| 一般情况 | |
|---|---|
 | 品种：中毛猫 |
| 年龄：10岁 | |
| 性别：雌 | |
| 是否绝育：是 | |
| 诊断：不全性骨折 | |
01 主诉及病史
右后肢跛行2个月。
该猫在1岁时曾因持续不明原因高钙血症而被诊断为特发性高钙血症（IHC），医生给它开了泼尼松龙和阿仑膦酸钠来控制病情，并根据血钙水平逐渐调整用药剂量。最后一次有记录的IHC发生在确诊后的3年。目前的药物包括阿仑膦酸钠（10 mg/周）、泼尼松龙（2.5 mg/日）和加巴喷丁（100 mg/8小时）。
02 检查
右后肢中度负重跛行，跗关节中度过度屈曲。右跗关节活动范围正常，可触及轻微捻发音。X光检查发现右侧小腿骨完全横向骨折，骨折端有轻度移位和中度硬化，骨折部位活动度极小（下图）。虽然建议进行手术治疗，但由于随着时间的推移情况有所好转，主人选择了非手术治疗。
6周后，该猫因左后肢急性非负重性跛行再次就诊。检查证实该猫左后肢无负重跛行，右后肢轻度负重跛行，并伴有持续性跗骨外翻。X光片显示，左侧胫骨近端骨骺和腓骨完全横向骨折（下图a）。右侧小腿骨的骨折仍处于静止状态，骨折线持续存在，骨质硬化，活动度极小（下图b）。除总钙含量略低（8.2 mg/dL，区间：9.1-10.7）外无明显异常，钙（5.5 mg/dL，区间：5.1-6.0）和磷（5.3 mg/dL，区间：2.7-5.7）均在正常范围内。
03 手术
通过内侧入路进行了左侧胫骨切开复位和内固定术。放置了一块 1.5 mm的六孔加压钢板用于纠正骨折。内侧放置了一块1.5/2.0 mm的T型七孔加压钢板。术后X光片显示解剖对位、植入位置适当（下图）。虽然考虑过进行骨活检，但由于骨质较脆，可用于修复的骨量较少，因此没有进行。
04 预后
术后住院期间使用美沙酮（0.2 mg/kg IV，q6h）镇痛。第二天出院，使用金刚烷胺（2.9 mg/kg PO q24h）以增加镇痛效果，并继续服用目前的药物（泼尼松龙 2.5 mg q24h，加巴喷丁 100 mg q8h），但停用阿仑膦酸钠。 在术后17个月随访时，对骨盆、左侧胫骨、右侧胫骨（下图）和双侧跗骨进行了X光检查，未发现骨折的迹象。
05 讨论
双膦酸盐（Bisphosphonate，BP）在人类医学中的应用非常广泛，它在治疗骨质疏松症、恶性肿瘤高钙血症、骨转移和成骨不全等方面的研究很多[1-3]。在兽医领域，BP在治疗甲状旁腺功能亢进、特发性高钙血症（Idiopathic hypercalcemia，IHC）、继发性高钙血症、牙齿吸收和肿瘤性骨痛等方面越来越受到青睐[3-10]。
BP是强效的破骨细胞抑制剂，可减少破骨细胞诱导的骨吸收和重塑[1,11]。最广泛使用的BP含氮，包括阿仑膦酸盐、利塞膦酸盐和唑来膦酸盐。这些化合物与骨结合，经内吞进入破骨细胞，并通过抑制多种酶（主要是法尼酰二磷酸合酶）阻碍代谢途径[12]。这种代谢途径能够破坏破骨细胞参与骨吸收的活动[12]。破骨细胞凋亡也可能发生，但并非为抑制骨吸收的必要条件[13,14]。
在人类文献报道的使用BP所产生的不良反应中，非典型应力性骨折或不全性骨折最受关注[15-26]。不全性骨折发生在没有外伤的情况下，当生理应力作用在异常骨骼上时[27,28]，而应力性骨折则是指当重复力作用在正常骨骼上时造成的损伤[29,30]。
人类使用BP可能引起的其他并发症包括颌骨骨坏死[31-34]、肌肉骨骼疼痛[35]、心房颤动[36-38]和食道刺激[2]。在兽医领域，大多数BP的使用都是短暂的，因此尚未发现常见的副作用。然而，长期使用BP治疗与一只猫的双侧非典型髌骨骨折和颌骨骨坏死有关[9,39]。
本病例报告描述了一只服用阿仑膦酸钠控制IHC的猫在没有外伤的情况下发生非典型骨折。这是仅有的第二例BP相关性猫骨折病例，也是第一例通过手术治疗骨折并进行长期随访的病例。
