Pamidronate increases markers of bone formation in patients with multiple myeloma in plateau phase under interferon-alpha treatment

Abstract

Bisphosphonates are potent inhibitors of osteoclastic activity and reduce the disease-related skeletal complications when they are used in combination with chemotherapy in patients with multiple myeloma (MM). Pamidronate also inhibits apoptosis of primary osteoblastic cells and probably induces apoptosis on human MM cells and osteoclasts. It has been reported that interferon-alpha (IFN-alpha) decreases bone resorption and that low doses of IFN-alpha result in a significant increase in serum osteocalcin (OSC). The aim of this study was to determine the effects of pamidronate treatment on biochemical markers of bone resorption [cross-linked N-telopeptides of type I collagen (NTx)], bone formation [bone alkaline phosphatase (BAP) and OSC], disease activity [beta2-microglobulin, CRP, paraprotein], and interleukin-6 (IL-6) in patients with MM in plateau phase under IFN-alpha maintenance. The above parameters were evaluated in 28 patients (13 M, 15 F, median age 70 years) during maintenance treatment, before the addition of pamidronate and after 1, 3, 6, 9, 12, and 14 months of the combined therapy. The addition of pamidronate to maintenance treatment resulted in a significant reduction of NTx, IL-6, beta2-microglobulin, CRP from the 3rd month and paraprotein from the 6th month of treatment, whereas BAP and OSC were significantly increased from the 6th month. These changes continued during the 14-month follow-up of the combined treatment. Multivariate analysis showed a significant negative correlation between changes of BAP and OSC and the patients' age. The greater increase of the bone formation markers was observed in younger patients. These results suggest that, in addition to the inhibition of osteoclastic activity, pamidronate in combination with IFN-alpha was shown to induce bone formation in patients with MM in the plateau phase.

Autologous stem cell transplantation normalizes abnormal bone remodeling and sRANKL/osteoprotegerin ratio in patients with multiple myeloma

“…These data also confirm that myeloma clone may disturb bone turnover independently of paraprotein production and are in consistence with evidence of persistent excessive osteoclast activity and increased bone resorption even in plateau phase of myeloma. 23,24 Furthermore, the increased levels of TRACP-5b in myeloma patients pre-ASCT, an enzyme that is produced only by activated osteoclasts, 25 suggest that there is increased osteoclast activity in patients at partial remission. As the sRANKL/OPG ratio is also increased in this cohort of patients, we may assume that this abnormality in the RANKL/OPG pathway may be responsible for the osteoclast activation, which leads to increased bone resorption and increased collagen type-I degradation products (NTX).…”

“…This result, as well as the notion that not all patients normalized NTX, also confirms the observation that increased bone resorption may be apparent even in patients with PR or in plateau phase of the disease. 23 Conversely, the increase in OPG levels may compensate this increased bone resorption leading to no bone disease progression in most patients.…”

The use of biochemical markers of bone remodeling in multiple myeloma: a report of the International Myeloma Working Group

“…71 Bone markers during anti-resorptive therapy Biochemical markers of bone turnover have been used in MM both to monitor bisphosphonate treatment, and to determine 71 Terpos et al showed that the addition of pamidronate to CC significantly reduced urinary NTX and disease-related pain compared with CC alone, 49 and that pamidronate in combination with interferon-a induced bone formation in MM patients at plateau phase. 61 Ibandronate at a dose of 2 mg showed a substantial reduction of CTX and OC in only one-third of MM patients, 74 whereas in a randomized study, monthly pamidronate (90 mg, IV) produced a greater reduction of NTX and TRACP-5b compared with monthly ibandronate (4 mg, IV). 56,75 In a large, randomized study comparing 4 mg zoledronic acid with 90 mg pamidronate, given IV every 3-4 weeks in patients with bone metastases from breast cancer or with MM osteolytic disease, urinary NTX was strongly suppressed (up to 64% below baseline in both treatment groups) for the duration of the study.…”

“…[43][44][45][46][47][48][49][50][51][52][53][54][55][56][57][58][59][60] As has been shown in multiple studies, urine levels of PYD, DPD and NTX and serum levels of CTX, ICTP and TRACP-5b were elevated in MM patients compared with healthy controls, and correlated with the extent of osteolytic disease. 46,48,[51][52][53][54][55][56][58][59][60] Urinary NTX levels were increased even in myeloma patients who had reached a clinical plateau phase of their disease, 61 whereas PYD, DPD and NTX were also elevated in myeloma patients before autologous transplantation. 62,63 A histomorphometric study in bone marrow biopsies of myeloma patients showed that urinary NTX correlated most positively with dynamic histomorphometric indices of bone resorption, followed by serum ICTP and urine DPD; urine PYD did not correlate with the histomorphometric findings.…”

The Role of Bisphosphonates in Multiple Myeloma: Mechanisms, Side Effects, and the Future

“…However, it has not yet been established whether or not maintenance treatment with BPs may result in longer survival and prevention or reduction of relapses and long-term complications. A small study published in 2001 [91] …”