Bisphosphonates and osteonecrosis an open matter

双膦酸盐治疗对口腔种植患者的影响【摘要】在全球范围内，双膦酸盐对转移性癌症、多发性骨髓瘤、骨质疏松患者的临床疗效已得到很好的证实。

尽管口服双膦酸盐后的患者在种植术后发生颌骨坏死的风险较低，但是仍然有关于种植后发生颌骨坏死的报道。

本人就这一话题进行简单回顾。

【关键词】双膦酸盐种植修复颌骨坏死最早在2003年，Marx和Migliorati第一次报道了一系列关于经过双膦酸盐治疗的患者发生颌骨坏死（osteonecrosis of the jaw, ONJ）的病例[1]。

静脉注射双膦酸盐后，发生颌骨坏死的几率最高（0.7～12%），然而，没有发现口服双膦酸盐与颌骨坏死发生率之间有显著性统计学差异[2]。

根据对双膦酸盐和种植牙手术的系统性回顾研究，口服双膦酸盐对种植牙短期（1～4年）对存活率没有影响。

然而，2007年，Mavrokokki等发现颌骨坏死的发生率为0.01%～0.04%，Sedghizadeh等发现这一数字在2009年上升至4%。

由于可能存在严重漏报，而导致口服双膦酸盐引起颌骨坏死的数据有限，因此其实际发生率可能远比制药公司报道的高。

Lazarovici等发现接受双膦酸盐（如静脉注射方式）治疗的患者容易在更短的时间内发生颌骨坏死[3]。

引起颌骨坏死的危险因素有拔牙、佩戴假牙、像隆突、骨刺和下颌舌骨嵴这样的衬有较薄粘膜的骨性突起。

然而，在没有任何危险因素的情况下，也可能发生颌骨坏死（下颌比上颌约为2:1）。

虽然颌骨坏死的发生率在逐年上升，但是有口服双膦酸盐史的患者在接受种植手术后，发生颌骨坏死的相关资料还是很少的。

多项研究表明，双膦酸盐的使用并不影响植体存活。

Jeffcoat研究了25名双膦酸盐治疗患者，并根据年龄匹配了25名绝经后患者作为对照组，经过3年的评估发现，两组植体的存活并没有显著性差异，双膦酸盐组治疗成功率为100%，且3年后无并发症[4]。

Bell平均随访3年（最短的4个月，最长的7年5个月）的研究结果显示双膦酸盐治疗后的患者植体存活率为95%，对照组为96.5%，42例患者均无颌骨坏死症状。

突破｜传统中草药荜茇的一种单体可能是治疗帕金森病的潜在药物荜茇酰胺（Piperlongumine，PLG) 是传统中草药荜茇的一种生物碱单体成分，其具有较好的抗炎、抗氧化作用，且PLG已经证实可以在鱼藤酮、6-OHDA、MPTP等多种PD 模型中起到神经保护作用。

首都医科大学基础医学院杨慧教授课题组发现鱼藤酮处理造成线粒体损伤及细胞凋亡，而PLG 治疗后可以通过激活MAPK8信号通路，从而促进抗凋亡蛋白Bcl-2 磷酸化，后者一方面通过促进其与促凋亡蛋白Bax发生相互作用抑制细胞凋亡，另一方面通过与Beclin1 发生解离而激活自噬，进而清除受损线粒体，间接抑制细胞凋亡，最终通过调节自噬、凋亡再平衡而发挥神经保护作用（图1）。

图1. PLG通过促进BCL2磷酸化恢复细胞凋亡和自噬之间的平衡。

这一重要成果以“Piperlongumine restores the balance of autophagy and apoptosis by increasing BCL2 phosphorylation in rotenone-induced Parkinson disease models”为题发表于Autophagy（21 Feb 2018；自噬领域TOP期刊，2018年IF = 11.100）。

