Gains and losses of DNA sequences in osteosarcomas by comparative genomic hybridization.

Our aim was to identify chromosomal regions that are likely to harbor previously unknown genes with an important role in the genesis of osteosarcoma. Comparative genomic hybridization was used to screen for losses and gains of DNA sequences along all chromosome arms in 11 tumors. Extensive genetic aberrations, with an average of 11 changes/tumor (range, 1-20), were found in 10 of the 11 specimens. High level amplifications of small chromosomal regions were detected in eight tumors. These involved the 12q12-q13 region (known to contain the SAS-MDM2 locus) and several previously unreported amplification sites such as 17p11-p12, 3q26, and Xq12. When all DNA sequence gains were evaluated, the gains at 8q and Xp were most common (45%). The most common losses of DNA sequences were seen at 2q, 6q, 8p, and 10p (36%). In conclusion, despite the very complex pattern of genetic changes in osteosarcomas, certain chromosomal regions appear to be affected more often than others. Most of these regions have not previously been reported to be implicated in osteosarcomas and may thus highlight locations of novel genes with an important role in the development and progression of these tumors.

Adjuvant clodronate treatment does not reduce the frequency of skeletal metastases in node-positive breast cancer patients: 5-year results of a randomized controlled trial.

PURPOSE: Bisphosphonates have effectively reduced the development and progression of bone metastases in advanced breast cancer. The aim of this study was to determine whether bone metastases could be prevented by adjuvant clodronate treatment in patients with primary breast cancer. PATIENTS AND METHODS: Between 1990 and 1993, 299 women with primary node-positive breast cancer were randomized to clodronate (n = 149) or control groups (n = 150). Clodronate 1,600 mg daily was given orally for 3 years. All patients received adjuvant therapy: premenopausal six cycles of CMF chemotherapy and postmenopausal antiestrogens (randomized to tamoxifen 20 mg or toremifene 60 mg/d for 3 years). Seventeen patients were excluded from the analyses because of major protocol violations. The final population was 282 patients. Intent-to-treat analyses were also performed for all major end points. The follow-up time was 5 years for all patients. RESULTS: Bone metastases were detected equally often in the clodronate and control groups: 29 patients (21%) versus 24 patients (17%) (P: = .27). The development of nonskeletal recurrence was significantly higher in the clodronate group compared with controls: 60 patients (43%) versus 36 patients (25%) (P: = .0007). The overall survival (OS) and disease-free survival (DFS) rates were also significantly lower in the clodronate group than in the controls (OS, 70% v 83%, P: = .009; DFS, 56% v 71%, P: = .007, respectively). In multivariate analyses, clodronate remained significantly associated with DFS (P: = .009). CONCLUSION: Adjuvant clodronate treatment does not prevent the development of bone metastases in node-positive breast cancer patients. However, clodronate seems to have a negative effect on DFS by increasing the development of nonskeletal metastases.

Influence of treatment schedule on toxicity and efficacy of cyclophosphamide, epirubicin, and fluorouracil in metastatic breast cancer: a randomized trial comparing weekly and every-4-week administration.

PURPOSE: To compare the effect on toxicity and efficacy of the fluorouracil 500 mg/m2, epirubicin 60 mg/m2, and cyclophosphamide 500 mg/m2 (FEC) regimen divided into 4 weekly doses with conventional every-4-week administration in metastatic breast cancer. PATIENTS AND METHODS: The inclusion criteria demanded measurable or assessable metastases from breast cancer and a World Health Organization (WHO) performance index of 2 or less. One hundred seventy-three patients with metastatic breast cancer who had not been treated with anthracyclines were randomized to receive FEC once every 4 weeks or once a week. The scheduled monthly doses of the cytotoxic agents were identical in both groups. Three patients were excluded from analysis. RESULTS: Hematologic toxicity, alopecia, nausea, and vomiting were significantly more severe in the group that received treatment every 4 weeks. The response rate was higher in the group that received FEC every 4 weeks than in the group treated weekly (47% v 30%, P = .02). Time to progression was significantly (P = .005) longer with every-4-week FEC treatment (median, 9.2 months v 5.4 months for weekly treatment). Patients in the group treated every 4 weeks lived significantly (P = .01) longer than patients treated weekly (median survival times, 21.2 months v 11.8 months, respectively). The actually delivered monthly dose levels and treatment duration were similar in the two groups. CONCLUSION: Both efficacy and toxicity of FEC were greater when treatment was administered every 4 weeks rather than once a week, despite identical dose intensity.

