多发性骨髓瘤骨病临床特点及监测骨代谢标志物的临床意义

Clinical characteristics of bone disease in multiple myeloma and clinical significance of monitoring bone metabolic markers

目的观察多发性骨髓瘤（MM）患者骨病的临床特点以及监测骨代谢标志物的临床意义。方法回顾性分析2009年1月至2014年6月北京积水潭医院178例初治的MM患者的临床资料，分析骨病类型和骨病分级，比较不同分级骨病患者的临床特点。66例患者接受了骨代谢标志物的连续动态监测，观察治疗后2年内骨代谢标志物总I型前胶原氨基端延长肽（tPINP）和I型胶原羧基端肽β特殊序列（β—CTX）的变化。结果（1）178例初治的MM患者首诊时表现为骨痛者167例，合并高钙血症者35例，骨质疏松者83例，有溶骨性破坏者154例，有病理性骨折的73例。最常见的溶骨病变发生部位及骨折部位均是脊柱。（2）根据骨病分级将178例患者分为骨病较轻的A组（0～2级，51例）和骨病较重的B组（3～4级，127例），A组与B组患者性别、中位年龄、化疗有效／无效、中位总生存时间、中位疾病无进展生存时间、血清乳酸脱氢酶、血清白蛋白、尿轻链以及血肌酐水平差异均无统计学意义（均P〉0．05），但B组患者较A组患者血红蛋白水平更低[（99．78±29．93）比（108．84±29．30）∥L]，血钙水平更高[（2．47±0．40）比（2．30±0．29）mmol／L]、B2微球蛋白水平更高[（6．04±4．84）比（4．12±3．97）mg／L]，骨髓浆细胞比例更高（33．30％±24．87％比23．51％±22．67％）（均P〈0．05）。（3）治疗前，B组患者（47例）β—CTX、tPINP的表达水平及β-CTX／tPINP比值均明显高于A组患者（19例）（中位数0．78比0．42μg/L，60．95比43．47μg/L，0．017比0．012，均P〈0．05）。在治疗3个月后，A组和B组患者tPINP的表达水平与治疗前比较差异均无统计学意义，两组β-CTX的表达水平及B—CTX／tPINP比值均较治疗前有明显下降（中位数0．16比0．42μg／L，0．26比0．78μg／L；0．008比0．012，0．011比0．017；均P〈0．05）。治疗6个月、1年及2年后，A、B两组患者3个指标与治疗3个月后水平比较差异均无统计学意义。（4）根据化疗8周期后最大疗效将所有患者分为化疗有效组（部分缓解及以上疗效，48例）和化疗无效组（未达到部分缓解，18例），两组患者在治疗前血清p—CTX、tPINP和β—CTX／tPINP比值表达水平差异均无统计学意义。在治疗3个月后，化疗有效组和无效组患者tPINP的表达水平与治疗前比较差异均无统计学意义，两组患者β-CTX的表达水平及p-CTX／tPINP比值均较治疗前有明显下降（中位数0．24比0．60μg／L，0．44比0．95μg／L；0．005比0．012，0．005比0．011；均P〈0．05）。治疗6个月、1年及2年后，化疗有效组和无效组的3个指标与治疗3个月后水平比较差异均无统计学意义。结论骨髓瘤骨病常见的表现是骨痛、溶骨性破坏及病理性骨折，骨病严重程度可反映肿瘤负荷大小，但并不影响患者的化疗效果和生存时间。骨代谢标志物tPINP和β—CTX可用于骨病严重程度评估及骨病治疗效果监测。