研究思路与方法课题组首先发现，PLG可以缓解鱼藤酮诱导的PD动物模型中脑黑质多巴胺能神经元缺失以及运动行为学障碍，且线粒体可能为PLG 的干预靶点（图2）。

图2.PLG对鱼藤酮动物模型的神经保护作用。

随后，发现PLG可以缓解鱼藤酮诱导的Complex I 活力下降，mPTP 的开放，进而稳定线粒体膜电势而发挥细胞保护作用（图3）。

图3. PLG缓解鱼藤酮诱导的线粒体损伤。

上述结果初步表明PLG通过保护线粒体功能而缓解鱼藤酮诱导的细胞损伤。

第二步，课题组使用鱼藤酮和PLG 处理各组细胞后，通过western blots 的方法对各组细胞裂解液中自噬标志物 LC3-I 向 LC3-II的转化情况和自噬底物 p62（SQSTM1）的蛋白水平进行了检测，结果发现PLG 治疗组中自噬标志物LC3-II 水平显著增加，而自噬底物p62 水平有所降低，提示 PLG 与鱼藤酮共处理的情况下可以激活细胞内自噬水平（图4）。

双膦酸盐及其相关性颌骨坏死的机制和治疗魏斌;孙国文【摘要】双膦酸盐相关性颌骨坏死（BRONJ）是长期使用双膦酸盐治疗骨质疏松症，多发性骨髓瘤以及乳腺癌、前列腺癌和肺癌等其他恶性肿瘤骨转移所引起的骨相关性疾病的严重并发症。

BRONJ的发生发展与一些因素密切相关，譬如双膦酸盐的效能、用药方式、牙拔除和不良义齿修复等。

美国口腔颌面外科协会在2007年对BRONJ进行了定义、分级并颁布其治疗指南，在2009年和2014年进对其行了更新。

尽管BRONJ在国际上引起了广泛的重视，但其发病机制仍不完全清楚，治疗措施也存在着较大的争议。

本文就双膦酸盐及其相关性颌骨坏死的机制和治疗等研究进展作一综述。

%Bisphosphonate-related osteonecrosis of the jaw(BRONJ) is a severe complication that occurs f requently in patients subjected to long-term bisphosphonate treatment for osteoporosis, multiple myeloma, and oth er skeletal-related events induced by metastatic malignant diseases, such as breast, pros tate, and lung cancers. The development of BRONJ is associated with some ris k factors, such as bisphosphonate potency and administration model, dental extraction, and poor-fitting dentures. The definition, staging, and treatment guidelines of patients with BRONJ were established by the American Association of Oral and Maxill ofacial Surgeons in 2007 and then updated in 2009 and 2014. Although BRO NJ has been extensively investigated, the pathogenesis of this disease has yet to be fully elucidated, and corresponding treatments have remained controversial. This article briefly introduces new insights into the pathogenesis and tr eatments of BRONJ.【期刊名称】《国际口腔医学杂志》【年(卷),期】2016(043)004【总页数】4页(P445-448)【关键词】双膦酸盐;双膦酸盐相关性颌骨坏死;发病机制;治疗措施【作者】魏斌;孙国文【作者单位】南京市口腔医院•南京大学医学院附属口腔医院口腔颌面外科南京210008;南京市口腔医院•南京大学医学院附属口腔医院口腔颌面外科南京210008【正文语种】中文【中图分类】R782双膦酸盐是抑制骨吸收的一线药物，临床上常用于骨质疏松症、骨肿瘤以及乳腺癌、前列腺癌和肺癌等其他恶性肿瘤骨转移所引起的骨相关性疾病[1]。