Salvage therapies in women who fail to respond to first-line treatment with fluorouracil, epirubicin, and cyclophosphamide for advanced breast cancer.

PURPOSE: We studied all salvage therapies given until death or the end of follow-up evaluation in women who failed to respond to the same first-line cytotoxic therapy for metastatic breast cancer. PATIENTS AND METHODS: The study cohort consisted of 140 women who had received the fluorouracil, epirubicin, and cyclophosphamide (FEC) regimen for metastatic breast cancer. Eight patients were excluded. No exclusions with respect to disease site, performance status, or biochemical abnormalities were made. The median follow-up time was 29 months for surviving patients. RESULTS: Most patients (88%) died during the follow-up period. Patients received a median of three salvage therapies (range, zero to eight) during the course of disease. Most courses (52%) were not assessable for response. Fifty-percent of courses consisted of chemotherapy: 35% of hormonal and 15% of combination of cytotoxic and hormonal therapies. The median duration of therapy (DT) ranged from 4 to 1 months, and decreased with advancing stages of therapy. Similarly, median time to treatment failure (TTF) ranged from 3 to 0.5 months. For unknown causes, patients who received second-line hormonal therapy fared better than those who received other forms of therapy. Of 366 analyzed courses, only one complete response (CR) and 18 partial responses (PRs) were observed (response rate, 11% for assessable and 5% for all courses). Stable disease for at least 3 months was found in 20% to 25% of courses. Most responses (n = 10) occurred during first salvage therapy, and no responses were observed after third salvage therapy. CONCLUSIONS: Response rates for salvage therapies were low, and median treatment times short. The value of offering more than two salvage chemotherapy regimens to an unselected group of patients is questionable.

Antiatherogenic effects of adjuvant antiestrogens: a randomized trial comparing the effects of tamoxifen and toremifene on plasma lipid levels in postmenopausal women with node-positive breast cancer.

PURPOSE: To evaluate whether a novel antiestrogen, toremifene, has similar antiatherogenic effects as tamoxifen. PATIENTS AND METHODS: Forty-nine postmenopausal patients with node-positive breast cancer were randomized in a trial that compared the effects of tamoxifen and toremifene on serum lipoproteins. Tamoxifen was given at 20 mg and toremifene at 60 mg orally per day for 3 years. Serum concentrations of apolipoprotein (apo) A-I, A-II, and B, and lipoprotein(a) [Lp(a)], cholesterol, triglyceride, high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, follicle-stimulating hormone (FSH), luteinizing hormone (LH), and estradiol were measured before and after 12 months of antiestrogen therapy. RESULTS: Both antiestrogens significantly reduced serum total and LDL cholesterol and apo B levels. However, the response of HDL cholesterol to treatments was clearly different between the groups. Toremifene increased the HDL level by 14%, whereas tamoxifen decreased it by 5% (P = .001). As a consequence, both cholesterol-to-HDL and LDL-to-HDL ratios decreased more in the toremifene than tamoxifen group (P = .008 and P = .03, respectively). Toremifene also increased the apo A-I level (P = .00007) and apo A-I-to-A-II ratio (P = .018). Both tamoxifen and toremifene decreased the Lp(a) concentration significantly (change, 34% v 41%). CONCLUSION: These results provide positive evidence that toremifene has antiatherogenic properties with potency to improve all lipoproteins that are associated with increased coronary heart disease (CHD) risk.

Chemical castration induced by adjuvant cyclophosphamide, methotrexate, and fluorouracil chemotherapy causes rapid bone loss that is reduced by clodronate: a randomized study in premenopausal breast cancer patients.

