A prospective evaluation of the biochemical, metabolic, hormonal and structural bone changes associated with bortezomib response in multiple myeloma patients

Abstract

We prospectively evaluated the bone changes associated with proteasome inhibition using single agent bortezomib in relapsed or refractory myeloma patients. Ten patients received bortezomib 1.3 mg/m(2) per days 1, 4, 8 and 11 for three 21-day cycles, and 6 patients received 1 mg/m(2) per day with the same schedule. Bone architecture and metabolism changes were assessed by bone markers, micro-CT, bone histomorphometry, tetracycline labeling and serum parathormone levels. Bone parameter variations were compared by response to treatment. Microarchitectural changes were observed in all evaluable responsive patients. Bone alkaline phosphatase changes were associated with disease response (≥PR vs. others P=0.03 cycle 1, day 11) serum parathormone levels were also significantly increased (P=0.04 on days 11, 21, 33) in responding individuals. This study demonstrates that the myeloma control produced by proteasome inhibition is associated with bone changes and to a discrete pattern of hormonal variation.

Trial registration: ClinicalTrials.gov NCT00569868.

Figures

Figure 1.

Micro-CT rendering of the trabecular microarchitecture of representative bone biopsy specimens at baseline and after 12 infusions of bortezomib in a responsive patient (A). (B) Histomorphometric examination using Goldner’s Trichrome staining at baseline and after 12 infusions of bortezomib in a responsive patient. It shows increased osteoid and an increase in osteoblast (OB) visible on the active bone forming surface (arrows). The areas of increased osteoid correspond to areas of increased tetracycline label incorpotarion that are visible as a single tetracycline label under fluorescent microscopy.

Figure 2.

The averaged individual parathormone response during the first cycle of bortezomib (n=16 patients). The response shows the point averaged comparison of the responders (n=7) versus non-responders (n=9) and highlights both the difference in parathormone magnitude and response frequency in the responder group.