SOGC CLINICAL PRACTICE GUIDELINEAbstractObjective: To provide guidelines for the health care provider on the prevention, diagnosis, and clinical management of postmenopausal osteoporosis.Outcomes: Strategies for identifying and evaluating high-risk individuals, the use of bone mineral density (BMD) and bone turnover markers in assessing diagnosis and response tomanagement, and recommendations regarding nutrition, physical activity, and the selection of pharmacologic therapy to prevent and manage osteoporosis.Evidence: Published literature was retrieved through searches of PubMed and The Cochrane Library on August 30 and September 18, 2012, respectively. The strategy included the use ofappropriate controlled vocabulary (e.g., oteoporosis, bone density, menopause) and key words (e.g., bone health, bone loss, BMD). Results were restricted to systematic reviews, practice guidelines, randomized and controlled clinical trials, and observational studies published in English or French. The search was limited to the publication years 2009 and following, and updates were incorporated into the guideline to March 2013. Grey (unpublished) literature was identified through searching the websites of health technology assessment and health technology assessment-related agencies, clinical practice guideline collections, clinical trial registries, and national and international medical specialty societies.Values: The quality of the evidence was rated using the criteriadescribed by the Canadian Task Force on Preventive Health Care (Table 1).Sponsors: The Society of Obstetricians and Gynaecologists of Canada.RECOMMENDATIONS For Postmenopausal Women1. Health care providers should be aware that the goals ofosteoporosis management include assess m ent of fracture risk and prevention of fracture. (I-A) 2. Health care providers should understand that a stable orincreasing bone mineral density reflects a response to therapy in the absence of low-trauma fracture or height loss due to vertebral-compression fracture. A pro g ressive decrease in bone mineral density, with the magnitude of bone loss being greater than the precision error of the density assessment, indicates a lack of response to current ther a py. Management should be reviewed and modified appropriately. (I-A)No. 312, September 2014 (Replaces No. 222, January 2009)Osteoporosis in MenopauseThis clinical practice guideline has been prepared by the Menopause and Osteoporosis Working Group, reviewed by the Clinical Practice Gynaecology and Family Physician Advisory Committees, and approved by the Executive and Council of the Society of Obstetricians and Gynaecologists of Canada.PRINCIPAL AUTHORS Aliya Khan, MD, Hamilton ON Michel Fortier, MD, Quebec QC MENOPAUSE AND OSTEOPOROSIS WORKING GROUPMichel Fortier, MD (Co-Chair), Quebec QC Robert Reid, MD (Co-Chair), Kingston ON Beth L. Abramson, MD, Toronto ON Jennifer Blake, MD, Toronto ON Sophie Desindes, MD, Sherbrooke QC Sylvie Dodin, MD, Quebec QC Lisa Graves, MD, Toronto ON Bing Guthrie, MD, Yellowknife NT Shawna Johnston, MD, Kingston ON Aliya Khan, MD, Hamilton ON Timothy Rowe, MB BS, Vancouver BC Namrita Sodhi, MD, Toronto ON Penny Wilks, ND, Dundas ON Wendy Wolfman, MD, Toronto ONDisclosure statements have been received from all contributors.The literature searches and bibliographic support for this guideline were undertaken by Becky Skidmore, MedicalResearch Analyst, Society of Obstetricians and Gynaecologists of Canada.Key Words : Osteoporosis, prevention, treatment, diagnosis, bone mineral density, dual energy x-ray absorptiometry, bone turnover markers, vertebral fractures, fragility fractures, antiresorptive, hormone therapy, selective estrogen-receptor modulator, bisphosphonates, calcitonin, anabolic, bone forming agentJ Obstet Gynaecol Can 2014;36(9 eSuppl C):S1–S15SOGC CLINICAL PRACTICE GUIDELINE3. Health care providers should identify the absolute fracture riskby integrating the key risk factors for fracture; namely, age,bone mineral density, prior fracture, and glucocorticoid use.These risk factors allow estimation of fracture risk using the tool of the Canadian Association of Radiologists and Osteoporosis Canada. (I-A)4. The Fracture Risk Assessment tool of the World HealthOrganization (FRAX) has now been validated in a Canadianpopulation and may also be used and incorporates additionalrisk factors; namely, low body mass index, parental history offracture, smoking status, alcohol intake, and the presence ofsecondary causes of osteoporosis. (I-A)5. Health care providers should be aware that a