鲑鱼降钙素治疗骨质疏松骨折专家共识解读黄公怡教授.doc

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1、鲑鱼降钙素（密盖息）治疗骨质疏松骨折专家共识解读骨质疏松骨折的临床特点骨质疏松性骨折属脆性骨折，为完全性骨折，是骨质疏松最严重的后果。由于骨强度下降，轻微创伤或日常活动即可发生。常见的骨折部位是脊柱、髋部和桡骨远端。骨折后再次骨折的风险明显增大。骨折内固定的牢固程度差、易松动。骨折愈合过程迟缓。老年人群中患病率高，其并发症多更增加了治疗的复杂新和危险性，严重影响老年人的身心健康和生活质量，其致残率、致死率高。在治疗骨折的同时，应积极治疗骨质疏松(1)骨折后急性骨丢失的发生机制及危害目前多数学者比较一致地认为，运动及肢体生理负荷减少是急性制动后骨丢失的始动因素。制动或卧床使患者的肢体和躯干骨处于

2、非承重状态，同时四肢及躯干运动量明显减少，肌肉收缩频率及幅度减少。肢体骨骼的负荷下降首先影响骨的重建系统，进而影响钙的内环境调节系统，乃至自律神经系统，最终再次影响骨的重建过程，力学与生物学双重影响导致了废用性骨质疏松的发生与发展(2)。骨质疏松骨折手术内固定最主要的并发症是植入物与假体的松动和脱落。而且这种情况可以发生在手术过程中或之后的康复过程中。严重者导致手术失败需再次手术。总之， 急性骨丢失继发废用性骨质疏松，是导致下列并发症发生率进一步增高的主要原因之一：1. 骨质量降低导致骨折愈合延迟；2. 植入物周围骨溶解加剧导致植入物松动；3. 延长卧床期，并发症发生率、死亡率增高；4. 术中

3、医源性骨折；5. 术后骨折再发生率增高。鲑鱼降钙素治疗骨质疏松骨折中的应用1. 鲑鱼降钙素能够逆转骨折制动后的急性骨丢失证据一：制动后急性骨丢失具有大量、快速和持续等特点。据资料统计，患者在制动后每周骨丢失约占骨总量的1%，该数值相当于正常情况下一个人一年的“生理性骨丢失量” 。612个月内全身骨密度显著降低达510%，相当于正常个体5年的骨丢失量Petersen等人发现，髋部骨折后患者各部位骨密度和骨矿含量均出现降低。该研究中，采用双能X线吸收仪分别在骨折后、3个月和6个月时测定患者患侧腿和健侧腿等部位的骨密度和骨矿含量。结果显示， 3个月时伤侧腿股骨径骨密度降低达9.6%（CR：-10.2

4、%-3.5%)， 6个月股骨颈部位骨密度降低达14%，而在3个月时，胫骨近端骨密度降低竟达22%，在6个月时降低达19%。这一研究结果充分证明了骨折后急性骨丢失的存在。证据二：Tsakalakos N(4)等选择了40例存在新发髋部骨折的老年患者，所有患者在入院后1周接受外科内固定手术治疗，治疗后平均分为治疗组和对照组。其中治疗组患者从入院后立即进行围手术期治疗，即开始接受每日鲑鱼降钙素100IU针剂肌注治疗2周，并联用每日1,200mg钙剂治疗，安慰剂组患者单纯应用每日1,200mg钙剂。自研究开始即对两组患者的血清及尿的骨生化标记物进行监测。证据三：T.karachalios等选择了50位

5、患有股骨颈骨折、7080岁之间的绝经后妇女，分为两组，其中A组给予200IU鲑鱼降钙素鼻喷剂3个月，B组为安慰剂鼻喷剂，结果显示受伤后15天和45天时鲑鱼降钙素组患者的尿羟脯氨酸显著降低。证据四：是反映骨吸收的重要生化指标。Lyritis等人的研究中应用鲑鱼降钙素治疗患者的尿HOP/Cr比值在治疗4周期间快速并且持续下降。在治疗第一周即达到与基线相比的显著改善，此后这一比值持续下降，提示鲑鱼降钙素能够有效对抗制动后骨吸收。2. 鲑鱼降钙素有效控制骨折后疼痛，提高康复水平鲑鱼降钙素作用于中枢及外周神经系统，有效地缓解骨折造成的急性疼痛。临床研究显示(5)： 鲑鱼降钙素能够在12周内迅速发挥镇痛效

