Efficacy evaluation of denosumab in the treatment of patients with postmenopausal osteoporosis at high risk of fracture
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摘要:目的
评估地舒单抗与唑来膦酸在治疗骨折高风险绝经后骨质疏松症（postmenopausal osteoporosis, PMOP）患者中的疗效差异，优化PMOP患者的用药策略。
方法选择2021年9月至2024年3月于海军军医大学第二附属医院就诊的骨折高风险PMOP患者123例，随机分为地舒单抗组（n＝63）和唑来膦酸组（n＝60），治疗、随访1年。观察两组患者的骨代谢指标，腰椎、股骨颈以及全髋骨密度（bone mineral density，BMD）的变化，并记录不良反应发生情况。
结果治疗后，地舒单抗组和唑来膦酸组患者的腰椎和全髋BMD均显著增加（P＜0.05）；唑来膦酸组患者的股骨颈BMD也显著增加（P＜0.05）。地舒单抗组的腰椎BMD改善效果显著优于唑来膦酸组，而唑来膦酸组股骨颈和全髋BMD的改善效果显著优于地舒单抗组（P＜0.05）。两组患者的骨代谢指标均得到明显改善（P＜0.05），未出现明显的肝肾功能异常。唑来膦酸组7例患者发生不良反应，地舒单抗组5例患者发生不良反应，均为轻度。
结论地舒单抗治疗骨折高风险PMOP可明显增加腰椎BMD、改善骨代谢指标，降低骨折风险，且安全性较高。
Abstract:ObjectiveTo explore the difference of efficacy and safety between denosumab and zoledronic acid in the treatment of patients with postmenopausal osteoporosis (PMOP), and to optimize the medication regimen for PMOP patients.
MethodsA total of 123 PMOP patients with high risk of fracture at the Second Affiliated Hospital of Naval Medical University from September 2021 to March 2024 were selected and randomly divided into two groups: the denosumab group (n=63) and the zoledronic acid group (n=60). Both groups underwent one-year treatment and follow-up, bone metabolism indexes, lumbar vertebrae, femoral neck, and total hip bone mineral density (BMD) were monitored, and any adverse reactions were documented.
ResultsAfter treatment, the lumbar vertebrae and total hip BMD of patients in the denosumab group and the zoledronic acid group were significantly improved (P＜0.05); the femoral neck BMD of patients in the zoledronic acid group was also significantly improved (P＜0.05). The improvement of lumbar vertebrae BMD in the denosumab group was significantly better than that in the zoledronic acid group, while the improvement of femoral neck and total hip BMD in the zoledronic acid group was significantly better than that in the denosumab group (P＜0.05). Bone metabolism indicators were significantly improved in both groups (P＜0.05), and no significant liver and kidney dysfunction were observed. A total of 7 patients in the zoledronic acid group had mild adverse reactions and 5 patients in the denosumab group had mild adverse reactions.
ConclusionsDenosumab significantly increased lumbar vertebrae BMD and improved bone metabolism markers in PMOP patients, thus reducing risk of fracture and demonstrating good safety.
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Keywords:
- high risk of fracture /
- postmenopausal osteoporosis /
- denosumab /
- zoledronic acid