fragility fracturemarkedly increases the risk of a future fracture and confirms the diagnosis of osteo p orosis irrespective of the results of the bone density assessment, (I-A) and that the presence of a low-trauma fracture of a vertebra or hip or more than 1 fragility fractureconfirms a high fracture risk regardless of the bone mineraldensity. (I-A)6. Treatment should be initiated according to the results of the10-year absolute fracture risk assessment. (I-A)Calcium and Vitamin D7. Adequate calcium and vitamin D supplementation is keyto ensuring prevention of progressive bone loss. Forpostmenopausal women a total daily intake of 1200 mg ofelemental calcium from dietary and supplemental sourcesand daily supplementation with 800 to 2000 IU of vitamin Dare recommended. Calcium and vitamin D supplementationalone is insufficient to prevent fracture in those withosteoporosis; however, it is an important adjunct topharmacologic intervention with antiresorptive and anabolictherapy. (I-B)Hormone Therapy8. Hormone therapy should be prescribed for symptomaticpostmenopausal women as the most effective option formenopausal symptom relief. (I-A) It represents a reasonablechoice for the prevention of bone loss and fracture in this patient population. (I-A)9. Physicians may recommend low- and ultralow-dosage estrogentherapy to symptomatic women for relief of menopausalsymptoms (I-A) but should inform their patients that, despitethe fact that such therapy has demonstrated a beneficial effectin osteoporosis preven t ion, (I-A) no data are yet available onreduction of fracture risk.Bisphosphonates10. Alendronate, risedronate, and zoledronic acid are valuablefirst-line agents of choice in the treatment of postmenopausalosteoporosis and should be considered to decrease the risk ofvertebral, non-vertebral, and hip fractures. (I-A)11. Etidronate is a weak antiresorptive agent and is notrecommended as a first-line agent of choice for the treatmentof osteoporosis. (I-D)RANKL Inhibitor12. Denosumab is an effective antiresorptive agent, shown toreduce the risk of vertebral, non-vertebral, and hip fractures, (I-A) and should be considered as a first-line agent of choice in thetreatment of postmenopausal osteoporosis in women at a highfracture risk. (I-A)Table 1. Key to evidence statements and grading of recommendations, using the ranking of the Canadian Task Force on Preventive Health CareQuality of evidence assessment*Classification of recommendations†I: Evidence obtained from at least one properly randomizedcontrolled trialA. There is good evidence to recommend the clinical preventive actionII-1: Evidence from well-designed controlled trials withoutrandomizationB. There is fair evidence to recommend the clinical preventive actionII-2: Evidence from well-designed cohort (prospective or retrospective) or case–control studies, preferably from more than one centre or research group C. The existing evidence is conflicting and does not allow to make arecommendation for or against use of the clinical preventive action;however, other factors may influence decision-makingII-3: Evidence obtained from comparisons between times or places with or without the intervention. Dramatic results inuncontrolled experiments (such as the results of treatment with penicillin in the 1940s) could also be included in this category D. There is fair evidence to recommend against the clinical preventive actionE. There is good evidence to recommend against the clinical preventiveactionIII: Opinions of respected authorities, based on clinical experience, descriptive studies, or reports of expert committees L. There is insufficient evidence (in quantity or quality) to makea recommendation; however, other factors may influencedecision-making*The quality of evidence reported in these guidelines has been adapted from The Evaluation of Evidence criteria described in the Canadian Task Force on Preventive Health Care.89†Recommendations included in these guidelines have been adapted from the Classification of Recommendations criteria described in the Canadian Task Force on Preventive Health Care.89ABBREVIATIONSAFF atypical femoral fractureBMD bone mineral densityET estrogen therapyFIT Fracture Intervention TrialHR hazard ratioHT hormone therapyONJ osteonecrosis of the jawRANKL receptor activator of nuclear factor kappa-B ligandRCT randomized controlled trialSERM selective estrogen-receptor modulatorWHI Women’s Health InitiativeOsteoporosis in MenopauseSelective Estrogen-Receptor Modulators13. Treatment with raloxifene may be considered to decrease