6、果，患者在用药后疼痛VAS评分和安慰剂组相比有显著的下降。镇痛作用在四周内持续显著发挥，缓解患者的骨痛。通过良好的镇痛作用，鲑鱼降钙素帮助患者提前3周下地活动；在无痛下，增进和改善了患者康复水平，在显著改善患者的生活质量的同时有效的减少由卧床引起的废用性骨丢失，降低再发骨折的风险。3. 鲑鱼降钙素改善骨密度和骨质量T.karachalios(2)研究结果显示， 在给药后3个月时降钙素组患者的腰椎BMD增高了3.14%，而安慰剂组患者下降了4.52%；12个月时降钙素组患者的腰椎BMD增高了2.04%，而安慰剂组则下降到10.71%。无论是在3个月时还是在一年后，两组间患者的腰椎BMD变化均有显

7、著的统计学意义（分别为p0.03和 p 0.002）。 在3个月时鲑鱼降钙素组的患者股骨颈BMD增加了2.52%，12个月时增加了3.63%。而安慰剂组的患者的股骨颈BMD分别降低了7.4%和9.2%。在3个月和12个月时两组之间都具有显著的统计学差异，p0.05。4. 鲑鱼降钙素可以降低骨折发生率与再骨折发生率PROOF研究(6)是在美国42个中心和英国5个中心进行的，共入选了1,255位，平均年龄为68岁的绝经后妇女，这些患者大多数曾患有15处椎体骨折。患者入选后随机分为四组，分别接受100、200和400单位等不同剂量的鲑鱼降钙素治疗，对照组患者接受安慰剂治疗。四组患者均接受1,000m

8、g钙剂和维生素D400IU辅助治疗。 在安慰剂组203例患者中，发生椎体骨折的百分比为29.6%，而在鲑鱼降钙素治疗组患者中，发生椎体骨折的百分比仅为19.3%。研究数据显示，对于既往曾发生过15次椎体骨折的患者，鲑鱼降钙素能够显著降低患者骨折危险性达36%。 之后，PROOF研究小组又开展了进一步的分析，以70岁或75岁为界将病人细分为两组。 结果发现，在大于70岁的238例患者中，鲑鱼降钙素200IU鼻喷剂治疗后仅有19.4%的患者发生骨折，而安慰剂组有33.7%的患者发生骨折，两组间具有显著统计学差异，P=0.012，因此每日鼻喷鲑鱼降钙素200IU可以减少椎体骨折危险53%。在大于75

9、岁的105例患者中，鲑鱼降钙素200IU鼻喷剂治疗后仅有20.7%的患者发生骨折，而安慰剂组发生骨折的患者数高达40.4%，两组间同样具有显著性统计学差异，P=0.028，在大于75岁的患者亚组中，200IU鲑鱼降钙素鼻喷剂治疗使椎体骨折危险减少62%。5. 实验研究显示：鲑鱼降钙素可能有益于骨折愈合鲑鱼降钙素不仅能够抑制破骨细胞的活性， 田庆显(7)等的动物试验证明，它还能够促进成骨细胞的增殖。李晓林等(8)的研究表明鲑鱼降钙素能够促进矿化，加快骨痂的形成。骨痂的组织学观察显示，在骨折后早期鲑鱼降钙素治疗组大鼠纤维性骨痂和软骨性骨痂的数量显著高于对照组；在骨折后第7周，软骨性骨痂被骨性骨痂取

10、代的过程中，鲑鱼降钙素治疗组形成的骨小梁较粗、致密排列与应力方向一致，而对照组仍可见较多的软骨性骨痂，向骨性骨痂的转换过程缓慢。研究证明鲑鱼降钙素可能有益于骨折的愈合。6. 鲑鱼降钙素用于骨质疏松骨折治疗的推荐方案1) 鲑鱼降钙素用于骨折急性期治疗的国外用药经验研究组织者病例数用药剂量给药方法用药时间N.tsakalakos(4)69人100IU/QD肌注14天Lyritis(5)100人200IU/QD鼻喷28天Lyritis(9)40人200IU/QD鼻喷28天2) 鲑鱼降钙素用于骨折愈合期治疗的国外用药经验研究组织者病例数用药剂量给药方法用药时间Huusko (9)229200IU/QD