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骨质疏松症（osteoporosis，OP）是一种全身性骨骼疾病，其特点是骨量减少和骨微结构损害，导致骨骼强度下降和脆性增加，容易发生骨折。OP分为原发性和继发性[1-2]，原发性OP包括绝经后、老年及特发性，多见于绝经后女性和老年男性，尤其是50岁以上的绝经女性[3]，因雌激素水平下降，易发生绝经后骨质疏松症（postmenopausal osteoporosis，PMOP）。
骨质疏松性骨折是老年患者残疾和死亡的主要原因之一。有效的抗OP药物治疗可以增加骨密度（bone mineral density，BMD）、改善骨质量，显著降低骨折的发生风险。最新的指南[2]表明，骨折高风险OP患者推荐使用双膦酸盐或地舒单抗治疗。双膦酸盐类是国内外治疗OP的一线药物[4]，包括唑来膦酸、伊班膦酸和阿仑膦酸钠等，是目前临床上用于治疗PMOP的首选药物，可以有效提高PMOP患者BMD，降低骨折风险。但临床研究[5]发现，双膦酸盐类药物对于部分骨折高风险的PMOP疗效欠佳，且可能引起一过性流感样症状和胃肠道反应。另外，估算的肾小球滤过率（estimated glomerular filtration rate, eGFR）＜35 mL·min﹣1·(1.73 m)﹣2的患者禁用此类药物。地舒单抗是一种人源化IgG2单克隆抗体，可特异性阻断RANK/RANKL信号通路，有效抑制破骨细胞分化，从而改善BMD[6]。该药物于2010年在欧洲和美国获批上市，并在2020年正式进入中国市场[7-8]。由于地舒单抗在我国上市时间较短，有关PMOP患者的国内临床研究较少，且缺少与唑来膦酸的“头对头”比较研究。因此，本研究通过与唑来膦酸对比，探究地舒单抗治疗骨折高风险PMOP的临床疗效以及安全性，为PMOP患者临床用药提供更多参考。
1. 资料与方法
1.1 研究对象
选取2021年9月至2024年3月于海军军医大学第二附属医院就诊的骨折高风险PMOP患者。纳入标准：（1）患者符合《原发性骨质疏松症诊疗指南（2017）》[9]的OP诊断标准，自然绝经或手术绝经，绝经时间≥12个月；（2）对于存在髋部或椎体骨质疏松性骨折史的患者，BMD检查结果T值＜−2.0，且包含以下至少1个危险因素：存在髋部或椎体以外部位骨折史，存在父亲/母亲髋部骨折家族史，体质量指数（body mass index，BMI）＜18.5 kg/m2，吸烟者；既往未发生过骨折的患者，BMD的T值小于−3.0。排除标准：（1）存在严重心、肝、肾功能不全的患者；（2）合并其他骨病者；（3）长期使用影响骨代谢药物如糖皮质激素的患者；（4）有口腔疾病需在治疗期间行手术治疗的患者；（5）继发性或特发性OP患者。
1.2 治疗方法
采用计算机生成的随机数字序列，将研究对象按照1∶1的比例随机分配至地舒单抗组与唑来膦酸组。两组患者均接受口服钙剂（碳酸钙维生素D3片，每片含钙500 mg和维生素D3 200 IU，每日2片；北京朗迪制药有限公司）和骨化三醇（口服骨化三醇胶丸，0.25 µg/粒，每日1粒；上海罗氏制药有限公司）的基础治疗。在此基础上，地舒单抗组予以地舒单抗注射液（60 mg，安进公司），每6个月皮下注射1次。唑来膦酸组予以唑来膦酸注射液（100 mL∶5 mg，北京诺华制药有限公司），每年1次，配伍0.9%氯化钠注射液1 000 mL静脉滴注。两组治疗时长均为1年。
1.3 观察指标
1.3.1 基线、随访资料
基于预先设计的病例观察表（case report form, CRF），收集患者一般资料，包括年龄、绝经年龄、身高、体质量、BMI、脆性骨折史、父母髋部骨折史、饮酒史、吸烟史以及其他导致继发性OP的疾病史等。
1.3.2 腰椎、股骨颈BMD
以治疗12个月后的腰椎BMD作为主要终点；全髋关节、股骨颈BMD为次要终点。使用Lunar iDXA骨密度仪分别在研究第1天和治疗12个月后，对受试者腰椎、左股骨近端（检测全髋关节和股骨颈BMD，仅在左股骨不适合分析的情况下采用右股骨扫描）进行双能X线吸收测定法（dual-energy X-ray absorptiometry，DXA）扫描。
1.3.3 骨代谢指标
所有受试者分别于研究第1天和治疗12个月后，采用电化学发光免疫分析法检查血清中骨转换标志物β-I型胶原交联C末端肽（β-C-terminal telopeptide of type I collagen，β-CTX），骨形成标志物碱性磷酸酶（alkaline phosphatase，ALP）和骨钙素（osteocalcin，OC）；检测血钙、血磷、25-羟基维生素D[25-hydroxy-vitamin D，25-(OH)D]和甲状旁腺激素（parathyroid hormone，PTH）水平。所有受试者均为清晨空腹、给药前采集肘静脉血样，按规范流程送至我院检验科进行检测。
1.3.4 安全性评价
记录患者的不良反应发生情况，包括肝肾功能异常、骨折、颌骨坏死等，以及相应处理措施。
1.4 统计学处理
通过查阅以往相关研究[10-11]，并结合实际情况及预期，设定组间差异（δ）为1.38%，综合标准差（σ）取2.25%，显著性水平（α）为0.05，统计功效（1－β）为0.80。使用G*Power软件进行样本量计算，每组需要至少42例受试者。综合考虑受试者提前退出、失访及其他情况，每组至少纳入60例。采用SPSS 25.0进行数据统计分析。符合正态分布的数据采用$\bar x \pm s $表示，两组间比较使用成组t检验，组内比较使用配对样本t检验。不符合正态分布的数据以M（P25, P75）表示。非正态分布的数据与方差不齐的数据均采用Wilcoxon秩和检验。检验水准（α）为0.05。
2. 结 果
2.1 PMOP患者一般资料
