Biochemical markers of bone formation in patients with plasma cell dyscrasias and benign osteoporosis.

BACKGROUND: Myeloma-induced bone loss is related to an uncoupling of bone formation and bone resorption. The aim of the present study was to assess the potential clinical value of biochemical markers of bone formation in the work up of patients with plasma cell dyscrasias. METHODS: Serum total alkaline phosphatase, bone-specific alkaline phosphatase (BAP), and osteocalcin (OC) were measured in 43 patients with newly diagnosed multiple myeloma (MM), in 40 patients with monoclonal gammopathy of undetermined significance (MGUS), in 40 patients with untreated benign vertebral osteoporosis (OPO), and in 48 healthy adults. RESULTS: In MM and MGUS patients, serum BAP, but not serum OC, was lower than in healthy controls (P<0.05). Serum OC was higher in patients with OPO than in healthy controls (P<0.05). The strongest associations between markers were found in OPO patients and in healthy adults. MM patients with early-stage disease or without detectable osteolysis had decreased serum BAP values (P<0.05). Serum OC was higher in MM patients with stage III disease (P<0.05) than in healthy controls. MM patients with OPO-like bone involvement had lower BAP values than sex- and age-matched MGUS patients with OPO-like bone involvement and patients with benign OPO (P<0.05). CONCLUSIONS: In patients with plasma cell dyscrasias, serum BAP, rather than serum OC, appears to reflect a suppressed bone formation rate and may be helpful in the differentiation between benign and myeloma-induced OPO. However, the overall clinical use of biochemical markers of bone formation in patients with plasma cell dyscrasia appears limited.

Serum bone sialoprotein as a marker of tumour burden and neoplastic bone involvement and as a prognostic factor in multiple myeloma.

To test the potential of immunoreactive BSP, a non-collagenous bone matrix component, as a clinical guide in patients with plasma cell dyscrasias, serum BSP concentrations were measured in 62 patients with newly diagnosed multiple myeloma (MM) followed over a period of 4 years, in 46 patients with monoclonal gammopathy of undetermined significance (MGUS), in 71 patients with untreated benign vertebral osteoporosis (OPO), and in 139 healthy adults. Results were compared with clinical and laboratory data, including serum osteocalcin (OC), and urinary pyridinoline (PYD) and deoxypyridinoline (DPD) as markers of bone turnover. In MM, serum BSP, and urinary PYD and DPD were higher than in healthy controls and in MGUS or OPO (P< 0.001). BSP levels correlated with the bone marrow plasma cell content (r = 0.40, P< 0.001), and serum beta2-microglobulin (r = 0.31, P < 0.01). The differentiation of MM from healthy controls and from MGUS or OPO was highest for BSP. After chemotherapy, BSP reflected the response to treatment and correlated with the change in monoclonal protein (r = 0.55, P< 0.001). MM patients with normal baseline BSP levels survived longer than patients with initially elevated BSP values (P< 0.001, log rank test). Only serum monoclonal protein and BSP were independent predictors of survival. We conclude that in MM, BSP levels are associated with skeletal involvement and tumour cell burden. The quantification of serum BSP may be a non-invasive method for the diagnosis and follow-up, and may improve the prognostic value of conventional staging in MM.

Effect of first treatment with aminobisphosphonates pamidronate and ibandronate on circulating lymphocyte subpopulations.

Up to 60% of patients receiving their first infusion of the bisphosphonate pamidronate experience an acute-phase reaction. In this study, we used flow cytometry to determine the effects of pamidronate treatment on circulating lymphocyte subpopulations, and we investigated whether pamidronate and ibandronate treatment affect lymphocyte subpopulations differently. Twenty patients received a pamidronate infusion, 20 patients received intravenously injected ibandronate, and 10 controls received a clodronate infusion. Pamidronate treatment was followed by a significant increase in median body temperature at the 10-hour measurement and a significant decrease in counts of circulating lymphocytes, natural killer cells, T cells, and CD4+ and CD8+ T-cell subsets. Ibandronate treatment did not affect median body temperature, and it was associated at the 10-hour measurement with maximum increases in total lymphocyte count, B cells, T cells, and CD4+ and CD8+ T-cell subsets. Thus, there is a substantial difference in the hematologic response to initial treatments with pamidronate and ibandronate. Clodronate treatment did not induce changes in body temperature or significantly affect the number of circulating T cells and NK cells. The reduction in lymphocyte subsets after initial pamidronate therapy might be mediated by the release of tumor necrosis factor alpha, whose source in the acute-phase reaction could be T cells.

Comparative tolerability of drug therapies for hypercalcaemia of malignancy.