11、鼻喷3个月T.karachalios(2)50200IU/QD鼻喷3个月3) 根据国内患者的实际情况，我们推荐的用法为： 急性期：骨折后，50100IU/d 缓慢静注或分次肌注，连续用药24周; 骨折愈合期： 鼻喷剂给药，200IU/Qd或Qod,疗程个月注：骨质疏松并发骨折往往提示骨质量下降的程度已经很严重，因此建议在骨折急性期治疗成功后，要积极的针对原发病制定长期规范的后续治疗方案，降低患者再次发生骨折的风险。 总 结1. 鲑鱼降钙素能够抑阻骨折制动后的急性骨丢失鲑鱼降钙素能够有效逆转骨质疏松骨折患者在急性期制动状态和手术后引起的进行性骨丢失2. 鲑鱼降钙素有效缓解骨折后疼痛鲑鱼降钙素能够

12、作用于中枢及外周神经系统，有效的缓解骨折造成的急性疼痛。3. 鲑鱼降钙素可以改善骨密度和骨质量4. 鲑鱼降钙素可以降低骨折发生率与再骨折发生率5. 鲑鱼降钙素可能有益骨折愈合参考文献1. 中华医学会骨质疏松骨折诊疗指南2005.9 2. T.karachalios et al. The effects of calcitonin on acute bone loss after pertrochanteric fractures: A PROSPECTIVE, RANDOMISED TRIAL. J Bone Joint Surg (Br), 2004;86-B:350-8We investi

13、gated the effect of calcitonin in the prevention of acute bone loss after a pertrochanteric fracture and its ability to reduce the incidence of further fractures in the same patient. Fifty women aged between 70 and 80 years who had a pertrochanteric fracture of the hip were randomly allocated to gro

14、up A (200 IU of nasal salmon calcitonin daily for three months) or group B (placebo). Patients in group A showed a significantly higher level of total alkaline phosphatase and osteocalcin on the 15th day after injury and a significantly higher level of bone alkaline phosphatase on the 90th day after

15、 surgery. These patients also had significantly lower levels of urinary C-telopeptide (CrossLaps) on the 15th, 45th and 90th days after injury and lower levels of urinary hydroxyproline on the 15th and 45th days after injury. Patients in group A had significantly higher bone mineral density at all r

16、ecorded sites except the greater trochanter at three months and one year after operation. After a four-year period of clinical observation, five patients (24%) in group B sustained a new fracture, in four of whom (20%) it was of the contralateral hip. Our findings show that calcitonin reduces acute

17、bone loss in patients with pertrochanteric fractures and may prevent the occurrence of new fractures of the contralateral hip in the elderly. 3. Peichl P, Griesmacher A, et al. Clinical outcome of salmon calcitonin nasal spray treatment in postmenopausal women after total hip arthroplasty. Gerontolo

18、gy. 2005 Jul-Aug; 51(4):242-52. OBJECTIVE: The increasing rate of hip fractures is giving rise to a number of socio-economic problems for the aging community. In addition to being unable to resume their previous living habits, many patients fail to achieve full functional recovery after the fracture

19、s. Total hip arthroplasty (THA) is a successful operation for the majority of patients with all forms of hip fractures, being performed increasingly often throughout the world. Revision rates for THA range up to 20% per year. Aseptic loosening is the reason for 75% of the revisions. An additional pr

20、oblem post-THA is the rate of heterotopic soft tissue calcification after THA, resulting in severely impaired function, pain, and a reduced range of hip movement. SUBJECTS: In an open study, 37 women who had undergone cementless THA after accidental hip fractures were treated twice daily with 200 IU

21、 of salmon calcitonin nasal spray for 12 months. Simultaneously the patients received one bag of 1,000 mg calcium plus 880 IU vitamin D daily throughout the treatment period of 1 year. A parallel group of 38 women with a similar clinical status in terms of hip fractures and cementless THA were treat

22、ed with only one bag of 1,000 mg calcium plus 880 IU vitamin D daily through the treatment period. RESULTS: The results of this 12-month clinical trial show that 200 IU of salmon calcitonin nasal spray per day significantly improves the clinical outcome of postmenopausal elderly women following THA.