共筛选138例PMOP患者，其中提前退出、失访及其他情况15例（地舒单抗组7例，唑来膦酸组8例），最终纳入123例PMOP患者（地舒单抗组63例，唑来膦酸组60例）。123例患者平均年龄（67.21±7.38）岁。其中，地舒单抗组平均年龄（66.69±7.58）岁，年龄范围为47～86岁，绝经年龄（50.23±3.92）岁，BMI（21.69±4.50）kg/m2，脆性骨折史29例、父母髋部骨折史11例，患者均无吸烟、饮酒史以及其他导致继发性OP的疾病史；唑来膦酸组平均年龄（67.75±7.22）岁，年龄范围为46～81岁，绝经年龄（49.77±2.89）岁，BMI（21.57±2.94）kg/m2，脆性骨折史21例、父母髋部骨折史12例，饮酒史1例，吸烟史3例，无其他导致继发性OP的疾病史。两组患者的一般资料差异无统计学意义（表1）。
表 1 两组PMOP患者一般资料比较Table 1. Comparison of general data between the two groups of patients with PMOPIndex Denosumab group (n＝63) Zoledronic acid group (n＝60) t P Age/year 66.69±7.58 67.75±7.22 −1.06 0.29 Menopausal age/year 50.23±3.92 49.77±2.89 0.80 0.43 BMI/(kg·m−2) 21.69±4.50 21.57±2.94 0.13 0.89 Serum calcium/(mmol·L−1) 2.28±0.12 2.27±0.10 1.01 0.31 Serum phosphorus/(mmol·L−1) 1.20±0.17 1.23±0.15 −0.97 0.33 25-(OH)D/(ng·mL−1) 25.77±8.46 23.25±8.83 1.48 0.14 β-CTX/(ng·mL−1) 0.24±0.16 0.26±0.18 −0.96 0.34 OC/(ng·mL−1) 13.65±5.28 14.64±10.05 −0.83 0.41 PTH/(ng·mL−1) 43.67±23.73 43.63±19.01 0.64 0.52 ALP/(U·L−1) 72.60±21.89 75.05±24.50 −0.16 0.87 T score of lumbar vertebrae (L1-4) −2.87±0.75 −2.77±0.93 −0.06 0.95 T score of femoral neck −2.23±0.63 −2.21±0.75 −1.18 0.24 T score of total hip −2.21±0.81 −2.18±1.17 −0.34 0.73 PMOP: postmenopausal osteoporosis; BMI: body mass index; 25-(OH)D: 25-hydroxy-vitamin D; β-CTX: β-C-terminal telopeptide of type I collagen; OC: osteocalcin; PTH: parathyroid hormone; ALP: alkaline phosphatase. 2.2 两组患者治疗前后BMD
结果（表2）显示：治疗后，地舒单抗组和唑来膦酸组患者的腰椎和全髋BMD均显著提高（P＜0.05）；唑来膦酸组患者的股骨颈BMD也显著提高（P＜0.05）。地舒单抗组的腰椎BMD改善效果显著优于唑来膦酸组，而唑来膦酸对股骨颈和全髋BMD的改善效果显著优于地舒单抗（P＜0.05）。
表 2 两组患者治疗前与治疗1年后骨密度比较Table 2. Comparison of bone mineral density between the two groups at baseline and one year after treatmentGroup T score of L1-4 T score of femoral neck T score of total hip Denosumab group (n＝63) Baseline −2.87±0.75 −2.23±0.63 −2.21±0.81 After treatment −2.48±0.92 −2.20±0.62 −2.13±0.81 t −5.78 −0.44 −1.91 Pa ＜0.001 0.662 0.030 Zoledronic acid group (n＝60) Baseline −2.77±0.93 −2.21±0.75 −2.18±1.17 After treatment −2.49±0.92 −2.03±0.74 −1.83±0.87 t −3.24 −2.21 −3.04 Pb ＜0.001 0.023 0.004 Change from baseline Denosumab group 0.41±0.68 0.03±0.38 0.07±0.39 Zoledronic acid group 0.14±0.86 0.36±0.92 0.35±0.83 t 2.11 −2.64 −2.20 Pc 0.037 0.011 0.029 aComparison of BMD T scores in the denosumab group between baseline and one year after treatment. bComparison of BMD T scores in the zoledronic acid group between baseline and one year after treatment. cComparison of BMD T scores change from baseline to one year after treatment between denosumab group and zoledronic acid group. BMD: bone mineral density. 2.3 两组患者治疗前后骨代谢
结果（表3）显示：治疗1年后，地舒单抗组的血钙、25-(OH)D和ALP水平较基线显著改善（P＜0.05）。唑来膦酸组的血钙、OC、PTH、ALP水平较基线显著改善（P＜0.05）。两组患者骨代谢的改善水平差异无统计学意义。
表 3 两组患者治疗前与治疗1年后骨代谢指标比较Table 3. Comparison of bone metabolism between the two groups at baseline and one year after treatmentGroup Serum calcium/
