Abstract

Bortezomib (B) has been shown to increase osteoblast activity and inhibit osteoclast formation, thus promoting bone formation. We have previously reported a correlation between increased alkaline phosphatase (ALP) and the response to B in patients with MM. We now report results of a detailed prospective study examining the skeletal effects of B treatment in MM patients using histomorphometry, micro computed tomography (microCT) and markers of bone metabolism.

Methods: Single agent B (1.3 mg/m2 patients 1–10; 1mg/m2 patient 11–20), was administered on days 1, 4, 8 and 11 on a 21 day intervals for a total of 3 cycles; no patients were receiving concurrent bisphosphonates or steroids during the entire study period. The dynamic indices of bone turnover were prospectively evaluated via tetracycline labeling prior to transiliac bone biopsies obtained at baseline and after 3 cycles of treatment. Biopsy specimens were examined by high-resolution microCT prior to histomorphometric analyses. Architectural parameters such as bone volume/total volume (BVTV), trabecular number (TbN), and thickness (Tb.Th) were recorded. Osteocalcin, and alkaline phosphatase on days 1,4,8,11 were measured before and after each B dose and every 4 hours thereafter, daily for the other days of the treatment cycle.

Results: Histomorphometric analyses were compared in 7 of the 11 patients who completed the trial. All 11 patients underwent bone biopsy at baseline nine of those 11 at the end of the study (2 samples were not adequate). Baseline BV/TV values ranged from 13% to 80%. After 3 cycles of B treatment % increase (mean 37%) in BV/TV was shown in 6 of 7 patients (P<0.034). Tb.Th was also increased from baseline (range 20%–456%) in 5 of 7 patients (71%) who responded to B. Histological bone histomorphometry demonstrated a lack of osteoid formation and osteoblast activity at baseline and a marked increased in osteoid and osteoblast numbers on trabecular and cortical bone surface following B treatment. Tetracycline incorporation into bone was observed in only 2 of 11 of patients (18%) at baseline, reflecting the extremely low levels of bone turnover in MM patients prior to treatment. However, post-B tetracycline labeling was observed in 7 of 11 (63%) samples (p<0.03; baseline vs post treatment score changes), reflecting the dramatic increases in bone turnover elicited by B treatment. Interestingly, after B treatment, the rate of bone formation was accelerated in the 2 patients with measurable baseline tetracycline labeling. Baseline osteocalcin values were below the reference intervals (11–50 ng/ml) in 10 of 11 patients but increased in 9 of 11 patients at the end of the third B cycle. Overall osteocalcin changes increased from baseline by 403% (p<0.037). BALP ranged from 4.5 to 48.4 ug/l at baseline and increased in 6 of 10 patients following B treatment.

Conclusion: In this first prospective single agent B study we demonstrate that even a short course (3 cycles or 12 doses) of B treatment has a significant and potent anabolic bone effect in MM patients, demonstrated by serum turnover markers, micro-CT measures of bone architecture and by static and dynamic histomorphometry.

Author notes

Disclosure:Consultancy: Millennium Pharmaceuticals, Inc. Celgene, Inc., OrthoBio Tech. Research Funding: Millennium. Honoraria Information: Ortho-Biotech, Millennium, Celgene. Membership Information: Millennium, Ortho-Biotech, Celgene.