PURPOSE: In the majority of premenopausal breast cancer patients, an adjuvant chemotherapy-induced early menopause occurs, which is known to be a strong predictor of osteoporosis. We present data on the effect of adjuvant cyclophosphamide, methotrexate, and fluorouracil (CMF) therapy on bone mineral density (BMD) and the efficacy of clodronate on the prevention of bone loss in 148 premenopausal breast cancer patients without skeletal metastases. MATERIALS AND METHODS: Patients were randomized to receive oral clodronate 1,600 mg/d or to a control group. In addition, patients were treated with six cycles of CMF therapy. BMD of the lumbar spine and femoral neck was measured by dual-energy x-ray absorptiometry (DEXA) before therapy and at 1 and 2 years. RESULTS: Changes in the BMD of lumbar spine and femoral neck were -5.9% and -2.0% without clodronate and -2.2% and +0.9% with clodronate at 2 years (P = .0005 and .017, respectively). Patients who developed amenorrhea after chemotherapy had a rapid bone loss, which was significantly reduced by clodronate. In controls, bone loss was 9.5% in the lumbar spine and 4.6% in the femoral neck, while in the clodronate group, bone loss was 5.9% and 0.4%, respectively, at 2 years. Patients with preserved menstruation had only marginal changes in BMD. CONCLUSION: Chemotherapy-induced ovarian failure causes rapid bone loss in premenopausal breast cancer patients. Women older than 40 years are at particularly high risk. Clodronate significantly reduces this bone loss.

Treatment of osteosarcoma of the extremities with the T-10 protocol, with emphasis on the effects of preoperative chemotherapy with single-agent high-dose methotrexate: a Scandinavian Sarcoma Group study.

From 1982 to 1989, 97 patients with extremity-localized, high-grade osteosarcoma were treated according to the T-10 protocol. Two thirds of the patients consisted of the near-complete national patient materials from Norway and Finland. Eighty patients (82%) received four courses of high-dose methotrexate (HD MTX, 8 to 12 g/m2) at weekly intervals as their only preoperative treatment, and 77 patients (79%) were assessable for histologic response grading according to Rosen et al (Cancer 49:1221-1230, 1991). Observed histologic response was no certain chemotherapy effect (grade I) in 21%, grade II effect in 62%, and grade III or IV effect in 17%. Nonresponders had significantly lower serum MTX concentrations after 24 and 48 hours than responders; the significance of the difference at 48 hours was maintained in a multivariate analysis. After a median follow-up of 45 months, projected 5-year overall and relapse-free survival for all patients were 64% and 54%, respectively. Patients with a good response to preoperative chemotherapy (grade III/IV) had a significantly better survival than grade I/II responders, despite a switch to postoperative cisplatin/doxorubicin chemotherapy in the latter group. These results were obtained in a largely nonselected group of patients. We conclude that a good initial chemotherapy effect is important for the final outcome in osteosarcoma, and that HD MTX alone is insufficient preoperative treatment for the majority of patients. The individual MTX excretion rate is of importance for tumor response, suggesting a dose-response relationship for HD MTX treatment.

Effects of chemotherapy-induced castration on serum lipids and apoproteins in premenopausal women with node-positive breast cancer.

The purpose of this study was to determine the effect of adjuvant chemotherapy on serum lipids and lipoproteins in premenopausal nonmetastatic breast cancer patients. Fifty-nine premenopausal breast cancer patients were treated with adjuvant chemotherapy comprising cyclophosphamide, methotrexate, and 5-fluorouracil. Levels of serum FSH, LH, and estradiol; fasting plasma levels of total cholesterol, high density lipoprotein cholesterol (HDL), low density lipoprotein cholesterol (LDL), triglyceride, and apolipoprotein A-I, A-II, and B levels; and lipoprotein(a) [Lp(a)] were measured before treatment and 12 months after the beginning of chemotherapy. The changes in serum lipids after chemotherapy correlated significantly to changes in menstruation. Total cholesterol, LDL, and HDL cholesterol levels increased significantly only in patients with chemotherapy-induced ovarian dysfunction. Changes in apo B paralleled those in LDL and apo A-I and A-II HDL cholesterol. The serum concentration of Lp(a) increased significantly only in patients who developed permanent amenorrhea. There were no significant changes in triglyceride levels. Chemotherapy per se has no effect on serum lipids unless associated with induction of ovarian dysfunction. Ovarian failure after chemotherapy has an unfavorable effect on serum total and LDL cholesterol, apo B, and Lp(a) levels, but a favorable effect on HDL cholesterol.