(mmol·L−1)Serum phosphorus/
(mmol·L−1)25-(OH)D/
(ng·mL−1)β-CTX/
(ng·mL−1)OC/
(ng·mL−1)PTH/
(ng·mL−1)ALP/
(U·L−1)Denosumab group
(n＝63)Baseline 2.28±0.12 1.20±0.17 25.77±8.46 0.24±0.16 12.65±5.28 43.67±23.73 72.61±21.89 After treatment 2.31±0.14 1.19±0.18 29.56±11.53 0.12±0.15 11.17±10.37 36.42±15.38 63.34±23.89 t −1.31 0.35 −2.32 3.39 0.86 1.94 2.42 Pa 0.048 0.749 0.030 0.019 0.121 0.031 0.016 Zoledronic acid group
(n＝60)Baseline 2.27±0.10 1.23±0.15 24.24±8.94 0.25±0.16 11.93±5.10 44.24±15.22 75.05±24.50 After treatment 2.22±0.13 1.17±0.18 26.78±9.46 0.20±0.09 9.13±2.23 42.88±17.01 65.50±20.41 t 2.31 1.85 −2.11 1.75 3.88 0.58 4.15 Pb 0.023 0.554 0.041 0.082 ＜0.001 0.045 ＜0.001 Change from baseline
beween the two groupst 1.97 1.39 0.11 1 0.12 1.44 0.16 Pc 0.051 0.167 0.914 0.319 0.907 0.149 0.871 aComparison of bone metabolism in the denosumab group between baseline and one year after treatment. bComparison of bone metabolism in the zoledronic acid group between baseline and one year after treatment. cComparison of bone metabolism change from baseline to one year after treatment between denosumab group and zoledronic acid group. 25-(OH)D: 25-hydroxy-vitamin D; β- CTX: β-C-terminal telopeptide of type I collagen; OC: osteocalcin; PTH: parathyroid hormone; ALP: alkaline phosphatase. 2.4 安全性
2.4.1 两组患者治疗前后肝肾功能
结果（表4）显示：两组患者的基线血白蛋白（albumin，Alb）和血清肌酐（serum creatinine，Scr）差异存在统计学意义（P＜0.05）。治疗期间，两组均出现肝肾功能改变或超过正常值，均为轻度异常。地舒单抗组出现肝功能异常14例（22.2%），肾功能指标异常11例（17.4%）；唑来膦酸组出现肝功能异常22例（36.6%），肾功能指标异常9例（15%）。两组患者的γ-谷氨酰转移酶（gamma-glutamyltransferase，GGT）水平相对基线变化差异有统计学意义（P＜0.05），肝肾功能其他指标相对基线变化的差异均无统计学意义。
表 4 两组患者治疗前后肝肾功能比较Table 4. Comparison of liver and renal function between two groups before and after treatmentIndex Denosumab group (n＝63) Zoledronic acid group (n＝60) t Pa Baseline After treatment Baseline After treatment Liver function ALT/(U·L−1) 18.51±7.58 18.12±7.69 19.18±10.35 17.35±8.38 0.20 0.838 AST/(U·L−1) 24.53±7.22 23.83±6.15 22.40±8.03 22.53±8.49 0.01 0.992 GGT/(U·L−1) 23.34±15.95 23.65±19.28 23.18±19.10 22.00±17.83 2.11 0.035 Alb/(g·L−1) 43.05±5.65 42.33±7.43 39.77±3.02* 38.95±3.00 0.36 0.718 TBil/(µmol·L−1) 12.55±5.54 12.73±8.00 11.58±4.50 12.40±4.38 0.11 0.910 Renal function Scr/(µmol·L−1) 67.15±13.60 68.75±18.53 59.63±11.16* 61.48±12.89 0.66 0.509 Urea/(mmol·L−1) 6.70±3.00 7.88±8.48 6.30±1.36 6.29±1.41 0.27 0.791 UA/(µmol·L−1) 300.35±70.30 309.83±78.44 285.13±67.93 293.43±75.14 0.15 0.883 aComparison of indices changes from baseline to after treatment between denosumab group and zoledronic acid group. ALT: alanine aminotransferase; AST: aspartate aminotransferase; GGT: gamma-glutamyltransferase; Alb: albumin; TBil: total bilirubin; Scr: serum creatinine; UA: uric acid. *P＜0.05 vs baseline in denosumab group. 2.4.2 两组患者治疗期间不良反应
