non-severe side effects were seen in only 39 cycles (13.6%). We conclude that cyclic intravenous pamidronate treatment is beneficial to patients with low bone mass or osteoporotic fractures following transplant, even when not immediately initiated.

Adult↗

PubMed2006

Intravenous pamidronate for pain relief in recent osteoporotic vertebral compression fracture: a randomized double-blind controlled study.

INTRODUCTION: We performed a randomized, double-blind, controlled clinical trial comparing intravenous pamidronate and placebo for pain relief in recent osteoporotic vertebral compression fractures (VCF). METHODS: Patients suffered from recent (<21 days), painful, osteoporosis-related VCF. They were randomized to receive daily intravenous infusions of either placebo or 30 mg pamidronate for three consecutive days (total pamidronate: 90 mg). The main criterion for efficacy was improvement in standing pain on a 100-mm visual analogical scale (VAS) at day 7. Secondary criteria were standing pain at days 3 and 30; supine pain at days 3, 7, and 30; patients' overall assessment of improvement; mobility index; and number of "20% responders" and "50% responders" (respectively, 20% and 50% improvement in standing pain at days 7 and 30). Statistical analysis with non-parametric tests was carried out on an intention to treat basis. RESULTS: Thirty-two patients were enrolled in the study; 16 were given placebo and 16 pamidronate. Thirty-one patients were evaluated at day 7 and 26 patients at day 30. VAS pain decreased significantly in both groups at day 7 (placebo -23 mm, pamidronate -42 mm, p<0.01). The difference in pain scores between groups was -23.25 mm (confidence interval (CI) [-42.3; -4.2], p=0.018) at day 7 and -26 mm at day 30 (p=0.03), in favor of pamidronate. At day 7, there were 4 versus 12 "50% responders," respectively, in the placebo and in the pamidronate groups (likelihood ratio: 8.372; p=0.004) and 9 versus 14 "20% responders" (likelihood ratio: 4.038; p=0.044). At day 30, there were 5 versus 10 "50% responders," respectively, in the placebo and in the pamidronate groups, and 7 versus 11 "20% responders." Patients' overall assessment of improvement at day 7 was 37+/-26 mm in the placebo group and 59+/-30 mm in the pamidronate group (p=0.019), and 42+/-26 mm and 72+/-21 mm at day 30 (p=0.07). The two groups did not differ significantly at days 7 and 30 for supine pain, Schober index, or finger-ground distance. No significant adverse reaction related to treatment occurred. CONCLUSION: Pamidronate provides rapid and sustained pain relief in patients with acute painful osteoporotic VCF and is well tolerated. Further investigations are needed to better define the place of pamidronate in the management of painful recent osteoporotic collapse.

Acute Disease↗

PubMed1999

Bone histomorphometric evaluation of pamidronate treatment in clinically manifest osteoporosis.

The effect of pamidronate therapy on bone histology was studied in patients with osteoporosis with at least one vertebral fracture in a randomized, double-masked, placebo-controlled, multi-center trial. Patients received pamidronate 150 mg/day or placebo in addition to calcium 500 mg/day and vitamin D3 400 IU/day. Transiliac bone biopsies were obtained before and after 1 or 2 years of treatment. Of these, 23 pairs of biopsies obtained from 14 women and 9 men (mean age +/- SD, 61.5 +/- 10 years) were of sufficient quality for histomorphometry. Histomorphometry was performed on sections stained with Goldner's trichrome, using a drawing tube and a digitizer. Urinary hydroxyproline excretion decreased significantly (p < 0.005) following pamidronate treatment, indicating a decrease in bone resorption. Osteoid volume and osteoid surface also decreased significantly in the pamidronate group (p < 0.004 and p < 0.003 respectively), consistent with a secondary decrease in bone formation. Osteoid variables did not change in the placebo-treated patients. Cortical thickness, trabecular bone volume and trabecular thickness did not change after pamidronate or placebo treatment. Wall thickness, however, showed a borderline increase following pamidronate treatment. After pamidronate, eroded surface and mineral apposition rate did not change significantly in the placebo and pamidronate groups. Mineralizing surface and activation frequency showed a borderline decrease in the placebo and pamidronate groups. The decrease in mineralization lag time was of borderline significance in the pamidronate group, corroborating the absence of any negative effect on mineralization. In conclusion, pamidronate treatment led to a decrease in bone turnover and did not interfere with bone mineralization.

Adult↗

PubMed2006

Pamidronate distribution in pediatric renal and rheumatologic patients.

