Biomarkers of Bone Remodeling in Multiple Myeloma Patients to Tailor Bisphosphonate Therapy

Abstract

Background: Patients with multiple myeloma may be susceptible to osteonecrosis of the jaw (ONJ) and stress fractures due to long-term aminobisphosphonate (aBP) therapy. However, it is unknown whether urinary N-telopeptide (NTX) or other bone biomarkers are predictive of skeletal-related events (SRE) or the impact of cessation of aBP therapy on bone remodeling.Methods: We studied markers of bone turnover over a 6-month period after a single dose of zoledronic acid in 29 patients with multiple myeloma in remission who previously received 8 to 12 doses of pamidronate or zoledronate (NCT00577642). Our primary objective was to determine the duration of time urinary NTX levels remain suppressed after a single dose of zoledronate. A secondary objective was to identify and correlate other markers of bone remodeling with NTX changes. Thirty cytokines, based on their possible role in bone remodeling, were tested using cytokine arrays. Candidates were confirmed by ELISA.Results: All patients had continued suppression of NTX levels, except 1 patient who had an increase in NTX levels associated with an SRE. GDF-15 and decorin were found to decrease, whereas bone-specific alkaline phosphatase (BSALP) increased. Although not significant in aggregate, osteopontin and osteoprotegerin levels increased in at least half of the patients.Conclusion: Our data show that NTX levels continue to be suppressed after aBP therapy, and suggest that suppressed NTX levels may be predictive of freedom from SRE in this patient population. Furthermore, osteoblast suppression by aBP may be reversible in myeloma. These data provide the basis for less frequent dosing of aBPs. Clin Cancer Res; 20(15); 3955-61. Ó2014 AACR.

Cytokines Behavior in Multiple Myeloma Patients during Zoledronic Acid Treatment

“…However, differently from what observed in solid tumors [10], a single infusion of zoledronic acid produced a statistically significant decrease of PDGF on day 2, unexpectedly followed by a statistically significant increase of VEGF on day 7. Except of this single occasion, throughout the entire period of study, these two cytokines remained always within the normal range.…”

“…In conclusion, we described the modification in serum level of important cytokine in MM. About the anti-angiogenic effect recently demonstrated in vivo although the lack of long-lasting reduction of VEGF and PDGF that we noticed differently from what happen in solid cancer [10,20], we could not exclude that zoledronic acid express its anti-myeloma activity by inhibiting VEGF (reduced after day 7) and PDGF, even though zoledronic acid may not have an effect on the cytokine themselves. It is possible that this drug may have an impact on the effect of VEGF and PDGF on signalling that leads to blood vessel development or it also may have an impact on the effect of VEGF and PDGF on myeloma cells directly like hypothesized in some recent study, previously mentioned.…”

“…As known, zoledronic acid is clearly effective at inhibiting the development of myeloma bone disease, but the exact mechanism of its anti-MM action is still unexplained. There are different hypothesis: it has been proposed that because less bone is destroyed following bisphosphonate treatment, there is less volume available for tumor expansion [2][3][4][5][6][7][8][9][10][11].…”

“…The authors propose that this effect is mediated by a complex interaction of increased pro-apoptotic factors and decreased cell cycle proteins. About the use of zoledronic acid in solid tumor, Santini et al [4] reported that in patients with advanced solid cancer and bone metastasis, pamidronate [2] and zoledronic acid [4][5][6][7][8][9][10][11][12][13] showed antiangiogenic properties which were associated with a significant and long-lasting decrease of VEGF serum levels following bisphosphonates infusion. These observations were later confirmed by Ferretti et al [14] who observed a transient but significant reduction of VEGF and bFGF, 48 hours after the infusion of zoledronic acid in breast cancer patients with bone metastasis.…”

Serum Markers of Bone Turnover and Angiogenesis in Patients With Bisphosphonate-Related Osteonecrosis of the Jaw After Discontinuation of Long-Term Intravenous Bisphosphonate Therapy

“…25–29 A randomized clinical trial in postmenopausal women noted that a single dose of 5 mg intravenous zoledronate stably decreased bone turnover and increased bone mineral density that lasted for at least 5 years. 26 Throughout the 5-year follow-up period, the mean level of β-CTX remained 48% lower in the zoledronate group compared with placebo group.…”