Cytogenetic investigations of patients on clodronate therapy for Paget's disease of bone.

In order to judge whether or not clodronate used for treatment of patients with Paget's disease of bone had an effect on the haematopoetic tissue, the frequency of chromosome/chromatid breaks in bone marrows and blood cells was evaluated. Seven patients were studied before treatment, after a few days of treatment and after greater than or equal to 2 months of treatment. Three additional patients were studied after exposure to clodronate for greater than or equal to 6 months. There was no significant increase in the occurrence of chromosomal aberrations induced by treatment. Thus no negative effect of clodronate on the haematopoetic tissue could be noted.

Evaluation of salmon calcitonin treatment in bone metastases from breast cancer--a controlled trial.

Salmon calcitonin 100 MRCU/day or a saline placebo were given in daily injections for at least three months to 49 patients with bone metastases from breast cancer in a randomized double-blind trial. All patients were normocalcemic, and most patients had stable or regressing disease at start of trial. No improvement in general performance or bone pain was detected as measured by a visual analogue scale, the daily duration of pain or consumption of analgetic drugs. Calcitonin had no effect on disease progression as judged by bone scans and radiographs. Calcitonin therapy did not affect serum calcium, alkaline phosphatase, bone gla-protein, or the urinary excretion of calcium and hydroxyproline. Serum phosphate and magnesium decreased significantly during calcitonin treatment (p = 0.01, and 0.00005, respectively). It was concluded that salmon calcitonin in this dosage has no discernible effect on skeletal pain, general performance, bone metabolism or disease progression in patients with breast cancer metastatic to bone. A significant decrease in serum phosphate and magnesium probably indicated an effect of calcitonin on the renal excretion of these ions.

Treatment of skeletal disease in breast cancer: a controlled clodronate trial.

Normocalcaemic breast cancer patients with progressive osteolytic bone metastases were treated with clodronate 1.6 g/day (17) or placebo (17) for 12 months. Bone pain, extension of bone metastases and formation of new osteolytic foci were reduced by clodronate, and development of severe hypercalcaemia was prevented. After withdrawal of treatment the patients were followed-up for at at least 12 months. New bone metastases developed in both groups. There were, however, less fractures and less hypercalcaemia in the clodronate than in the placebo group. The survival rate was higher in the clodronate group than in the placebo group. No haematological toxicity was observed in the clodronate group.

Histomorphometric evidence for osteoclast-mediated bone resorption in metastatic breast cancer.

We studied bone biopsies from 65 normocalcaemic women with breast cancer and predominantly osteolytic bone metastases in order to examine the pathophysiology of bone destruction in metastatic bone disease. Quantitative histomorphometric measurements were made at sites of tumour involvement, at sites adjacent to tumour tissue and at sites distant from tumour tissue. There were no significant differences in bone volume or in indices of bone resorption or formation between biopsies taken from sites distant from tumour and the controls. Bone resorption, as judged by eroded surface, increased progressively from bone distant from tumour to tumour-laden bone. The number of osteoclasts was significantly increased in bone immediately adjacent to tumour and within metastases. There was no decrease in the ratio of osteoclast to eroded surface in breast cancer compared to controls suggesting that increased resorption in breast cancer was mainly osteoclast mediated and locally activated by the tumour. Two thirds of the biopsies taken from tumour involved regions showed osteosclerosis with woven bone formation. The volume of the pre-existing lamellar trabecular bone was lower than normal in 75% of these biopsies, suggesting that bone resorption must have been increased before the onset of woven bone formation. Since all patients were receiving hormonal treatment or chemotherapy, it is likely that osteosclerosis at sites of previous resorption mainly resulted from the basic cancer treatment as a sign of response to treatment. Osteoclastic bone resorption was, however, not completely inhibited by the active cancer treatment.