OBJECTIVE: To evaluate the distribution and elimination of pamidronate in a population of pediatric patients with renal and rheumatologic disease. METHODS: Pamidronate whole blood levels were collected for the first 4 h after first exposure in 7 patients. The relationship between the rate of urinary excretion of pamidronate and bone formation or resorption was examined in 18 patients while receiving pamidronate at a total dose of 1 mg/kg/dose infused intravenously over a 4-h period. The urinary pamidronate clearances were correlated with renal function, calcium levels and measures of bone formation and resorption. RESULTS: Pamidronate levels reached steady state concentrations of 0.9-1.5 microg/ml within 30 min and the clearance of the drug (mean+/-SE) from blood was 180.0+/-64.2 ml/kg/h with an elimination half-life of less than 1 h. The mean urinary excretion of 31.5+/-2.2% of the administered dose indicated that about 68% of the drug was incorporated into bone, confirming the uptake of pamidronate into bone was similar in pediatric patients compared to that previously reported for adults. Bone specific alkaline phosphatase, which is a marker for bone growth and formation, had significant correlation with the uptake of pamidronate into bone (p=0.002). No correlation was demonstrated with a marker for bone resorption (urinary N-telopeptide/creatinine ratio), or with creatinine clearance or calciuria when assessed 2 months after treatment. CONCLUSION: Pamidronate at a dose of 1 mg/kg/dose every 2 months appears safe in the short term for pediatric patients, achieves relatively low whole blood pamidronate levels, and has similar skeletal uptake of pamidronate compared to adults.

Adolescent↗

PubMed2004

A randomized clinical trial comparing oral alendronate and intravenous pamidronate for the treatment of Paget's disease of bone.

Second and third generation bisphosphonates are the treatment of choice for Paget's disease of bone. These drugs are more effective than calcitonin and etidronate, but there have been no head to head, randomized controlled trials comparing potent bisphosphonates. We conducted a 2-year, randomized, open-label trial comparing oral alendronate and intravenous pamidronate in 72 subjects with Paget's disease. Randomization was stratified according to baseline plasma total alkaline phosphatase (ALP) and previous bisphosphonate treatment (yes or no). All previously treated patients had received pamidronate but not alendronate. Assigned treatments were pamidronate (60 mg) every 3 months as a single infusion or alendronate (40 mg) daily in 3-month blocks, continued until biochemical remission (defined as both ALP and urine deoxypyridinoline (DPD)/creatinine ratio in the reference range) or a clear plateau effect was observed. At 1 year, nonresponders to pamidronate were crossed over to alendronate treatment. At 1 year, 31/36 (86%) subjects randomized to alendronate achieved biochemical remission compared with 21/36 (56%) for pamidronate (P = 0.017). There was a significantly greater reduction in ALP (P < 0.001) and DPD/creatinine ratio (P < 0.001) for alendronate compared with pamidronate treatment. In previously untreated patients, alendronate resulted in remission in 20/22 (91%) subjects compared with 19/22 (86%) of pamidronate-treated subjects, which was not significantly different; however, alendronate resulted in a significantly greater reduction in ALP (P = 0.014) and DPD/creatinine ratio (P < 0.001). In previously treated patients, alendronate resulted in remission in 11/14 (79%) subjects compared with 2/14 (14%) for pamidronate (P < 0.001), with a significantly (P < 0.001) greater reduction in both ALP and DPD/creatinine ratio. Of subjects crossed over from pamidronate to alendronate, 10/14 (71%) achieved remission, including 9/11 (82%) previously treated patients. We conclude that, in patients with previously untreated Paget's disease of bone, alendronate and pamidronate have similar efficacy in achieving biochemical remission. In patients previously treated with pamidronate, alendronate is more effective.

Administration, Oral↗

PubMed2005

Pamidronate induced anti-proliferative, apoptotic, and anti-migratory effects in hepatocellular carcinoma.

BACKGROUND/AIMS: The small GTPase of Ras and Rho families are widely involved in human tumorgenesis and metastasis. It has recently been reported that pamidronate inhibits the mevalonate pathway, which is required for the prenylation of the small GTPase. We demonstrated a possible beneficial use of pamidronate in the treatment of hepatocellular carcinoma (HCC). METHODS: The effect of pamidronate on cell proliferation was analyzed with five hepatoma cell lines using MTT assay. Apoptosis was evaluated by staining with DAPI and a histon ELISA assay. A cell migration assay was performed using the Modified Boyden Chamber. To analyze anti-proliferation effect of pamidronate in vivo, tumor volumes were monitored with the intraperitoneal injection of pamidronate after subcutaneous inoculation of PLC/PRF/5 cells into nude mice. RESULTS: Pamidronate inhibited cell growth for all hepatoma cell lines. The amount of membrane associated Ras and phosphorylated extracellular signal-regulated kinase 2 (ERK 2) were reduced after pamidronate treatment. Pamidronate increased apoptosis and cleavage of Caspase-3, and -9. Pamidronate suppressed membrane associated RhoA and cell motility. In vivo, tumor volumes were significantly suppressed by pamidronate at three weeks (P<0.03). CONCLUSIONS: We conclude that pamidronate has therapeutic potential in inducing anti-proliferative, apoptotic, and anti-migratory effects in HCC.