结果（表5）显示：治疗期间，唑来膦酸组出现7例不良反应，地舒单抗组出现5例，均为轻度。唑来膦酸组主要不良反应为一过性上呼吸道感染样症状、发热、过敏、肢体疼痛、低钙血症等；地舒单抗组主要不良反应为低钙血症、肢体肌肉疼痛，偶见超敏反应。
表 5 两组患者治疗期间不良反应发生情况Table 5. Adverse reactions during treatment in two groups of patientsCase Combined illness Adverse reaction Therapy Outcome Relevance Zoledronic acid group Case 3 — Fever and muscle aches after taking medication Without targeted treatment Condition improved Maybe related Case 17 — Fever and chills 3 days after taking the medication Without targeted treatment Condition improved Maybe related Case 23 — Low serum potassium accompanied by calcium deficiency 1 day after medication use Potassium chloride sustained-release tablets for potassium supplementation; calcium carbonate tablets for calcium supplementation Condition improved Maybe related Case 45 Type 2 diabetes, viral hepatitis Sacrococcygeal pain 3 days after taking the medication Celebrex 200 mg orally to relieve pain Condition improved Maybe related Case 48 Brittle fractures (6 times), gastrectomy Weakness, vomiting, and diarrhea 3 days after taking the medication Calcitriol + calcium carbonate granules Condition improved Maybe related Case 52 — Fever and chills 2 days after taking the medication Physical cooling Condition improved Maybe related Case 59 — Allergy 3 days after taking the medication Loratadine 10 mg orally and compound clobetasol propionate cream to anti-allergy Condition improved Maybe related Denosumab group Case 4 Brittle fractures (4 times) Hypocalcemia (2.00 mmol/L) Without targeted treatment Condition improved Maybe related Case 15 — Hypocalcemia (1.90 mmol/L) Adjust calcium carbonate dosage Condition improved Maybe related Case 34 Gastroesophageal reflux Hypocalcemia (1.91 mmol/L) Without targeted treatment Condition improved Maybe related Case 57 High blood pressure, breast cancer Skin itching after medication use External application compound clobetasol propionate cream Condition improved Maybe related Case 62 Left ankle fracture (twice), coronary heart disease Left hip pain after medication use Adjust calcium carbonate dosage Condition improved Maybe related 3. 讨 论
随着我国人口老龄化呈现不断上升趋势，PMOP患者数量不断增加。据统计[12-13]，我国50岁以上OP人群中，女性占比高达32.1%，65岁以上女性的PMOP患病率为51.6%，PMOP总患病率为38.8%。绝经后女性体内雌激素水平与RANKL表达负相关，致使骨吸收活跃、骨量流失和骨脆性风险上升[14]。更严重的是，随着病情进展，患者可能会在日常活动中发生椎体、髋部等部位的骨折。
