Eur J Haematol 2000: 65: 331±336 Printed in UK. All rights reserved
Copyright # Munksgaard 2000 EUROPEAN JOURNAL OF HAEMATOLOGY
ISSN 0902-4441
Effect of pamidronate administration on markers of bone turnover and disease activity in multiple myeloma Terpos E, Palermos J, Tsionos K, Anargyrou K, Viniou N, Papassavas P, Meletis J, Yataganas X. Effect of pamidronate administration on markers of bone turnover and disease activity in multiple myeloma. Eur J Haematol 2000: 65: 331±336. # Munksgaard 2000. Abstract: Aim: Bisphosphonates are potent inhibitors of osteoclastic activity and are used in the treatment of multiple myeloma (MM) in combination with chemotherapy. The effect of pamidronate on markers of bone resorption [cross-linked N-telopeptides of type I collagen (NTx)], markers of bone formation [serum alkaline phosphatase (BAP) and osteocalcin (OSC)], interleukin-6 (IL-6), b2-microglobulin, CRP, paraprotein and disease-related pain and skeletal events has been evaluated in 62 newly diagnosed patients with MM. Patients and methods: The patients were randomly assigned to two groups: the ®rst included 32 patients under chemotherapy and pamidronate (group I) and the second 30 patients on chemotherapy only (group II). Pamidronate was administered at a monthly dose of 90 mg iv, and the above parameters were evaluated at the beginning of this study and after 1, 3, 6, 9, 12 and 14 months of treatment. Results: The addition of pamidronate to chemotherapy resulted in a signi®cant reduction of NTx, IL-6 and paraprotein from the 3rd month and of b2-microglobulin, CRP and pain from the 6th month of treatment. No changes of NTx, IL-6, b2microglobulin, CRP or skeletal events were observed in patients of group II, while paraprotein was signi®cantly reduced after 6 months of treatment. The differences in NTx, IL-6, paraprotein and b2-microglobulin were statistically signi®cant between the two groups. Multivariate analysis revealed a signi®cant correlation between changes of NTx, changes of IL-6 in both groups and reduction of pain and paraprotein in group I. Conclusions: These results suggest that pamidronate may have a synergistic action with chemotherapy in decreasing osteoclastic activity, in reducing markers of myeloma activity and myeloma related pain and in improving the quality of life in patients with MM.
Multiple myeloma (MM) is a malignancy of B-cells characterized by osteolytic bone destruction that is responsible for the most prominent and distressing clinical features of the disease (1). Even patients responding to chemotherapy may have progression of skeletal disease (2) that can lead to pathological fractures, hypercalcaemia and spinal cord compression. The pathogenesis of bone disease in MM is related to increased osteoclast activity which is not accompanied by a comparable increase in bone
Evangelos Terpos1, John Palermos2, Konstantinos Tsionos3, Konstantinos Anargyrou1, Nora Viniou1, Pantelis Papassavas3, John Meletis1, Xenophon Yataganas1 1
First Department of Internal Medicine, University of Athens Medical School, Laiko Hospital, Athens, 2 3 Department of Immunology, and Department of Haematology, 251 General Air Force Hospital, Athens, Greece
Key words: multiple myeloma; bisphosphonates; pamidronate; cross-linked N-telopeptides of type I collagen (NTx); interleukin-6; bone alkaline phosphatase; osteocalcin; paraprotein; b2-microglobulin Correspondence: Evangelos Terpos, MD, First Department of Internal Medicine, University of Athens Medical School, Kazani str 2, 115±26 Athens, Greece Tel: +301 6911418 Fax: +301 6998327 e-mail:
[email protected] Accepted for publication 2 August 2000
formation (1). This phenomenon is mediated by cytokines that are produced locally in the bone marrow microenvironment by cells of tumor or nontumor origin, including tumor necrosis factors (TNFs), interleukin-1b (IL-1b) and interleukin-6 (IL-6) (1, 3). Various urine tests have been used to re¯ect osteoclastic activity. Recently, the cross-linked Ntelopeptides of type I collagen have been proposed as the most speci®c biochemical marker of bone 331
Terpos et al. resorption (4±6). On the other hand the most useful markers of bone formation are bone alkaline phosphatase (BAP) and osteocalcin (OSC) (7). Bisphosphonates are potent inhibitors of osteoclast activity by preventing the maturation of precursor cells into osteoclasts, being directly toxic to osteoclasts and preventing them from attaching to the bone (8). Furthermore they probably induce apoptosis on human MM cells (9, 10). The effect of several types of bisphosphonates has been evaluated in the treatment of MM in randomized trials (11± 15). The second-generation aminobisphosphonate, pamidronate, has been shown to reduce skeletal events, including pathological fractures and the need for radiation therapy, to reduce pain and improve quality of life (16). Pamidronate is extremely effective in the treatment of hypercalcaemia associated with MM (17) and reduces NTx values in patients with MM and breast cancer (18). The purpose of this study was to determine the effects of pamidronate treatment on biochemical markers of bone resorption (NTx), bone formation (BAP, OSC), disease activity (b2-microglobulin, CRP, paraprotein) and IL-6, as well as the effects on clinical data including pain and pathological fractures.