23、 Treatment with a salmon calcitonin nasal spray significantly reduces bone turnover, loss of bone density, and pain. The functional status of the patients was improved and the risk of falling reduced by rehabilitation during the observation period of 12 months. Additionally, calcitonin promoted the

24、repair of hip fractures and was associated with a significantly lesser rate of refractures as well as periprosthetic ossifications. CONCLUSION: The increasing revision rate for THA during the first year and the patients problem of resuming their previous living habits are the main foci of our study.

25、 Calcitonin nasal spray seems to cause few side effects. The additive treatment appears to improve the clinical outcome of THA in elderly postmenopausal women. 4. Tsakalakos N, Magiasis B, Tsekoura M, Lyritis G. The effect of short-term calcitonin administration on biochemical bone markers in patien

26、ts with acute immobilization following hip fracture. Osteoporos Int. 1993 Dec; 3(6):337-40.The effect of salmon calcitonin on changes in mineral metabolism was studied in 40 elderly patients with recent hip fracture. All patients underwent surgery (internal fixation) 1 week after admission and were

27、randomly divided into two equal groups: group A, which received no treatment, and group B, which received 100 IU/day salmon calcitonin intramuscularly for 2 weeks starting on admission. Blood and 24-h urine parameters of mineral metabolism were measured on admission and at the end of weeks 1 and 2.

28、No intra- or intergroup changes in serum calcium, phosphorus or alkaline phosphatase were observed. At the end of week 2 biochemical markers of bone resorption (urinary calcium and hydroxyproline) had significantly increased in group A and significantly decreased in group B, indicating a reduction i

29、n bone resorption in group B. Urinary phosphorus had also increased in group B, possibly due to the phosphaturic effect of calcitonin. It is concluded that immobilization resulting from a hip fracture, and possibly surgery itself, causes significant changes in biochemical markers of bone resorption.

30、 Calcitonin successfully reverses these changes and may also be effective in preventing subsequent bone loss, particularly in patients who cannot be remobilized immediately.5. Lyritis GP, Paspati I, et al. Pain relief from nasal salmon calcitonin in osteoporotic vertebral crush fractures. A double b

31、lind, placebo-controlled clinical study. Acta Orthop Scand Suppl. 1997 Oct; 275: 112-4.We examined the analgesic effect of nasal salmon calcitonin in patients with acute pain due to recent, nontraumatic osteoporotic vertebral crush fractures. 32 men and 68 postmenopausal women were studied using a p

32、rospective, double-blind, placebo-controlled clinical design. Men and women taking 200 IU of nasal salmon calcitonin daily for a period of 28 days had a dramatic decrease of spinal pain. This analgesic effect was accompanied by early mobilization and gradual restoration of the locomotor functions, s

33、uch as sitting, standing and walking. Patients receiving the placebo nasal spray remained in bed for almost the entire period of observation. The consumption of high doses of paracetamol did not help placebo patients to get out of bed during the 4 weeks of hospitalization. Nasal salmon calcitonin an

34、d early mobilization also reduced hydroxyproline excretion, thus preventing massive bone loss during the period of bedrest.6. Chesnut CH 3rd, Silverman S, Andriano K, et al. A randomized trial of nasal spray salmon calcitonin in postmenopausal women with established osteoporosis: the prevent recurre

35、nce of osteoporotic fractures study. Am J Med, 2000, 109:267-276.PURPOSE: We conducted a 5-year, double-blind, randomized, placebo-controlled study to determine whether salmon calcitonin nasal spray reduced the risk of new vertebral fractures in postmenopausal women with osteoporosis.SUBJECTS AND ME

36、THODS: A total of 1,255 postmenopausal women with established osteoporosis were randomly assigned to receive salmon calcitonin nasal spray (100, 200, or 400 IU) or placebo daily. All participants received elemental calcium (1,000 mg) and vitamin D (400 IU) daily. Vertebral fractures were assessed wi