新型抗骨吸收药物地舒单抗的DE环可与RANK竞争性结合RANKL蛋白，抑制破骨细胞功能，增加患者的骨密度，也是目前唯一获批用于治疗骨折高风险PMOP患者的RANKL抑制剂[15]。相较于以往一线抗PMOP治疗，地舒单抗具有多种优势：（1）没有治疗平台期，可长期使用，持续提高各部位BMD；（2）暂无胃肠道不良反应报道；（3）每年只需皮下注射2次，患者的依从性高[16]；（4）可逆、特异地靶向RANKL从而抑制骨转换，不会在骨基质中沉积；（5）不经肾脏代谢，可应用于肾功能损害的患者[17]；（6）适用于肾功能差、免疫力低下患者，不增加患者感染发生[18]；（7）双膦酸盐仅对松质骨产生作用，而地舒单抗可以作用于皮质骨和松质骨，抑制皮质内重构，较双膦酸盐有更强的抗骨吸收作用。但地舒单抗在我国使用时间较短，临床数据较少。因此，本研究选取抗PMOP一线用药唑来膦酸作为对照，评估地舒单抗治疗骨折高风险PMOP的临床疗效和安全性，为PMOP治疗方案提供临床证据。
本研究结果显示，较双膦酸盐类药物，地舒单抗可显著提高PMOP患者的腰椎BMD，这与其他研究[11, 17]结论相符。此外，研究[19-21]发现，地舒单抗可大幅度降低新发骨折风险，有效改善PMOP患者的骨代谢异常，调控骨形成与骨吸收间平衡，减少骨流失，提高BMD，降低患者的骨折风险，进一步证实了地舒单抗对PMOP人群的治疗有效性。
然而，与既往研究[22-23]不同，本研究中地舒单抗较唑来膦酸未表现出对全髋和股骨颈BMD的显著提高作用。分析其原因：（1）本研究为单中心研究，可能存在潜在选择偏倚；（2）本研究仅随访1年，药物的长期疗效和安全性仍待进一步观察和评估；（3）患者对地舒单抗的依从性差异会影响其临床疗效。地舒单抗的注射间隔时间越长，全髋关节和腰椎BMD的改善越不理想[20]。本治疗方案规定需注射2次地舒单抗。受疫情影响，有7例受试者存在地舒单抗延迟注射的情况（即两剂注射间隔大于6个月），第1剂与第2剂注射的平均间隔时间为（9.13±2.63）个月，最长注射间隔为17个月。而研究[24]发现，停用该药可能会发生骨转换抑制快速逆转，导致各部位骨密度下降。而唑来膦酸仅需输注1次，不会受此影响。为避免对结果分析造成影响，本研究剔除了此类病例。临床实践中，地舒单抗延迟注射的情况难以避免，因此，临床使用地舒单抗时，医师和临床药师需关注长期用药管理，加强患者教育，督促患者及时用药、定期复查，切实提高患者对于地舒单抗的长期用药依从性，以获得更好的治疗结果。
关于地舒单抗注射液的安全性，临床预测其受众范围广，而本研究数据显示，部分患者接受地舒单抗治疗后，出现轻度肝肾功能损伤。地舒单抗为单克隆抗体，一般不经肝、肾代谢清除、排泄，其药物代谢动力学和药效不受肝肾功能的影响。因此，本组PMOP患者肝肾功能损伤可能与高龄，合并糖尿病、心血管疾病等基础疾病有关。例如，合并糖尿病可能导致肾功能减退，高血压患者未有效控制血压也可损伤肝肾功能。此外，基础疾病患者需联合使用多种药物，如糖尿病患者口服二甲双胍、格列吡嗪、格列美脲等磺脲类药物，高脂血症患者服用他汀类药物等，也可能导致肝肾功能损伤。
从药物经济学角度，使用地舒单抗治疗的成本效益较唑来膦酸更具有优势[25]，同时其不良反应发生率较唑来膦酸更低[26]。因此，地舒单抗是治疗PMOP患者的较好选择。未来，本课题组将开展多中心大样本量研究，以探讨PMOP患者远期用药的有效性及安全性。
综上所述，地舒单抗注射液对骨折高风险PMOP的临床疗效好，能提高患者腰椎BMD，并改善患者骨代谢指标，安全性较高，是治疗骨折高风险PMOP的理想选择。
伦理声明 本研究经医院伦理委员会批准（2022SL047），患者及家属知情并同意参与本研究。
利益冲突 所有作者声明不存在利益冲突。
作者贡献 周婧、侯幸赟：研究设计、研究实施、数据分析、文章撰写；刘婷婷：研究实施、数据收集；郑骄阳：研究指导、文章修改。
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表 1 两组PMOP患者一般资料比较
Table 1 Comparison of general data between the two groups of patients with PMOP
Index Denosumab group (n＝63) Zoledronic acid group (n＝60) t P Age/year 66.69±7.58 67.75±7.22 −1.06 0.29 Menopausal age/year 50.23±3.92 49.77±2.89 0.80 0.43 BMI/(kg·m−2) 21.69±4.50 21.57±2.94 0.13 0.89 Serum calcium/(mmol·L−1) 2.28±0.12 2.27±0.10 1.01 0.31 Serum phosphorus/(mmol·L−1) 1.20±0.17 1.23±0.15 −0.97 0.33 25-(OH)D/(ng·mL−1) 25.77±8.46 23.25±8.83 1.48 0.14 β-CTX/(ng·mL−1) 0.24±0.16 0.26±0.18 −0.96 0.34 OC/(ng·mL−1) 13.65±5.28 14.64±10.05 −0.83 0.41 PTH/(ng·mL−1) 43.67±23.73 43.63±19.01 0.64 0.52 ALP/(U·L−1) 72.60±21.89 75.05±24.50 −0.16 0.87 T score of lumbar vertebrae (L1-4) −2.87±0.75 −2.77±0.93 −0.06 0.95 T score of femoral neck −2.23±0.63 −2.21±0.75 −1.18 0.24 T score of total hip −2.21±0.81 −2.18±1.17 −0.34 0.73 PMOP: postmenopausal osteoporosis; BMI: body mass index; 25-(OH)D: 25-hydroxy-vitamin D; β-CTX: β-C-terminal telopeptide of type I collagen; OC: osteocalcin; PTH: parathyroid hormone; ALP: alkaline phosphatase. 