the riskof vertebral fractures, bearing in mind that this agent has not been shown to be effective in reducing the risk of non-vertebral or hipfractures. (I-A)Parathyroid Hormone14. Treatment with teriparatide should be considered to decrease therisk of vertebral and non-vertebral fractures in postmenopausalwomen with severe osteoporosis (I-A) and should also beconsidered in postmenopausal women experiencing bone loss ora new fracture despite antiresorptive therapy. (I-A) INTRODUCTIONO steoporosis is defined as an impairment in bone strength due to an abnormal quantity and/or quality of bone. Quantity is evaluated by measuring BMD. Quality is affected by many factors, including the degree of mineral i zation, the rate of bone remodelling, the connectivity of the bony trabeculae, the quality of the collagen fibres, and the health of the bone cells. The 3 types of bone cells are osteoblasts, osteoclasts, and osteocytes. The osteocytes function as “mechanostats”, sensing the degree of microdamage and triggering remodel­ling in areas of stress and strain, thus allowing continual renewal, repair, and replacement of bone. This process of remodelling maintains bone strength.Adequate calcium and vitamin D intake is necessary to attain and maintain normal bone quantity and quality and thus achieve optimal bone strength. Early assessment of skeletal health and then initiation of appropriate calcium and vitamin D supplementation and an exercise program are essential in the prevention and treatment of osteoporosis. Individuals at increased risk for fracture should also be offered pharma­cologic therapy in order to reduce the fracture risk. Absolute frac t ure risk is identified by integrating age and BMD with other key risk factors for fracture including prior fracture history and use of glucocorticoid therapy. The decision to treat is based on the risk of fracture, and the quantification of absolute fracture risk enables targeting of treatment to those at greatest risk.RISK ASSESSMENT AND MANAGEMENTBone strength is determined by both bone quantity and bone quality. Bone densitometry provides information on BMD, which is a reflection of bone quantity. Bone quality is determined by a number of factors, including the rate of remodelling, bone mineralization, function of the bone cells, and quality of the collagen fibres. It is necessary to identify risk factors for fracture that may be present and the risk of falls. The timed “get up and go” test is valuable in assessing gait stability and is a reflection of fall risk. Risk factors for osteoporosis have been identi fi ed (Table 2),1 and the presence of risk factors in a postmenopausal woman justifies bone densitometry.2In 2005 Osteoporosis Canada recommended identifying absolute fracture risk by integrating the key risk factors for fracture; namely, age, BMD, prior fracture, and glucocorticoid use.3 The 10­year risk of fragility fractures is thus determined (Figure)1and defined as high if it is greater than 20%, moderate if it is 10% to 20%, and low if it is less than 10%.4 The additional effect of a pre­existing fragility fracture or glucocorticoid use moves the patient 1 risk category higher. These guidelines were based on Swedish data and have been recalibrated using Canadian hip fracture data. The version developed by the Canadian Association of Radiologists and Osteoporosis Canada4 has now been validated in 2 Canadian cohorts and has close to 90% agreement with the FRAX5 score (the FRAX tool can be downloaded from the Osteoporosis Canada website, http://www.osteoporosis.ca). The presence of a vertebral or hip fracture or more than 1 fragility fracture increases the fracture risk to high. Fracture risk is evaluated on the basis of femoral neck BMD and age and is modified by the presence of prior fragility fracture or the use of glucocorticoid therapy (7.5 mg for 3 months or longer); these modifiers increase the fracture risk to the next risk category.1 A BMD T­score of −2.5 or less at either the lumbar spine or the femoral neck denotes at least a moderate risk of fracture.1 Height should be measured annually, and a decrease in measured height of more than 2 cm should be further evaluated by radiographs of the thoracic and lumbar spine with exclusion of vertebral fractures.6A more comprehensive calculation of the 10­year absolute fracture risk, now available from the World Health Organization, incorporates additional risk factors: parental history of hip fracture, current tobacco smoking, rheuma­toid arthritis or other secondary causes of bone loss, and