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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↗
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↗
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↗
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↗
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↗
PubMedDate not supplied

Comparative evaluation of safety and efficacy of pamidronate and zoledronic acid in multiple myeloma patients (single center experience).

Osteolytic bone destruction, caused by the aberrant production and activation of osteoclasts, results in significant morbidity for patients with multiple myeloma (MM). Pamidronate [(3-amino-1-hydroxypropylidene)-1,1-bis-phosphonate] inhibits osteoclastic activity and reduces bone resorption. A potency of zoledronic acid (2-[imidazol-1-yl]-1-hydroxyethylidene-1,1-bisphosphonic acid, a new third generation bisphosphonate, as inhibitor of resorption was 850-fold greater than pamidronate, as was shown in preclinical models of bone resorption. Randomized, double-blind study was conducted to compare the efficacy and safety of zoledronic acid and pamidronate for treating myeloma bone disease. Since March 1999 the efficacy and safety of pamidronate and zoledronic acid is evaluated in MM patients all receiving anti-myeloma chemotherapy acc. to VMCP/VBAP alternating regimen. Nine patients with stage III myeloma and osteolytic lesions (3 female, 6 male, median age 57 years, range 52-67, with monoclonal protein: IgG-7, IgA-2) were randomly assigned (1:1:1 ratio) to treatment with either 4 or 8 mg of zoledronic acid via 15-minute intravenous infusion or 90 mg of pamidronate via 2-hour intravenous infusion every 3 to 4 weeks for 12 months. All patients have received 500 mg of calcium supplements and 500 IU of vit.D, orally, once daily, for the duration of administration of study medication. In extension phase of the study (June 2000-April 2002) patients did not received bisphosphonates. In 7 patients 18 cycles of assessed treatment was administered to each of them and one patient received 16 cycles. One patient died after receiving of 12 pamidronate therapy cycles at 11 month of the trial duration (and at 49 month since MM diagnosis and anti-tumour treatment). The patient's death occurred during the progression of plasma cell proliferation due to acute left ventricle cardiac failure. During the 12-month-period of bisphosphonate treatment skeletal related events (SRE) and progression of osteolysis occurred with the same frequency in 3 treatment groups. One patient experienced spinal cord compression and received radiation to bone and 2 patients experienced vertebral fracture. Time from study entry to the first SRE was 304 days in pamidronate and 366 and 392 days in 4 and 8 mg zoledronic acid group, respectively. The skeletal morbidity rate was identical in all treatment groups. Single hypocalcemic events occurred in 2 patients, mild hypertransaminasemia was observed in 3, worsening of renal function parameters in 2 patients (transient in one of them). Muscular pain and fever up to 39 degrees C (transient and self-limiting "flu-like" symptoms) occurred in 6 patients after several or some dozens of hours from study drug administration. Adverse events were similar in nature and frequency with zoledronic acid and pamidronate and were experienced by a similar proportion of patients in each treatment group. Median time of patient's observation duration after completing of administered treatment with zoledronic acid and pamidronate amounts to 20 months. At present actual median survival time of analysed patients since MM diagnosis is 42 months, since the beginning of treatment with pamidronate and zoledronic acid--33 months, and since completing treatment--20 months and is similar in 3 treatment groups. As was shown in our single center study in MM patients the safety and efficacy of pamidronate 90 mg and zoledronic acid 4 mg and 8 mg in monthly i.v. infusion are comparable. Thus the recommended dosage of zoledronic acid is 4 mg administered as a 15 minute i.v. infusion at intervals of 3 to 4 weeks.

Aged↗
PubMed1997

Pamidronate content and turnover in sternum, vertebral body, and iliac bones of dogs.