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表 2 两组患者治疗前与治疗1年后骨密度比较
Table 2 Comparison of bone mineral density between the two groups at baseline and one year after treatment
Group T score of L1-4 T score of femoral neck T score of total hip Denosumab group (n＝63) Baseline −2.87±0.75 −2.23±0.63 −2.21±0.81 After treatment −2.48±0.92 −2.20±0.62 −2.13±0.81 t −5.78 −0.44 −1.91 Pa ＜0.001 0.662 0.030 Zoledronic acid group (n＝60) Baseline −2.77±0.93 −2.21±0.75 −2.18±1.17 After treatment −2.49±0.92 −2.03±0.74 −1.83±0.87 t −3.24 −2.21 −3.04 Pb ＜0.001 0.023 0.004 Change from baseline Denosumab group 0.41±0.68 0.03±0.38 0.07±0.39 Zoledronic acid group 0.14±0.86 0.36±0.92 0.35±0.83 t 2.11 −2.64 −2.20 Pc 0.037 0.011 0.029 aComparison of BMD T scores in the denosumab group between baseline and one year after treatment. bComparison of BMD T scores in the zoledronic acid group between baseline and one year after treatment. cComparison of BMD T scores change from baseline to one year after treatment between denosumab group and zoledronic acid group. BMD: bone mineral density.
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表 3 两组患者治疗前与治疗1年后骨代谢指标比较
Table 3 Comparison of bone metabolism between the two groups at baseline and one year after treatment
Group Serum calcium/
(mmol·L−1)Serum phosphorus/
(mmol·L−1)25-(OH)D/
(ng·mL−1)β-CTX/
(ng·mL−1)OC/
(ng·mL−1)PTH/
(ng·mL−1)ALP/
(U·L−1)Denosumab group
(n＝63)Baseline 2.28±0.12 1.20±0.17 25.77±8.46 0.24±0.16 12.65±5.28 43.67±23.73 72.61±21.89 After treatment 2.31±0.14 1.19±0.18 29.56±11.53 0.12±0.15 11.17±10.37 36.42±15.38 63.34±23.89 t −1.31 0.35 −2.32 3.39 0.86 1.94 2.42 Pa 0.048 0.749 0.030 0.019 0.121 0.031 0.016 Zoledronic acid group
(n＝60)Baseline 2.27±0.10 1.23±0.15 24.24±8.94 0.25±0.16 11.93±5.10 44.24±15.22 75.05±24.50 After treatment 2.22±0.13 1.17±0.18 26.78±9.46 0.20±0.09 9.13±2.23 42.88±17.01 65.50±20.41 t 2.31 1.85 −2.11 1.75 3.88 0.58 4.15 Pb 0.023 0.554 0.041 0.082 ＜0.001 0.045 ＜0.001 Change from baseline
beween the two groupst 1.97 1.39 0.11 1 0.12 1.44 0.16 Pc 0.051 0.167 0.914 0.319 0.907 0.149 0.871 aComparison of bone metabolism in the denosumab group between baseline and one year after treatment. bComparison of bone metabolism in the zoledronic acid group between baseline and one year after treatment. cComparison of bone metabolism change from baseline to one year after treatment between denosumab group and zoledronic acid group. 25-(OH)D: 25-hydroxy-vitamin D; β- CTX: β-C-terminal telopeptide of type I collagen; OC: osteocalcin; PTH: parathyroid hormone; ALP: alkaline phosphatase.
