Long‐term Effects of Parenteral Dichloromethylene Bisphosphonate (Cl2mbp) on Bone Disease of Myeloma Patients Treated With Chemotherapy

Merlini, Giampaolo; Parrinello, Giuseppe Attardo; Piccinini, L; Crema, Francesca; Fiorentini, M; Riccardi, Alberto; Pavesi, Franco; Novazzi, Francesco; Silingardi, Vittorio; Ascari, E

doi:10.1002/hon.2900080104

Cited by 67 publications

(18 citation statements)

References 11 publications

(12 reference statements)

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“…ICTP was also superior to M protein, when these markers were correlated with survival. It is known that production of the M component predicts the stage of the disease with resonable accuracy, but as a single parameter it does not predict survival (Durie & Salmon, 1975 (Elomaa et al, 1983;Merlini et al, 1990). Since the number of patients in the present study is small, we will test the validity of this conclusion in a much larger group of patients, participating in a randomised study on the effect of clodronate, combined with the ordinary treatment with melphalan and prednisolon.…”

Section: Discussionmentioning

confidence: 84%

Serum concentration of the cross-linked carboxyterminal telopeptide of type I collagen (ICTP) is a useful prognostic indicator in multiple myeloma

Elomaa

Virkkunen²,

Risteli³

et al. 1992

Br J Cancer

136

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Summary Type I collagen is the main collagen type found in mineralised bone. Specific immunoassays for PICP (carboxyterminal propeptide of type I procollagen) and ICTP (cross-linked carboxyterminal telopeptide region of type I collagen) allow simultaneous assessment of the synthesis and degradation of type I collagen in serum samples, respectively. Our aim was to find out whether these metabolites of type I collagen are useful markers for following bone turnover and evaluating treatment response in multiple myeloma, which is a good model disease of excessive osteolysis. Fifteen consecutive patients were studied before and throughout their treatment. Samples for serum PICP and ICTP were collected before starting each treatment course of melphalan and prednisolon. Response to treatment was evaluated by following the changes in M protein and bone roentgenograms. The disease was progressing in four and regressive in 11 patients, but in four of these a recurrence occurred. In nonresponders the ICTP concentration was permanently elevated despite treatment. In responders both increased or normal levels of ICTP were initially observed, but they returned to or remained in the reference interval during treatment. The ICTP concentration increased upon recurring disease. There was a strong correlation between the extent of bone lesions and ICTP. There was no correlation between ICTP and PICP, the latter mainly remaining within the reference range, a finding that suggests no change in bone formation. ICTP was a significant predictor for survival in this patient group (P < 0.05). We conclude that ICTP is a specific and sensitive marker for bone resorption. Simultaneous use of serum ICTP and PICP offers an additional and easy means to follow bone turnover and evaluate the response to therapy in multiple myeloma.Skeletal disease is a major cause of morbidity in myeloma. Bone pain and fractures result from loss of bone. Bone resorption is increased due to osteoclast activating factors, which are elaborated by myeloma cells. One of the most potent factors is lymphotoxin (Garrett et al., 1987).The mainstay of long-term management in multiple myeloma is adequate chemotherapy. The response to treatment has been evaluated by measuring the M proteins. A decrease in or disappearance of the M proteins indicates reduction of tumour mass in the bone marrow, but it does not reflect healing of the skeletal disease (Durie & Salmon, 1975). Therefore measurements of bone metabolism have been used (Kraenzlin et al., 1989).Until recently the only assays available for bone turnover were serum alkaline phosphatase for monitoring bone formation and urinary calcium and hydroxyproline for monitoring bone resorption. None of these is specific for bone and all have been proven insensitive and unreliable. Nowadays more specific assays, namely osteocalcin for the assessment of bone formation and pyridinoline cross-links for the assessment of bone resorption, have been developed (Kraenzlin et al., 1989). Serum osteocalcin is the most abundant noncollageno...

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Section: Discussionmentioning

confidence: 84%

Serum concentration of the cross-linked carboxyterminal telopeptide of type I collagen (ICTP) is a useful prognostic indicator in multiple myeloma

Elomaa

Virkkunen²,

Risteli³

et al. 1992

Br J Cancer

136

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“…Although it is not recommended to manage subclinical MM with chemotherapy until overt malignancy (i.e., anemia, bone lesions on radiography) was observed, our data could change this point of view. Furthermore, some bone sparing agents such as diphosphonates could be useful in early MM since they appeared to be beneficial as long-term treatment of mouse plasmacytoma (44) and overt human MM (45,46). …”

Section: Discussionmentioning

confidence: 99%

Recruitment of new osteoblasts and osteoclasts is the earliest critical event in the pathogenesis of human multiple myeloma.