The bisphosphonates are the treatment of choice in hypercalcaemia of malignancy. However, plicamycin (mithramycin) an calcitonin treatment may still be of value should bisphophonate treatment fail, and gallium nitrate has recently been introduced as an alternative therapy. We analysed the tolerability of different treatments based on articles identified in a Medline search covering the period 1979 through September 1998. Articles were included if they met two criteria: (i) quantitative assessment of adverse effects; (ii) inclusion of > or = 10 patients. Although bisphosphonates are generally well tolerated, elevation of serum creatinine level, nausea/vomiting and fever have been reported following their application. Patients receiving etidronate (n = 268) or clodronate (n = 127) more frequently experienced creatinine elevation (8 and 5%, respectively) than did patients receiving pamidronate (n = 424; 2%), aledronate (n = 79; 0%), or ibandronate (n = 203; <1%). The difference in the frequency of reported creatinine level elevations reached statistical significance only for etidronate (z-test: p < 0.001 versus pamidronate; p < 0.02 versus alendronate; p < 0.001 versus ibandronate). With regard to the frequency of creatinine level elevations, clodronate treatment did not differ significantly from treatment with pamidronate, alendronate and ibandronate. An exception among the bisphosphonates is tiludronate, which has been reported on s a treatment of hypercalcaemia in only 1 study (n = 19) resulting in 1 case of lethal and 1 case of manageable acute renal failure. Nausea and vomiting are rare adverse effects of bisphosphonate treatment but seem to be more frequent with first generation drugs: etidronate (8%) and clodronate (7%) versus pamidronate (2%) [p < 0.001 and 0.009, respectively] and versus ibandronate (<1%) [p< 0.002 and 0.02, respectively]. Bisphosphonates containing a nitrogen atom were associated with an acute phase reaction leading to reported fever in 16% of pamidronate, 20% of aledronate, and 11% of ibandronate-treated patients. The most frequently reported adverse effects of treatment with the cytostatic drug plicamycin were hepatotoxicity (26%), nausea/vomiting (23%), and serum creatinine level elevation (5%). Furthermore. plicamycin application was associated with bone marrow suppression and a bleeding tendency due to abnormalities in multiple clotting factors and platelet dysfunction. The use of calcitonin is limited more by the short duration of its therapeutic effect than by toxicities (most frequent: nausea/vomiting in 16% of treated cases). The few publications on gallium nitrate in the treatment of hypercalcaemia of malignancy characterise it as an efficient drug, which is, however, associated with a higher frequency of renal toxicity (10%) and of nausea and vomiting (14%) than are the bisphosphonates.

Novel serum markers of bone resorption: clinical assessment and comparison with established urinary indices.

Although urinary measurements of collagen degradation provide valid estimates of bone resorption, their clinical application is hampered by pronounced analytical and biological variability. Therefore, immunoassays for the determination of such parameters in serum have been developed. In this study, we assessed the performance of three new serum markers of bone turnover, i.e., C-terminal and N-terminal telopeptides of type I collagen (S-CTX and S-NTX) and bone sialoprotein. Results were compared with urinary total pyridinoline, total deoxypyridinoline, and urinary C-terminal telopeptides of type I collagen (U-CTX) and urinary N-terminal telopeptides of type I collagen (U-NTX). The study population included healthy men (n = 27), premenopausal (n = 30) and postmenopausal (n = 31) women, patients with hepatic dysfunction (HF, n = 24), renal failure (RF, n = 30), breast cancer without (BC-, n = 24) and with (BC+, n = 30) bone metastases, primary vertebral osteoporosis (OPO, n = 27), primary hyperparathyroidism (PHPT, n = 16), active Paget's disease of bone (n = 18), multiple myeloma (MM, n = 18), and patients with hypercalcemia of malignancy before and after treatment with pamidronate (HOM, n = 28). Changes in urinary and serum markers were similar in most metabolic bone diseases. However, differentiation between healthy controls and OPO, or PHPT, was improved by the serum markers. In MM, all serum and urinary markers were elevated (p < 0. 05 vs. controls). In BC+, skeletal involvement was reflected by significant increments in all indices (p < 0.01 vs. BC-), except U-CTX and S-CTX. In HOM, pamidronate-induced changes in biomarkers were most pronounced for U-CTX and S-CTX and S-NTX. HF and RF were associated with elevated levels of all serum markers (p < 0.05 vs. controls). In conclusion, measurements in serum reflect bone resorption to the same extent as the urinary indices. Since serum markers circumvent some of the limitations of urinary measurements, their use potentially improves the assessment of skeletal disorders.