alcohol intake of 3 or more units daily.5It is recommended that absolute fracture risk be calculated using the tool of either the Canadian Association of Radiologists and Osteoporosis Canada or FRAX and the decision to treat be based on the absolute fracture risk. Younger individuals at a low risk of fracture are appro­priately managed with lifestyle changes and strategies designed to prevent bone loss.Osteoporosis is diagnosed in a postmenopausal woman on the basis of a BMD T­score of less than −2.5 at theSOGC CLINICAL PRACTICE GUIDELINElumbar spine, hip (femoral neck or total hip), or radius (distal third). Clinically it is diagnosed in a postmenopausal woman in the presence of a low­trauma fracture. In a premenopausal woman osteoporosis is diagnosed only in the presence of fragility fractures; BMD alone cannot be used for diagnosis.7In premenopausal women a normal BMD is defined as being within 2 standard deviations of the age­matched reference mean. Comparison with the age­matched reference range is represented by the Z score, and in premenopausal women Z scores should be used instead of T scores. Low bone density is defined as a BMD Z score 2 or more standard deviations below the mean age­matched reference value.7Pharmacologic therapy is considered in postmenopausal women after exclusion of secondary causes of low bone density. If the 10­year absolute fracture risk is greater than 20% (high), then drug therapy is advised. In those with a moderate risk (10% to 20%), management decisions are indi v idualized. Those with a low fracture risk (< 10%) can be treated conservatively after exclusion of secondary causes of bone loss with prevention strategies based on ensuring adequate calcium and vitamin D supplementation. It is also important to emphasize regular exercise and reduced con s umption of alcohol (fewer than 2 drinks/d) and coffee (fewer than 4 cups/d). Smoking cessation should also be strongly advised.Failure of therapy is confirmed by the development of a low­trauma fracture or significant bone loss despite pharmacologic therapy for 2 years. In these individuals it is necessary to ensure that there are no secondary causes of bone loss. It is also important to ensure adequate adherence to therapy.8ADVANCES IN PHARMACOLOGIC THERAPYIn addition to adequate calcium, vitamin D, and exercise, options for the prevention and treatment of osteoporosis include antiresorptive and anabolic agents.9 Antiresorptive (anticatabolic) agents inhibit osteoclast activity and reduce bone turnover.9,10 The various agents have different mechanisms of action. Bisphosphonates reduce the rate of bone turnover, providing a longer time for bone to mineralize. Bisphosphonate therapy is thus associated with modest increases in BMD. Estrogen acts through the estrogen receptors on both osteoblasts and osteoclasts, suppressing receptor activator of nuclear factor κB ligand (RANKL)­induced osteoclast differentiation and thereby decreasing bone remodeling.11 Raloxifene, a SERM, can bind to estrogen receptors, with tissue­specific agonist or antagonist effects. Raloxifene decreases bone remodel­ling in addition to its extraskeletal effects. Osteoclastic bone resorption is also inhibited by calcitonin acting on calcitonin receptors. Denosumab is a monoclonal antibodyTable 2. Risk factors for osteoporosis: indications for measuring BMDOlder adults (age ≥ 50 years)Younger adults (age < 50 years)Age ≥ 65 years (both women and men) Fragility fractureClinical risk factors for fracture(menopausal women and men age 50 to 64 years)Prolonged use of glucocorticoids* Fragility fracture after age 40 years Use of other high-risk medications†Prolonged use of glucocorticoids*Hypogonadism or premature menopause(age < 45 years)Use of other high-risk medications Malabsorption syndromeParental hip fracture Primary hyperparathyroidismVertebral fracture or osteopenia identified on radiography Other disorders strongly associated with rapid bone loss and/or fractureCurrent smokingHigh alcohol intakeLow body weight (< 60 kg) or major weight loss(> 10% of body weight at age 25 years)Rheumatoid arthritisOther disorders strongly associated withosteoporosis*At least 3 months’ cumulative therapy in the previous year at a prednisone-equivalent dose ≥ 7.5 mg daily.