37、th lateral radiographs of the spine. The primary efficacy endpoint was the risk of new vertebral fractures in the salmon calcitonin nasal spray 200-IU group compared with the placebo group.RESULTS: During 5 years, 1,108 participants had at least one follow-up radiograph. A total of 783 women complet

38、ed 3 years of treatment, and 511 completed 5 years. The 200-IU dose of salmon calcitonin nasal spray significantly reduced the risk of new vertebral fractures by 33% compared with placebo 200 IU: 51 of 287, placebo: 70 of 270, relative risk (RR) = 0.67, 95% confidence interval (CI): 0.47 to 0.97, P

39、= 0.03. In the 817 women with one to five prevalent vertebral fractures at enrollment, the risk was reduced by 36% (RR = 0.64, 95% CI: 0.43 to 0.96, P = 0.03). The reductions in vertebral fractures in the 100-IU (RR = 0.85, 95% CI: 0.60 to 1.21) and the 400-IU (RR = 0.84, 95% CI: 0.59 to 1.18) group

40、s were not significantly different from placebo. Lumbar spine bone mineral density increased significantly from baseline (1% to 1.5%, P 0.01) in all active treatment groups. Bone turnover was inhibited, as shown by suppression of serum type-I collagen cross-linked telopeptide (C-telopeptide) by 12%

41、in the 200-IU group (P 0.01) and by 14% in the 400-IU group (P 0.01) as compared with placebo.CONCLUSION: Salmon calcitonin nasal spray at a dose of 200 IU daily significantly reduces the risk of new vertebral fractures in postmenopausal women with osteoporosis.7. 田庆显，黄公怡。降钙素对小鼠成骨细胞增殖及OPGRANKL表达的影响。

42、骨质疏松和骨矿盐疾病基础与临床。2004年9月第3卷第3期8. 李晓林，等。鲑鱼降钙素对骨质疏松大鼠骨折愈合的影响。中国骨质疏松杂志2003(5):111-1159. Lyritis GP, Ioannidis GV, et al. Analgesic effect of salmon calcitonin suppositories in patients with acute pain due to recent osteoporotic vertebral crush fractures: a prospective double-blind, randomized, placebo-c

43、ontrolled clinical study. Clin J Pain. 1999 Dec; 15(4):284-9.OBJECTIVE: To evaluate the analgesic efficacy of calcitonin suppositories (200 IU) in comparison with bed rest and paracetamol tablets, as a rescue analgesic. DESIGN: A prospective, double-blind, randomized, placebo-controlled, clinical tr

44、ial. PATIENTS: Forty patients (8 men and 32 postmenopausal women), who had recently (within the last 5 days) suffered a nontraumatic osteoporotic vertebral fracture. SETTING AND INTERVENTIONS: All patients were admitted to the hospital, divided randomly into two groups and received either one calcit

45、onin or placebo suppository once a day, respectively, for 28 days. All patients were allowed to take paracetamol tablets (500 mg), with a maximum dose of six tablets daily. OUTCOME MEASURES: Spinal pain evaluation was performed at the beginning of the study (before the initiation of treatment) and t

46、hen daily until the end of the study (day 28) using the Huskinssons visual analog scale (VAS) and a painmeter device, by direct pressure on the fractured vertebra. Pain was evaluated with the patients attempting or performing four different locomotor functions, e.g., bed rest, sitting, standing, and

47、 walking functions. Biochemical urine and plasma measurements were carried out before the initiation of treatment and on days 14 and 28. RESULTS: All calcitonin-treated patients experienced an overall statistically significant (all p values 0.001) decrease of spinal pain as assessed by the VAS and t

48、he painmeter device. Pain relief allowed for early mobilization and the gradual restoration of the locomotive functions in the calcitonin-treated group. Placebo-treated patients remained in bed for almost the whole of the observation period. At the end of the study (28th day), fasting osteocalcin, hydroxyproline/creatinine, and calcium/creatinine ratio values were statistically significantly (all p values 0.001), lower in the calcitonin-treated than in the placebo-treated patients. In the placebo group these values showed a gradual increase. In the