Testicular function after chemotherapy for osteosarcoma.

Testicular volume, sperm count and four hormones were measured in 18 patients 1-13 years after chemotherapy for osteosarcoma. The testicles were small in 13 patients. 17 patients gave semen samples: 10 were azoospermic and 2 were oligozoospermic. Testicular volume and sperm count were possibly associated with the type of chemotherapy. Of the 7 patients who had received cisplatin-containing chemotherapy, 6 had small testes and azoospermia; 1 was oligozoospermic with normal-sized testes. In 3 of the 11 patients whose chemotherapy had not included cisplatin, testicular size and sperm count were normal.

Prognostic effect of amenorrhoea and elevated serum gonadotropin levels induced by adjuvant chemotherapy in premenopausal node-positive breast cancer patients.

The purpose of the study was to determine the correlation between prognosis and chemotherapy induced amenorrhoea or elevated gonadotropin levels in node-positive breast cancer patients. Since we have previously found a better prognosis in patients with more profound leucopenia induced by adjuvant chemotherapy, we examined whether this effect was mediated through more efficient induction of amenorrhoea. The study population consisted of 126 premenopausal, primarily operable, node-positive breast cancer patients treated with cyclophosphamide, methotrexate and 5-fluorouracil (CMF) adjuvant chemotherapy at the Department of Oncology, Helsinki University Central Hospital between 1990 and 1993. 12 months after the beginning of adjuvant chemotherapy, the patients were divided into groups with respect to their menstrual function (regular menstruation, irregular menstruation or amenorrhoea). Information about menstruation status and serum concentration of follicle stimulating hormone (FSH) and oestradiol were recorded at 12 and 24 months from the beginning of adjuvant chemotherapy. Median follow-up time was 72 months. Women who experienced amenorrhoea or had irregular menstruation after chemotherapy had a significantly better 5-year disease-free survival (DFS) in univariate analysis than women who continued to menstruate (P = 0.02). Amenorrhoea and irregular menstruation were associated with a better DFS among patients with oestrogen receptor (ER) positive primary tumours (P = 0.007), whereas no such association was found in ER negative cases (P = 0.86). 5-year overall survival (OS) in univariate analysis was also better in patients who experienced amenorrhoea (81%) or who had irregular menstruation (90%) after chemotherapy as compared with patients with regular menstruation (68%; 81 versus 68%, P = 0.05). The serum FSH level did not correlate significantly with outcome irrespective of the cut-off point chosen. Nodal status, tumour size and menstruation status after chemotherapy were also significantly associated with DFS in a multivariate analysis. The menstruation status after chemotherapy lost its significance for OS in a multivariate analysis whilst the number of affected lymph nodes, tumour size and oestrogen/progesterone receptor status retained their impact. There was no association between the degree of leucopenia and induction of amenorrhoea by CMF. Chemotherapy-induced ovarian function suppression (amenorrhoea/irregular menstruation) after chemotherapy had a favourable effect on DFS in premenopausal breast cancer patients. The post-chemotherapy menstruation status is a clinically usable marker for sufficient endocrine effect of chemotherapy in ER/PR-positive patients in all premenopausal age groups. FSH level seemed to be a less reliable indicator of the castration effect of adjuvant chemotherapy in this study.

Surgical treatment of myeloma of bone.

