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

Abstract

The osteoprotegerin (OPG)/receptor activator of NF-kappa B ligand (RANKL) system has a major role in the pathogenesis of bone disease in myeloma (MM). The effect of autologous stem cell transplantation (ASCT) on bone turnover in MM was evaluated in 51 patients (35M/16F). Markers of bone resorption (NTX, TRACP-5b), bone formation (bone-alkaline phosphatase (bALP), osteocalcin), OPG and sRANKL were measured preand every month post-ASCT. The median follow-up period was 12 months. Four patients were transplanted in CR, 44 were transplanted in PR and three patients had progressive/resistant disease. All patients received bisphosphonates both pre-and post-ASCT. At baseline the majority of patients had increased NTX, TRACP-5b levels, and sRANKL/OPG ratio, while markers of bone formation were strongly suppressed. ASCT produced a significant reduction of sRANKL/OPG ratio, with a concomitant decrease of NTX, and TRACP-5b levels, starting the second month post-ASCT. Bone formation markers, osteocalcin and bALP, started to increase after the 9th and 11th month post-ASCT, respectively, while the increase of OPG preceded this. These results provide biochemical evidence that ASCT normalizes the abnormal bone resorption in MM patients possibly through the decrease of RANKL/OPG ratio, while bone formation requires a longer period to return to normal.

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

“…83 The RANKL/OPG ratio has been found to correlate with OS in MM. This result has not been confirmed in all reported studies to date, 63,69,83,84 may be due to differences in patient populations and/or therapies administered. Further studies are needed before measurement of serum RANKL and OPG levels in the everyday clinical setting should be considered.…”

“…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. 64 Moreover, comparison between these four markers (PYD, DPD, NTX and ICTP) revealed that serum ICTP and urinary NTX better reflected the extent of myeloma bone disease and could better predict early progression of the bone disease after conventional chemotherapy (CC).…”

“…Indeed, Heider et al found an attenuated increase in bALP in patients who received VD compared with those who received bortezomib monotherapy. 95 Thus, although different effective anti-myeloma regimens in combination with bisphosphonates can reduce bone resorption through reduction of tumor burden and inhibition of osteoclast function, 63 to-date only bortezomib has clearly shown an anabolic bone effect in MM.…”

“…[2][3][4] Multiple studies have now documented that in MM, serum OPG levels are reduced, whereas the soluble RANKL/OPG ratio is increased. 63,[79][80][81][82] This altered ratio correlates with extent of bone disease, markers of bone resorption, such as NTX and TRACP-5b and myeloma stage. 63,81 The administration of zoledronic acid in patients with asymptomatic myeloma was found to increase serum levels of OPG and thus reduce the RANKL/OPG ratio, likely accounting for the effect of zoledronic acid on osteoblast and/or bone marrow stromal cells together with its direct effect on osteoclasts.…”

Serum concentrations of Dickkopf‐1 protein are increased in patients with multiple myeloma and reduced after autologous stem cell transplantation

“…However, markers of bone formation do not return to normal until the 8 month postASCT, providing an indication that bone formation may be delayed in normalizing. 15 It has been suggested that the failure of serum markers of bone formation to increase in the period after increased bone resorption is due to the selective impairment of the osteoblastic compartment after HDT. 16,17 Our results could indicate that osteoblasts may resume their function when the inhibitory effect of DKK-1 is no longer present.…”