Bataille

Chappard²,

Marcelli³

et al. 1991

J. Clin. Invest.

233

163

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Considering the special relation of human multiple myeloma (MM) to bones, it is of importance to clarify the early steps of bone involvement in this disease. In this work, using bone histomorphometry (including histoenzymologic and kinetic studies for the first time), we have evaluated the bone remodeling (i.e., bone resorption and bone formation rates) of 16 individuals with early MM in comparison with that of 10 with benign monoclonal gammopathy (BMG) and that of 17 patients with previously untreated overt MM. A significantly increased osteoblastic recruitment was observed in the individuals with early MM when compared with those with BMG (P < 0.01). A significant (P < 0.01) increased bone resorption (i.e., eroded surfaces, osteoclast numbers and surfaces) was observed from the early stage of MM in comparison with the BMG status where bone resorption remained within the normal range. At the tissue level, there was no difference in terms of bone resorption between early and overt MM. On the other hand, osteoblast activity was significantly reduced in patients with overt MM (P < 0.05 by comparison with those with early MM).A significant enhancement of osteoblastic recruitment with an increased generation of new osteoclasts is an early critical event in the pathogenesis of human MM. Of particular importance is the early stimulation of osteoblasts, since these cells produce high amounts of IL-6, a potent myeloma cell growth factor and a critical cytokine for the formation of osteoclasts in the bone marrow. (J. Clin. Invest. 1991. 88:62-66.)

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“…In an open trial with parenteral clodronate in plasmocytoma a favorable bone response was observed as well [16], In contrast the bisphosphonate etidronate had no positive effect on bone pain, hypercalcemia, and vertebral fractures [7], In breast cancer patients with bone métastasés a beneficial effect of oral clodronate (1.6 g) could be shown in a double blind controlled trial [17]. Ir.…”

Section: Discussionmentioning

confidence: 99%

Prospective Randomized Trial of Dichloromethylene Bisphosphonate (Clodronate) in Patients with Multiple Myeloma Requiring Treatment. A Multicenter Study

et al. 1995

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Background: Characteristic features of multiple myeloma are bone resorption, osteoporosis and osteolytic lesions. Bisphosphonates can inhibit osteoclast activity and bone resorption. In this controlled randomized multicenter trial the effect of the bisphosphonate clodronate on the progression of bone involvement in multiple myeloma was evaluated. Patients and Methods: 170 patients with multiple myeloma requiring treatment and with bone involvement were recruited and randomized. All patients received 15 mg/m² i.v. melphalan on day 1 and 60 mg/m2 p.o. predisone on days 1-4 every 4 weeks. Patients randomized to the bisphosphonate arm received 1,600 mg clodronate p.o./day for 1 year. Bone response was evaluated on the basis of X-ray controls of the skeleton at baseline, 6, and 12 months staging. In addition chemotherapy response, blood chemistry, cytology, pain, and analgesic drug consumption were documented. Results: After one year of treatment there was a higher bone response in the clodronate group (13%) when compared to the control group (6%, n.s.). The difference was mainly due to the change of the osteolytic lesions. Hypercalcemia was observed more often in the control group. The number of progressive sites was lower in the clodronate group (mean 0.49 vs. 0.66, result after one year, p = 0.09). The bone resorption index was significantly reduced in the clodronate group, but not in the control group. A reduction of pain and analgesic consumption was observed under clodronate treatment.

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Long‐term Effects of Parenteral Dichloromethylene Bisphosphonate (Cl2mbp) on Bone Disease of Myeloma Patients Treated With Chemotherapy

Cited by 67 publications

References 11 publications

Serum concentration of the cross-linked carboxyterminal telopeptide of type I collagen (ICTP) is a useful prognostic indicator in multiple myeloma

Serum concentration of the cross-linked carboxyterminal telopeptide of type I collagen (ICTP) is a useful prognostic indicator in multiple myeloma

Recruitment of new osteoblasts and osteoclasts is the earliest critical event in the pathogenesis of human multiple myeloma.

Prospective Randomized Trial of Dichloromethylene Bisphosphonate (Clodronate) in Patients with Multiple Myeloma Requiring Treatment. A Multicenter Study

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