Patients and methods Patients
Sixty-two newly diagnosed patients with MM were separated in two groups. Group I included 32 patients treated with chemotherapy (MP or VAD) and pamidronate, while group II included 30 patients under chemotherapy treatment only (MP or VAD). Patients of both groups were randomly assigned to the two treatment modalities. Patients were ineligible if they had a skeletal-related event within 2 wk before enrolment, a serum creatinine concentration of >5 mg/dl, ascites, a serum total bilirubin concentration >2.5 mg/dl, or an abnormal electrocardiogram. Patients were also excluded for
the following treatment-related reasons: prior treatment with any kind of bisphosphonate within 3 months before enrolment, treatment with calcitonine or mithramycin within 2 wk before enrolment, or treatment with corticosteroids for any reason except part of the patient's chemotherapeutic regimen. The patients' characteristics are shown in Table 1. Pamidronate was administered at a monthly dose of 90 mg intravenously. The biochemical parameters (NTx, BAP, OSC, IL-6, b2-microglobulin, CRP and paraprotein) were evaluated 24 h before the beginning of treatment and 1, 3, 6, 9, 12 and 14 months after the initiation of therapy. Radiographic evaluation of the skull and the axial skeleton was made before and 6, 9 and 12 months after the initiation of treatment and whenever necessary due to clinical problems. Response to treatment was evaluated at 6 and 9 months after initiation of the study. Criteria for response to MM-speci®c therapy were as previously described (19). All patients gave a written consent at entry to the study. Evaluation of pain
The evaluation of pain was scored according to a monthly questionnaire, which included modi®cation of dosage and duration of analgesic and antiin¯ammatory treatment, number of days off work, number of days staying in bed and number of days hospitalized because of pain. The score for each of the above parameters is shown in Table 2. At the initiation of the study 26/32 patients of group I and 25/30 patients of group II had myeloma-related pain. Biochemical markers' assay
The NTx values were determined by enzyme-linked immunosorbent assay (ELISA; Ostex International, Inc., Seattle, WA). An ELISA assay was also used to determine the values of BAP (Metra Biosystems, Inc., USA), OSC (Osteometer BioTech A/S, Herlev,
Table 1. Patient characteristics Age (yr) Group (n)
Sex
Median
Range
Type of MM (n)
Stage (n)
Type of chemotherapy (n)
Response at 9 months (n)
I (32)
18M 14F
68
(55±78)
IgG (20) IgA (9) BJ (3)
IA (2) IIA (8) IIIA (15) IIIB (7)
MP (12) VAD (20)
PR (18) MR (10) NR (4)
II (30)
14M 16F
66
(46±78)
IgG (19) IgA (8) BJ (3)
IA (3) IIA (5) IIIA (16) IIIB (6)
MP (11) VAD (19)
PR (18) MR (7) NR (5)
MP, melphalan, prednisone; VAD, vincristine, adriamycin, dexamethasone; PR, partial response; MR, minimal response; NR, no response.
332
Effect of pamidronate on bone turnover in MM Table 2. Monthly evaluation of pain
Table 3. Mean values of pain score for the studied groups Score (points)
Decrease of analgesic treatment
76±100% 51±75% 26±50% 0±25%
0 1 2 3 4
0 1±2 3±4 5±7 >7
0 1 2 3 4
0 1±2 >2
0 2 4
Increase of analgesic treatment Days off work or staying in bed due to pain
Days of hospitalization due to pain
Baseline 1st month 3rd month 6th month 9th month 12th month 14th month
Group I
Group II
5.78 5.42 2.82 * 2.18* 1.96* 1.02* 0.8*
5.12 5.16 4.92 4.88 5.02 4.10 3.99
* p