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表 4 两组患者治疗前后肝肾功能比较
Table 4 Comparison of liver and renal function between two groups before and after treatment
Index Denosumab group (n＝63) Zoledronic acid group (n＝60) t Pa Baseline After treatment Baseline After treatment Liver function ALT/(U·L−1) 18.51±7.58 18.12±7.69 19.18±10.35 17.35±8.38 0.20 0.838 AST/(U·L−1) 24.53±7.22 23.83±6.15 22.40±8.03 22.53±8.49 0.01 0.992 GGT/(U·L−1) 23.34±15.95 23.65±19.28 23.18±19.10 22.00±17.83 2.11 0.035 Alb/(g·L−1) 43.05±5.65 42.33±7.43 39.77±3.02* 38.95±3.00 0.36 0.718 TBil/(µmol·L−1) 12.55±5.54 12.73±8.00 11.58±4.50 12.40±4.38 0.11 0.910 Renal function Scr/(µmol·L−1) 67.15±13.60 68.75±18.53 59.63±11.16* 61.48±12.89 0.66 0.509 Urea/(mmol·L−1) 6.70±3.00 7.88±8.48 6.30±1.36 6.29±1.41 0.27 0.791 UA/(µmol·L−1) 300.35±70.30 309.83±78.44 285.13±67.93 293.43±75.14 0.15 0.883 aComparison of indices changes from baseline to after treatment between denosumab group and zoledronic acid group. ALT: alanine aminotransferase; AST: aspartate aminotransferase; GGT: gamma-glutamyltransferase; Alb: albumin; TBil: total bilirubin; Scr: serum creatinine; UA: uric acid. *P＜0.05 vs baseline in denosumab group.
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表 5 两组患者治疗期间不良反应发生情况
Table 5 Adverse reactions during treatment in two groups of patients
Case Combined illness Adverse reaction Therapy Outcome Relevance Zoledronic acid group Case 3 — Fever and muscle aches after taking medication Without targeted treatment Condition improved Maybe related Case 17 — Fever and chills 3 days after taking the medication Without targeted treatment Condition improved Maybe related Case 23 — Low serum potassium accompanied by calcium deficiency 1 day after medication use Potassium chloride sustained-release tablets for potassium supplementation; calcium carbonate tablets for calcium supplementation Condition improved Maybe related Case 45 Type 2 diabetes, viral hepatitis Sacrococcygeal pain 3 days after taking the medication Celebrex 200 mg orally to relieve pain Condition improved Maybe related Case 48 Brittle fractures (6 times), gastrectomy Weakness, vomiting, and diarrhea 3 days after taking the medication Calcitriol + calcium carbonate granules Condition improved Maybe related Case 52 — Fever and chills 2 days after taking the medication Physical cooling Condition improved Maybe related Case 59 — Allergy 3 days after taking the medication Loratadine 10 mg orally and compound clobetasol propionate cream to anti-allergy Condition improved Maybe related Denosumab group Case 4 Brittle fractures (4 times) Hypocalcemia (2.00 mmol/L) Without targeted treatment Condition improved Maybe related Case 15 — Hypocalcemia (1.90 mmol/L) Adjust calcium carbonate dosage Condition improved Maybe related Case 34 Gastroesophageal reflux Hypocalcemia (1.91 mmol/L) Without targeted treatment Condition improved Maybe related Case 57 High blood pressure, breast cancer Skin itching after medication use External application compound clobetasol propionate cream Condition improved Maybe related Case 62 Left ankle fracture (twice), coronary heart disease Left hip pain after medication use Adjust calcium carbonate dosage Condition improved Maybe related
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