Massachusetts General Hospital Cancer Center;
Massachusetts General Hospital Cancer Center; Harvard Medical School, Boston, Massachusetts.
Clin Cancer Res. 2014 Aug 1;20(15):3955-61. doi: 10.1158/1078-0432.CCR-14-0434. Epub 2014 Jun 23.
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.
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.
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.
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.
由于长期使用氨基双膦酸盐（aBP）治疗，多发性骨髓瘤患者易发生颌骨坏死（ONJ）和应力性骨折。然而，尚不清楚尿 N 端肽（NTX）或其他骨生物标志物是否可预测骨骼相关事件（SRE），也不清楚停止 aBP 治疗对骨重塑的影响。
我们研究了 29 例缓解期多发性骨髓瘤患者单次唑来膦酸治疗后 6 个月内骨转换标志物的变化，这些患者先前接受了 8 至 12 剂帕米膦酸或唑来膦酸治疗（NCT00577642）。我们的主要目的是确定单次唑来膦酸治疗后尿 NTX 水平持续抑制的时间。次要目的是确定并比较其他骨重塑标志物与 NTX 变化的相关性。基于其在骨重塑中的可能作用，我们使用细胞因子阵列检测了 30 种细胞因子。候选物通过 ELISA 进行验证。
除了 1 例患者因 SRE 而出现 NTX 水平升高外，所有患者的 NTX 水平均持续受到抑制。GDF-15 和 decorin 降低，而骨碱性磷酸酶（BSALP）增加。虽然总体上没有统计学意义，但至少有一半患者的骨桥蛋白和护骨素水平升高。
我们的数据表明，NTX 水平在 aBP 治疗后仍持续受到抑制，并提示在该患者人群中，抑制的 NTX 水平可能预示着无 SRE。此外，aBP 对成骨细胞的抑制可能是可逆的。这些数据为更频繁地使用 aBP 提供了依据。