†For example, aromatase inhibitors or androgen deprivation therapy.Reproduced with permission of the Canadian Medical Association from Papaioannou A et al.1Osteoporosis in Menopauseto RANKL (receptor activator of nuclear factor κB) and binds to RANKL, lowering values to premenopausal levels. This results in a decrease in the formation, function, and survival of osteoclasts.Antiresorptive agents are effective in reducing frac t ure risk by approximately 30% to 68% in postmenopausal women. However, fractures may still occur, and anabolic therapy can complement antiresorptive therapy in the prevention of further fractures. Anabolic therapy can result in new bone formation, with increases in cortical thickness and trabecular connectivity, leading to major improvements in the quality and quantity of bone. Anabolic therapy can increase the production of new bone matrix by enhancing osteoblast function. Teriparatide (recombinant human parathyroid hormone, amino acid sequence 1 through 34) decreases the release of sclerostin from osteocytes. Sclerostin is a protein that decreases bone formation by inhibiting the Wnt signalling pathway in the osteoblast. With a decrease in this inhibitor of bone formation, there is an increase in new bone formation. Teriparatide, 20 μg daily, has been shown to reduce the risks of vertebral and non­vertebral fragility fractures by approximately 65% and 53%, respectively, over 18 months in postmenopausal women with osteoporosis.12 Teriparatide is the only anabolic agent available in Canada.CALCIUM AND VITAMIN D SUPPLEMENTATION The effectiveness of calcium and vitamin D supplement­ation in preventing hip fractures was evaluated in the WHI.13 The trial involved 36 282 postmenopausal women who daily received either 1000 mg of elemental cal c ium as calcium carbonate and 400 IU of vitamin D, or a placebo, for an average of7 years. Patients were allowed to take additional daily supplements of up to 1000 mg of cal c ium and 600 IU of vitamin D; approximately 38% of sub­jects took more than 1200 mg of elemental calcium daily. Personal use of bisphosphonates, calcitonin, SERMs, and ET was also permitted. The calcium and vita m in D study arm overlapped with the HT arm; thus, approximately 51% of women were receiving estrogen.Treatment compliance was poor: by the end of the study, only 59% of the women were taking 80% or more of their supplements. As compared with those taking placebo, the women taking 1000 mg of calcium and 400 IU of vitamin D daily showed a 1.06% increase in hip BMD (P < 0.01). In the treatment­compliant group, the HR for hip fracture was 0.71 (95% CI 0.52 to 0.97), representing a statistically significant 29% reduction in hip fracture risk among the women taking 80% or more of their calcium and vitamin D supplements. Estrogen use was associated with a 42% Assessment of basal 10-year risk of fracture with the 2010 tool of the Canadian Association of Radiologist and Osteoporosis Canada.Reproduced with permission of the Canadian Medical Association from Papaioannou A et al.1The T-score for the femoral neck should be derived from the National Health and Nutrition Education Survey III reference database for white women. Fragility fracture after age 40 or recent prolonged use of systemic glucocorticoids increases the basal risk by one category (ie, from low to moderate or moderate to high). This model reflects the theoretical risk for a hypothetical patient who is treatment-naive; it cannot be used to determine risk reduction associated with therapy. Individuals with fragility fracture of a vertebra or hip and those with more than one fragility fracture are at high risk of an additional fracture.WomenLow risk (< 10%)High risk (> 20%)Moderate riskAge (year)T–score,femoralneck0.0–1.0–2.0–3.0–4.050 55 60 65 70 75 80 85MenLow risk (< 10%)High risk (> 20%)Moderate riskAge (year)T–score,femoralneck0.0–1.0–2.0–3.0–4.050 55 60 65 70 75 80 85SOGC CLINICAL PRACTICE GUIDELINEreduction in hip fracture risk. A small but significant 17% increase in the risk of renal stones was noted in the treat­ment group as compared with the placebo group: the HR was 1.17 (95% CI 1.02 to 1.34). Inadequate blood levels of vitamin D were also noted in the WHI study and may have contributed to the findings. In the nested case–control study, the mean serum 25­hydroxy vitamin D level at baseline was 46.0 nmol/L in the women who had sustained hip fractures as compared with 48.4 nmol/L in their control subjects (P = 0.17). Vitamin D supplementation of more than 600 IU daily may have reduced the fracture risk, as has been demonstrated in other clinical trials.Calcium supplements have been linked to a possible increase in the risk of cardiovascular events.14 A recent 5­year RCT of 1200 mg of elemental calcium carbonate daily versus placebo in 1460 postmenopausal women did