Therapeutic efficacy of bisphosphonates depends on how much drug is present in bone. Therefore, it is important to measure the amount of bone bisphosphonate in toxicological and pharmacological studies. We analyzed pamidronate content of bone samples from two previously published long-term dose studies. In the first study, mature beagle dogs were given oral pamidronate at doses of 0, 2.5, 12.5 and 25 mg/kg per day for 1 year. The dogs in the second study received the same dosages for 1 year followed by 1 year without drug. In both studies, the amount of pamidronate measured was dependent upon dose in bone samples of ilium, sternum, and vertebral body. After 1 year of treatment, vertebral bone had more pamidronate than sternum or iliac bone on a permilligram basis. After 2 years, there was significantly less pamidronate in the vertebral body, sternum, and ilium than there had been at 1 year. The fall in pamidronate content was largest in vertebral body and least in the ilium. The higher uptake of pamidronate by the vertebral body during the 1 year study, and its greater loss of pamidronate after a year without drug treatment, would reflect the higher turnover of trabecular bone in the vertebral body vs. cortical bone in the ilium. The percent difference in bone pamidronate content between the 1 and 2 year dogs varied with dose. The largest percent loss occurred in the intermediate-dose group. These data suggest that, after 1 year without the drug, bone turnover rates in dogs treated with the highest dose of pamidronate were lower than at the intermediate dose. Thus, the time required for bone turnover rates to return to pretreatment levels is probably dose-dependent.

Animals↗
PubMed1997

Relationships between biochemical and symptomatic response in a double-blind randomised trial of pamidronate for metastatic bone disease.

PURPOSE: The aim of this study was to evaluate pamidronate for bone pain in a randomised double-blind trial and to evaluate the contribution of new markers of bone resorption in patients with bone metastases. PATIENTS AND METHODS: Fifty-two patients with painful bone metastases were randomised to receive a two-hour infusion of pamidronate 120 mg or an identical infusion of saline. Four weeks later, all patients received pamidronate 120 mg. Bone resorption markers measured included urinary calcium (uCa), hydroxyproline (Hyp), and the collagen breakdown products: NTx, Crosslaps and Free Dpd. RESULTS: Symptomatic response during the first four weeks was seen after pamidronate, but not with placebo (P < 0.05). Quality of life was maintained with pamidronate and deteriorated after placebo (P < 0.05). Resorption markers did not decrease after placebo, but NTx and Crosslaps both decreased by 70% after pamidronate (P = 0.001). A second infusion of pamidronate did not decrease resorption further, but maintained the suppression of resorption at similar levels for a further four weeks. Symptomatic response to pamidronate correlated closely with the rate of bone resorption; it was more frequent in those patients with an initial NTx value of < 2 times the upper limit of normal (17 of 27, 62%) and in those where the level of Ntx returned to normal (19 of 32, 59%), than in the patients with either high baseline values of NTx (> 2 times the upper limit of normal) or Ntx levels which failed to normalise for whom the response frequencies were 2 of 16 (13%) and 0 of 11 (0%), respectively. CONCLUSIONS: Subjective benefit after intravenous pamidronate is confirmed in this placebo-controlled study. The new bone resorption markers of collagen breakdown were able to predict clinical response to pamidronate.

Adult↗
PubMed1992

Plicamycin and pamidronate in symptomatic tumor-related hypercalcemia: a prospective randomized crossover trial.

We have conducted a randomized crossover comparative trial of a single-dose course of disodium (3-amino-1-hydroxypropylidene) bisphosphonate pentahydrate (pamidronate) and plicamycin in 48 patients with a first occurrence of tumor-related hypercalcemia. All patients had hypercalcaemia-associated symptoms and serum-calcium levels (corrected for total protein) greater than or equal to 2.80 mmol/l. Pamidronate and plicamycin were given concurrently with rehydration immediately after diagnosis of hypercalcaemia was made. Both agents lowered serum calcium levels significantly within 1 week, with 88% of the evaluable patients in the pamidronate group and 45% of those in the plicamycin group achieving normocalcemia (p less than 0.01). In the patients who received pamidronate, the duration of normocalcemia was longer (p less than 0.05) and there was a significant decrease in serum creatinine (p less than 0.05). Vomiting occurred in 8 of 22 evaluable patients (36%) who received plicamycin, but in none of 25 evaluable patients who received pamidronate (P less than 0.01). Phlebitis occurred at the infusion site in more of the pamidronate-treated patients (P less than 0.05). Hypocalcemia, which occurred in 8 of 25 evaluable patients (32%) in the pamidronate group and in 1 of 22 of those (5%) in the plicamycin group, was either clinically asymptomatic or mild, except in one pamidronate-treated patient. Overall, pamidronate was found to be more effective and better tolerated than plicamycin, thereby confirming results of previous studies that showed pamidronate to be an effective, simple, and safe agent for the relief of the morbidity associated with tumor-related hypercalcemia.