33 patients treated operatively for plasma cell disease were analysed. There were 21 men and 12 women with an average age of 54 years. There was an undefined bone tumour in 23 cases, and a pathologic fracture in 10 cases. In only 6 cases was the diagnosis known before the operation. The primary tumour localisations were: vertebral column in 13, pelvis in 7, femur in 6, humerus in 2, rib in 1, tibia in 1, fibula in 1, scapula in 1 and olecranon in 1 case. 16 diagnostic biopsies were taken. Vertebral tumours were mainly evacuated or decompressed, combined with a stabilising procedure in 8 cases. A total of six endoprostheses, five to the femur and one to the humerus were performed. Two primarily wide resections, to the fibula and to the scapula were done. There were no locally recurring tumours during a mean follow-up time of 4 years and 2 months, and we conclude that operative and oncologic treatment is successful in providing the patient with a stable, pain-free locomotive system.

The effect of clodronate on bone in metastatic prostate cancer. Histomorphometric report of a double-blind randomised placebo-controlled study.

57 patients with advanced prostate cancer and a failure of prior hormonal treatment were selected for a double-blind placebo-controlled trial, in which they were randomly allocated to receive either clodronate (C) or placebo concomitantly with the basic cancer treatment, estramustine phosphate (E) (560 mg daily). The treatment was started intravenously with 300 mg of C or placebo in 5 consecutive days, and thereafter maintained orally with 1600 mg of C or identical placebo daily for 3 months. Bone biopsies were taken at admission and at 3 months. Measurements of serum calcium, phosphate, alkaline phosphatase, prostate-specific antigen and creatinine were made at the time of both bone biopsies and at 1 month. Serum intact parathyroid hormone and vitamin D metabolites were measured at admission and at 3 months. Because of several discontinuations, the study groups at final analysis comprised 20 patients taking E + C and 19 patients taking E and placebo. Bone resorption, as judged by eroded surface and osteoclast number, was markedly increased especially in biopsies taken from tumour-involved bone. Treatments with E + C or E both induced a significant decrease in bone resorption, but were associated with the development of hypocalcaemia, secondary hypoparathyroidism, hypophosphataemia and severe impairment of mineralisation of newly formed bone, i.e. osteomalacia. Since the patients were not vitamin D deficient, we conclude that osteomalacia resulted from a relative deficiency of calcium and phosphate. The transiency of pain relief achieved with anti-resorptive agents in the treatment of bone metastases from prostate cancer may be due to the development of osteomalacia.

Long-term impact of chemotherapy-induced ovarian failure on bone mineral density (BMD) in premenopausal breast cancer patients. The effect of adjuvant clodronate treatment.

We present the 5-year results of the effect of adjuvant chemotherapy on bone mineral density (BMD) and the efficacy of clodronate in the prevention of bone loss in 73 premenopausal women with primary breast cancer. All patients were treated with cyclophosphamide, methotrexate, 5-fluorouracil (CMF) chemotherapy. The patients were randomised to oral clodronate 1600 mg daily for 3 years or to a control group. At 5 years, patients were divided into those with preserved menstruation and those with amenorrhoea. Changes in BMD correlated significantly with the menstrual function after chemotherapy. The change in the lumbar spine BMD at 3 and 5 years were +0.6 and -1.3% in the menstruating group and -7.5 and -10.4% in the amenorrhoeic group (P=0.0001 and 0.0001, respectively), and in femoral neck +1.7 and -0.3%, and -3.5 and -5.8% (P=0.002 and P=0.001, respectively). Three-year clodronate treatment significantly reduced the bone loss in the lumbar spine -3.0% compared with controls -7.4% at three years (P=0.003), but no significant difference was found in the femoral neck: -1.7% versus -2.8%, respectively (P=0.86). These differences between the study groups were still seen at 5 years: in the lumbar spine -5.8% versus -9.7% (P=0.008) and femoral neck -3.5% versus -5.1% (P=0.91). In conclusion, chemotherapy-induced ovarian failure in premenopausal women caused a temporary accelerated bone loss of the lumbar spine. Adjuvant clodronate treatment significantly reduced this bone loss. Two years after the termination of treatment, the bone loss was still significantly less in the clodronate group compared with the control group.