在长期服用BP的人类患者身上，可通过X光诊断出即将发生的骨折，进而发展为完全性骨折。这些应力反应通常是皮质内硬化或局灶性不透明增加的区域，但也可能只有皮质的轻微隆起[18,22]。有报告称，一只疑似小腿骨应力性骨折的猫也出现了类似的变化[42]。
本病例报告中详细描述的这只猫在左侧胫骨骨折前6周接受了左侧胫骨的X光检查，作为右侧骨折常规检查的一部分。但当时没有发现与左后肢有关的异常。回过头看，在6周前的左胫骨近端骨皮质处发现了应力反应，这与随后的胫骨骨折部位相符（下图）。
由于识别此类放射学特征有助于预测即将发生的骨折，因此可能需要对长期服用BP的猫进行连续的放射学监测。由于微损伤的积累导致骨折需要数年时间，而微裂缝密度与BP治疗持续时间呈线性关系，因此此类监测的时限仍不确定[43]。
由于两只患有BP相关骨折的猫都是在服药8年后才出现骨折，而人类往往在服药3-9年后才出现骨折[17,21,26]，因此可能不需要立即开始监测。在开始BP治疗时获得基线X线照相结果并考虑在5年后每年进行X线检查可能是一个合理的建议。如果出现疼痛或跛行等临床症状，则应更早开始监测。
目前尚不清楚猫体内BP在骨骼中的半衰期，但由于人（10年）[44]和狗（3年）[45]的半衰期较长，因此在停止治疗后的数年内仍需继续监测。在本报告详述的这只猫中，术后17个月进行的放射线监测显示没有骨折反应的迹象。
与在人类中的使用相比，在动物中使用BP的研究并不多，但有病例报告和回顾性研究描述了BP的使用和相关并发症[3-6,10,46-50]。在狗的治疗中，BP通常用于短期治疗，如用于引起高钙血症的中毒和骨肿瘤的姑息治疗，目前还没有BP相关骨折的报告[3,4,48,49]。
狗曾被用于评估BP对人类副作用的研究，但这些研究的治疗期相对较短[51-53]。这就降低了出现骨折的可能性，因为在其他物种中，不完全性骨折往往是在多年治疗后才出现的[17,21,26]。
在兽医学中，猫科动物IHC是长期使用BP的最常见适应症[4-6,10]。虽然对猫科动物IHC长期治疗病例的长期随访很少，因此不良反应的发生率尚不清楚。除了以前的报告[7]外，本报告还指出，应提醒饲养者注意不完全性骨折形成的风险。
长期的糖皮质激素治疗会减少骨转换，已被确定为不完全性骨折形成的一个危险因素[20]。长期服用类固醇会抑制家兔骨折的愈合[54]，而且已知类固醇会降低成骨细胞的活性，从而减少基质的合成[55-58]。应该考虑的是，长期泼尼松龙治疗可能会夸大阿仑膦酸钠在这只猫身上的作用，无论是在骨折易感性方面还是在延迟愈合方面都是如此。
在已发表的唯一一例与BP相关的猫骨折病例报告中，一只缅因猫因长期接受阿仑膦酸钠治疗以防止牙齿吸收进展，导致双侧髌骨骨折[7]。该猫的长骨皮质明显比对照组的厚[7]。根据之前描述的测量结果[7]，本报告中详细描述的这只猫的胫骨髓腔直径是通过每组射线照片计算得出的，但没有证据表明髓腔变窄或皮质变厚。
在人类[17,20,21]和本病例中都可以观察到接受BP治疗的患者不全性骨折延迟愈合的情况。在这只猫中，胫骨骨折修复后停止了阿仑膦酸钠治疗，以降低发生其他骨折的风险，并促进目前骨折的愈合。然而，根据之前对人类进行的一项研究表明，可能是由于阿仑膦酸钠的半衰期较长，停止阿仑膦酸钠治疗的患者与继续使用阿仑膦酸钠治疗的患者在骨折愈合方面没有差异[20]。
由于BP相关骨折的猫数量极少，因此无法就是否应该停用BP以降低未来骨折风险提出明确建议。不过，鉴于BP的半衰期较长，正如在狗和人身上的报道一样[44,45]，停用BP不太可能对已经发生的骨折愈合产生重大影响。
由于预计骨折愈合时间较长，因此应相应地制定计划。考虑到猫胫骨骨折稳定后钢板弯曲的风险[63]，使用正交钢板固定[64]或使用角度稳定的交锁钉[65]的风险较低，因此在BP相关胫骨骨折病例中应考虑后两种方法。本病例中的正交钢板植入术效果非常理想，在术后17个月未出现与植入物相关的并发症。
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