Adult↗
PubMed1992

Pamidronate.

OBJECTIVE: The primary objective of this article is to introduce readers to the use of a new agent, pamidronate. The article discusses its use in hypercalcemia of malignancy (HCM), osteolytic lesions, and Paget's disease. Pharmacokinetic data and clinical trials are reviewed, as well as adverse effects and dosage guidelines. DATA SOURCES: A MEDLINE search was used to identify English-language studies involving pamidronate for the period from 1970 to 1992. STUDY SELECTION: As comparative trials were few in number, trials using pamidronate as a single agent were also reviewed. DATA EXTRACTION: Sparse pharmacokinetic data were obtained from clinical trials. All clinical trials available at the time of publication that met the following criteria were reviewed: (1) allowed for adequate rehydration prior to drug therapy; (2) reported standardized and corrected serum calcium concentrations; (3) separated data obtained from patients who received pamidronate alone from those who received pamidronate and concurrent chemotherapy. RESULTS: Pamidronate has a pharmacologic profile similar to that of etidronate, but pamidronate is more potent and has a longer duration of effect. It has been investigated primarily in the treatment of HCM as well as in the treatment of osteolytic bone metastases and Paget's disease. In hypercalcemia of malignancy it appears to be as effective as established agents with the advantage that a single dose of pamidronate 90 mg iv provides a durable response. In Paget's disease chronic oral administration has also been shown to be effective in relieving bone pain. Adverse reactions with intravenous administration are transient and self-limiting and usually occur with the first dose. The most common adverse effect is a transient and self-limiting fever. Chronic oral administration of doses greater than 600 mg/d is associated with gastrointestinal toxicities. CONCLUSIONS: Although more well-designed clinical trials comparing pamidronate with standard therapies and other available agents are necessary, initial results indicate that pamidronate is an effective and promising alternative for use in the treatment of HCM.

Bone Neoplasms↗
PubMed1993

Palliative pamidronate treatment in patients with bone metastases from breast cancer.

PURPOSE: An open, randomized study was performed to assess the effects of supportive pamidronate treatment on morbidity from bone metastases in breast cancer patients. PATIENTS AND METHODS: Eighty-one pamidronate patients and 80 control patients were monitored for a median of 18 and 21 months, respectively, for events of skeletal morbidity and the radiologic course of metastatic bone disease. The oral pamidronate dose was 600 mg/d (high dose [HD]) during the earliest study years, then changed to 300 mg/d (low dose [LD]) because of gastrointestinal toxicity. Twenty-nine of 81 pamidronate (HD/LD) patients first received 600 mg/d and were then changed to 300 mg/d; 52 of 81 pamidronate LD patients received 300 mg/d throughout the study. Tumor treatment was unrestricted. RESULTS: An overall intent-to-treat analysis was performed. In the pamidronate group, the occurrence of hypercalcemia, severe bone pain, and symptomatic impending fractures decreased by 65%, 30%, and 50%, respectively; event-rates of systemic treatment and radiotherapy decreased by 35% (P < or = .02). The event-free period (EFP), radiologic course of disease, and survival did not improve. Subgroup analyses suggested a dose-dependent treatment effect. Compared with their controls, in pamidronate HD/LD patients, events occurred 60% to 90% less frequently (P < or = .03) and the EFP was prolonged (P = .002). In pamidronate LD patients, event-rates decreased by 15% to 45% (P < or = .04). Gastrointestinal toxicity of pamidronate caused a 23% drop-out rate, but other cancer-associated factors seemed to contribute to this toxicity. CONCLUSION: Pamidronate treatment of breast cancer patients efficaciously reduced skeletal morbidity. The effect appeared to be dose-dependent. Further research on dose and mode of treatment is mandatory.