Animals↗

PubMed2003

Effect of pamidronate on the stimulation of macrophage TNF-alpha release by ultra-high-molecular-weight polyethylene particles: a role for apoptosis.

The demonstration that one of the mechanisms of action of bisphosphonates (BPs) is the induction of osteoclast and macrophage apoptosis, suggests a potent therapeutic role for the BPs and other apoptosis-modulating agents in the management of periprosthetic osteolysis. The purpose of this study was to improve our understanding of the basic underlying molecular events leading to the inhibitory effect of pamidronate on the macrophage response to ultra-high-molecular-weight polyethylene (UHMWPE) particles. Murine J774 macrophages were incubated for 0-72 h in the presence of UHMWPE particles and/or pamidronate. TNF-alpha release was measured by ELISA while poly(ADP-ribose)polymerase (PARP) expression was measured by Western blot. DNA was analyzed on agarose. The appearance of PARP fragment and the fragmentation of DNA were used as markers of apoptosis. We observed a dose-dependent response to UHMWPE particles with TNF-alpha release reaching 4, 10, and 19 times control with 10, 25, and 125 particles/macrophage, respectively. UHMWPE particles (25 particles/macrophage) stimulate TNF-alpha release by a factor of 10, 7, and 6 after 24, 48, and 72 h, respectively, indicating a rapid stimulating effect of UHMWPE particles on TNF-alpha release. Our results also showed that at 10 particles/macrophage, pamidronate inhibits UHMWPE-induced TNF-alpha release by 12%, 14%, and 23% respectively after 24, 48, and 72 h (p<0.05 vs. 24 and 48 h). With 25 particles/macrophage, the inhibition of TNF-alpha reached 9%, 12%, and 15% after 24, 48, and 72 h (p<0.05 vs. 24 h), respectively. There is no significant difference between the inhibition by pamidronate of TNF-alpha release induced by 125 particles/macrophages at 24, 48, and 72 h. When cells are pre-incubated for 48 h with pamidronate prior to addition of UHMWPE particles for 24 h, we observed an increased inhibition of TNF-alpha compared to the co-incubation protocol. The inhibiting effect of pamidronate reaches 56% when pre-incubated with macrophages prior to incubation with 10 particles of UHMWPE/macrophage (p<0.05 vs. co-incubation).Co-incubation of pamidronate with UHMWPE particles also led to the appearance of the proteolytic PARP fragment after 24 h incubation. We also demonstrated the stimulation of DNA fragmentation (DNA laddering) after 48-72 h with pamidronate. The proteolytic cleavage of PARP, an early event in the induction of apoptosis, precedes the inhibition of UHMWPE particle-induced TNF-alpha release by pamidronate whereas the fragmentation of DNA, a late apoptotic event, parallels this inhibition. Our results suggest the induction of macrophage apoptosis is associated with the inhibitory effect of pamidronate on TNF-alpha release. There is a need for the development of medical management of periprosthetic osteolysis. The demonstration that drugs such as pamidronate induce specific apoptosis-related pathways in macrophages contributes data for a rational approach in the treatment and/or prevention of periprosthetic osteolysis.

Animals↗

PubMed2006

Effect of a convenient single 90-mg pamidronate dose on biochemical markers of bone metabolism in patients with acute spinal cord injury.

BACKGROUND/OBJECTIVE: To describe the biochemical and adverse effects of a convenient single 90 mg pamidronate dose in patients with acute spinal cord injury (SCI) and compare these effects with those observed in a previous similar study using a 30 mg/d x 3-day pamidronate dosing regimen. STUDY DESIGN: Retrospective cohort study. SETTING: University-based rehabilitation center in New York City. METHODS: A total of 32 patients with SCI were evaluated for biochemical response and adverse events associated with pamidronate therapy. All patients were screened at or near admission for acute rehabilitation, received calcium (1,000 mg daily) and calcitriol (0.25 micrg daily) therapy daily, and on day 4, received a single dose of pamidronate, 90 mg by intravenous infusion, over 4 hours. Serum calcium and phosphate levels were closely monitored, and 2 weeks after pamidronate, biochemical bone markers were re-evaluated. RESULTS: Responses of biochemical markers of bone resorption (N-telopeptide and 24-hour urinary calcium excretion) to pamidronate 90 mg were consistent with an antiresorptive effect, although less than that observed with a 30 mg/d x 3-day pamidronate dosing regimen. The frequency of hypocalcemia was greater, and hypophosphatemia was less than the 30 mg/d x 3-day pamidronate dosing regimen. Fever was more frequent (78%) with the 90-mg single dose of pamidronate compared with the 30 mg/d x 3-day pamidronate dosing regimen (20%). CONCLUSIONS: Single-dose pamidronate 90 mg is effective at reducing biochemical markers of bone hyperresorption in patients with acute SCI but is associated with a greater incidence of fever compared with a 30 mg/d x 3-day dosing regimen.

Adolescent↗