Evaluation of the effect of oral clodronate on skeletal metastases with type 1 collagen metabolites. A controlled trial of the Finnish Prostate Cancer Group.

Clodronate relieves bone pain in patients with skeletal metastases. Since the pain relieving mechanism of clodronate may be associated with the antiosteoclastic activity, we have investigated whether the drug has simultaneous actions on bone resorption and pain. Although osteosclerotic metastases are characteristic of prostate carcinoma, bone resorption is also accelerated. The resorbing process can be investigated using a specific immunoassay for ICTP (cross-linked carboxyterminal telopeptide region of type I collagen) which allows the measurement of the degradation of type I collagen in serum samples. We have also determined serum concentration of PICP (carboxyterminal propeptide of type I procollagen) which reflects the synthesis of type I collagen (osteoid). Patients who have relapsed after first-line hormonal therapy, were randomised to receive estramustine phosphate (E) with or without clodronate (C) (E + C, n = 50; E, n = 49). The dose of E was 560 mg and that of C 3.2 g for the first month, thereafter 1.6 g. We saw elevated ICTP and PICP levels in the majority of the patients. A transient decrease in ICTP values occurred simultaneously with pain relief. The changes were more accentuated in the E + C than in the E group but the difference was not significant. In each group serum phosphate concentration decreased markedly (P = 0.001) whereas the activity of alkaline phosphatase remained increased, both indicating a development of osteomalacia during E therapy. The short-term antiosteoclastic effect of C may be explained by the dose reduction, hyperosteoidosis and osteomalacia which inhibit the binding of C on the crystal surfaces and by the late phase of disease.

Comparative effects of clodronate and calcitonin on bone in metastatic breast cancer: a histomorphometric study.

We studied the effects of long-term treatment with clodronate, calcitonin or placebo on bone in 36 normocalcaemic women with osteolytic metastases due to breast cancer. Clodronate (1.6 g daily given to 12 patients) induced a significant decrease in osteoclast surface and osteoclast number, and a significant fall in serum calcium and urinary excretion of calcium and hydroxyproline, an effect not noted after treatment with calcitonin (100 U in 12 patients) or in 12 placebo-treated patients. Treatment with clodronate did not abnormally suppress bone turnover nor impair mineralisation, as measured by bone formation and mineral apposition rates.

Monitoring the action of clodronate with type I collagen metabolites in multiple myeloma.

In our previous double-blind trial, we reported that clodronate reduced the incidence of bone lesions, fractures, pain and hypercalcaemia in multiple myeloma. Recently, it has been assumed that the antiresorptive effect of bisphosphonates on the osteoclasts is mediated through the osteoblasts. We therefore determined, in 244 patients of the same trial, serum assays of aminoterminal propeptide of type I procollagen (PINP) and type I collagen degradation product (ICTP). PINP is an early synthesis product of proliferating osteoblasts, in comparison to the alkaline phosphatase (AP) which is secreted by differentiated osteoblasts during the maturation phase of collagen. ICTP circulates in serum when old bone is resorbed. Our results indicate that after 25 months, the PINP levels decreased in the clodronate group (from 68.9 +/- 4.4 micrograms/l to 37.2 +/- 3.5 micrograms/l; P < 0.001) but not in the control group (from 61.5 +/- 3.2 micrograms/l to 69.3 +/- 7.5 micrograms/l; P < NS). The fall in the ICTP levels was markedly steeper in the patients receiving clodronate (from 8.38 +/- 0.80 micrograms/l to 4.58 +/- 0.32 micrograms/l; P < 0.01) than placebo (from 7.84 +/- 0.53 micrograms/l to 6.45 +/- 0.95 micrograms/l; P = NS). A significant difference between the study groups was seen at 4 months in the PINP, at 7 months in the ICTP and at 13 months in the AP levels, suggesting that clodronate affected through the proliferating osteoblasts, the osteoclasts, and through the osteoclasts, the differentiated osteoblasts. High baseline ICTP, PINP and AP levels indicated a poor prognosis. The decrease of the markers by clodronate was more marked in survivors than in non-survivors.