Objective To observe the clinical characteristics of bone disease in patients with multiple myeloma （MM） and the clinical significance of monitoring bone metabolic markers. Methods The data of 178 MM cases newly diagnosed in Beijing Ji Shui Tan Hospital from January 2009 to June 2014 were reviewed to analysis the types and classification of bone disease and to observe the clinical characteristics of patients with different grades of bone disease. The levels of bone metabolic markers total procollagen type I N-terminal peptide （tPINP） and β C-terminal telopeptide of type I collagen （β-CTX） were monitored regularly in the two years following treatment in 66 cases. Results （ 1 ） Among the 178 newly diagnosed MM cases, 167 cases complained of pain in bones on first visit, 35 cases combined with hypercalcemia, 83 cases combined with osteoporosis, 154 cases combined with osteolytic bone destruction, and 73 cases combined with pathologic fracture. The most common osteolytic location was the spine. The most common fracture sites was the spine. （2） According to bone disease grading, the 178 cases were divided into group A （bone grade0-2, n=51） and group B（bone grade 3 -4, n= 127）. There were no significant differences between group A and group B in gender, median age, therapeutic effect/ineffec, median overall survival, median progress-free survival, mean serum lactic dehydrogenase, mean albumin, urine light chains and serum creatinine（ all P 〉0. 05）. Compared with group A, group B had lower hemoglobin level[ （99. 78 ± 29. 93）vs （ 108.84 ± 29. 30） g/L], and higher blood calcium level[ （2. 47 ± 0. 40） vs （2. 30 ± 0. 29） mmol/L], serum 132-microglobuin level[ （6. 04 ±4. 84）vs （4. 12 ±3.97） mg/L], and bone marrow plasma cells percentage（33. 30% ± 24. 87% vs 23.51% ± 22. 67% ） （ all P 〈 0. 05 ）. （3） Before treatment, the levels of β-CTX and tPINP in patients of group B （ n = 47 ） were higher than those in group A （ n = 19） （ median 0. 78 vs 0. 42μg/L,60. 95 vs 43.47μg/L, both P 〈 0. 05 ）. The ratio of β-CTX/tPINP in group B was higher than that in group A （median 0. 017 vs 0. 012, P 〈 0. 05 ）. After chemotherapy for 3 months, there were no differences in the level of tPINP compared with that before treatment in both group A and group B （ both P 〉 0. 05）, the level of β-CTX decreased significantly compared with that before treatment in both groups（ median 0. 16 vs 0. 42μg/L, 0. 26 vs 0. 78 μg/L, both P 〈 0. 05 ） ; the ratio of β-CTX /tPINP decreased significantly compared with that before treatment in both group A and in group B（ median 0. 008 vs 0. 012,0. 011 vs 0. 017, both P 〈0. 05）. There were no differences in the level of β-CTX, tPINP and 13- CTX/tPINP ratio after treatment for 6 months, 1 year and 2 years compared with that after 3 months in both group A and group B （ all P 〉 0. 05 ） . （ 4 ） All patients were divided into two groups according to the therapeutic effect： effective group included patients who reach the effect of partial remission or better remission（n =48）, while ineffective group included patients who did not reach the effect of partial remission （n = 18 ）. Before treatment there were no differences in the level of β-CTX, tPINP and β-CTX/tPINP ratio between the effective groupand the ineffective group （ all P 〉 0. 05 ）. After chemotherapy for 3 months, there were no differences in the level of tPINP compared with that before treatment in both effective group and ineffective group （ all P 〉 0. 05 ）, but the level of β-CTX decreased significantly compared with that before treatment both in effective group and ineffective group （median 0. 24 vs 0. 60 μg/L,0.44 vs 0. 95 μg/L, both P 〈 0. 05 ）. The ratio of β-CTX/tPINP decreased significantly compared with that before treatment both in effective group and ineffective group （median 0. 005 vs 0. 012,0. 005 vs 0. 011, both P 〈0. 05）. There were no differences in the level of β-CTX, tPINP and β-CTX/tPINP ratio after treatment for 6 months, 1 year and 2 years compared with that for 3 months both in effective group and ineffective group （ all P 〉 0.05）. Conclusions Pain in bones, osteolysis and pathological fracture are the most common clinical manifestations in myeloma-related bone disease. The severity of bone disease can reflect the tumor load, but may not affect the therapeutic effect and the overall survival. The bone metabolic markers tPINP and β-CTX can be used to evaluate the severity of myeloma-related bone disease at diagnosis and to monitor the effect of treatment for bone disease.