Bone Neoplasms↗
PubMed2002

A pharmacokinetic and pharmacodynamic model for intravenous bisphosphonate (pamidronate) in osteoporosis.

BACKGROUND: Bisphosphonates are used extensively in the management of skeletal disorders including osteoporosis. Intermittent i.v. regimens with bisphosphonates are being explored as alternatives to oral regimens. The design of therapeutic regimens with bisphosphonates is mainly based on pharmacodynamic (PD) information. A combined pharmacokinetic (PK) and PD model of bisphosphonate action can help in the design of more effective therapeutic strategies. AIM: The objective of this study was to hypothesise on a PK/PD model for intermittent i.v. pamidronate in patients with osteoporosis. METHODS: Serum and urine pamidronate PKs were studied in nine patients with osteoporosis treated with pamidronate (15 mg/day via i.v. infusion) on five consecutive days. Long-term renal excretion of pamidronate was extrapolated from literature data on alendronate. The PD response (urinary hydroxyproline) was assessed in 13 patients with osteoporosis, who were given the same regimen every 3 months for 1 year. Pooled serum and urine data were fitted into a physiology-based compartment model. In order to develop a mechanistically based PK and PD model, three different Emax models were examined. RESULTS: A physiology-based three-compartment model was able to describe pamidronate PKs with a central compartment representing the serum, a second compartment representing the bone surface and a third compartment representing deep bone. The typical effect of 1 year of 3-monthly i.v. therapy was described adequately using an Emax model, in which the effect depended on both the amount of pamidronate attached to bone (second compartment) and on the amount of pamidronate buried into bone (third compartment). CONCLUSIONS: A combined PK/PD model for pamidronate is described which incorporates the specific pharmacology of bisphosphonates. The model may be used to describe long-term effects of an i.v. pamidronate regimen in osteoporotic patients.

Adult↗
PubMed1995

A randomised double-blind comparison of intravenous pamidronate and clodronate in the hypercalcaemia of malignancy.

In conjunction with rehydration, the bisphosphonates are the treatment of choice for hypercalcaemia of malignancy. Single infusions of either pamidronate or clodronate are usually effective, but a direct comparison of the two agents given at the highest doses commonly used has not been performed. Forty-one patients (15 breast, 12 squamous carcinomas, four lymphomas, four bladder, two prostate and four others) with hypercalcaemia of malignancy (corrected serum calcium > 2.7 mmol l-1) persisting after 48 h of saline rehydration were randomly allocated to receive a 4 h intravenous (i.v.) infusion of either pamidronate 90 mg or clodronate 1500 mg. No other systemic anti-cancer treatment was prescribed. There were no significant differences in the post-hydration serum calcium values (mean 3.17 mmol l-1 for pamidronate and 3.06 mmol l-1 for clodronate), tumour type or frequency of bone metastases between the two treatments. One patient on each treatment died within 2 days and was not assessable for response. A total of 19/19 (100%) patients achieved normocalcaemia following pamidronate and 16/20 (80%) with clodronate. The median time to achieve normocalcaemia was 4 days (range 2-14) for pamidronate and 3 days (range 2-6) with clodronate. The median duration of normocalcaemia was 28 days (range 10-28+ days) after pamidronate and 14 days after clodronate (range 7-21 days) (P < 0.01). Two patients who failed to respond to clodronate were successfully treated with pamidronate and achieved normocalcaemia for 14 and > 28 days respectively. Two patients experienced fever after pamidronate but no significant toxicity was observed with either treatment. We conclude that both agents are effective in the management of hypercalcaemia of malignancy. At the doses studied, the effects of pamidronate are more complete and longer lasting than those of clodronate.

Bone Neoplasms↗