not demonstrate any difference in rates of death or hospitalization due to coronary events.15 In the EPIC study of 23 980 people between the ages of 35 and 64 years followed for 11 years with questionnaires, those with a calcium­enriched diet had a lower risk of myocardial infarction (HR 0.69; 95% CI 0.5 to 0.94), whereas those using a calcium supplement had a higher risk (HR 1.86; 95% CI 1.17 to 2.96).16Data from the WHI among those not using personal calcium or vitamin D supplements at baseline did not show an adverse effect of such supplementation on the risk of myocardial infarction, coronary heart disease, total heart disease, stroke, or overall cardiovascular disease.17 These RCT data are the best evidence currently available and do not support an increased risk of coronary events with calcium and vitamin D supplementation.It is recommended that the daily calcium requirement of 1200 mg be met ideally from dietary sources; if this is not possible, then supplements may be safely used. Calcium carbonate and calcium citrate are the supplements of choice.Ensuring adequate vitamin D supplementation is a key component of the prevention and treatment of osteoporosis. Although it might not be sufficient as the sole means of therapy for osteoporosis, routine supplementation with calcium (1000 mg/d) and vitamin D 3 (800 to 2000 IU/d) is still recommended as a mandatory adjunct to the main pharmacologic agents (antiresorptive and anabolic drugs). Vitamin D in doses of 800 IU daily has been shown to be effective in reducing the risk of falls by 49% over a 12­week period of therapy.18 Vitamin D supplementation at a dose of 10 000 IU once weekly has been suggested for women unable to take daily supplements in areas wheresuch a preparation is available. Doses of 100 000 IU ofvitamin D 3 given orally every 4 months have been shownto be effective in reducing the risk of osteoporotic fractures.19Vitamin D levels depend on a number of factors, including dietary intake, sun exposure, skin pigmentation, body mass index, and smoking status.20 Extraskeletal benefits are currently being evaluated and may include a reduction in the risk of certain malignant diseases as well as autoimmune disorders.HORMONE THERAPYEstrogen has significant antiresorptive effects. Spe c ifically, it enhances the osteoblastic production of osteoprotegerin, which has antiosteoclastic properties because of its ability to bind to RANKL and subsequently to block the RANKL/RANK interaction required for osteoclast recruitment and activation.21,22 Estrogen also decreases RANKL expression from the osteoblast. In the WHI, a pri m ary prevention trial, the estrogen­only arm demonstrated a 30% to 39% reductionin fracture rates.23 This trial theref ore confirmed the anti­fracture effects of ET suggested by previous clinical trials.24,25The combined estrogen/progestogen arm of the WHI had similar results: an increase in total hip BMD, together with a 34% reduction in hip and vertebral fractures and a 24% reduction in total osteoporotic fractures.26 In early­postmenopausal women, the combined therapy resulted in increases in BMD of 2% to 3% at the hip and spine over 2 years of therapy.24 A decline in the markers of bone turnover in response to HT was also seen in early­postmenopausal women.25HT (with estrogen alone or combined with a progestogen) is still considered the most effective therapy for the medical management of meno p ausal symptoms. Bone protection with HT at a usual dosage is considered an added benefit. Recent studies designed to test various dosages of estrogen for bone pro t ection have shown a linear dose response of the skeleton from the lowest to the highest dosages tested.24,27,28 These RCTs have shown that low­dosage ET can prevent postmenopausal osteoporosis, and ultralow­dosage ET has beneficial skeletal effects. However, no fracture trial has yet been carried out with low­ and ultralow­dosage HT. A low dose is 0.3 mg of conjugated estrogen or its equivalent (e.g., 0.5 mg of micronized estradiol); half this amount is considered ultralow.29SERM THERAPYSERMs have demonstrated tissue­specific estrogen­agonistic or estrogen­antagonistic effects.30 In the Multiple。

迥ｊＥ医药兰Ｑ塑生１２旦筮≥！鲞筮丝期望！匦丛型堡！！』！坠里堂：至Ｑ塑，！型！！里璺竺堕！：丝骨质疏松性骨折的诊治进展魏培健支忠继邸军【关键词】骨质疏松；骨折；文献综述【中图分类号】Ｒ５８９．５【文献标识码】Ａ【文章编号】１００２—７３８６（２００９）２４—３４１７—０３骨质疏松症（ｏｓｔｅｏｐｏｒｏｓｉｓ，ＯＰ）是一种以骨量低下，骨微结构破坏，导致骨脆性增加，易发生骨折为特征的全身性骨病。

骨质疏松性骨折是ＯＰ最严重的后果，属脆性骨折，由于骨强度下降，轻微创伤或日常活动中即可发生，一般轻微暴力可造成的骨折。

此类骨折属完全性骨折，在老年人中常见，严重威胁着老年人的身心健康并影响其生活质量，致残率、致死率均显著增高，同时给家庭和社会带来了巨大的压力，在目前我国正逐渐走向老龄化社会的阶段，越来越引起广泛重视。

本文将关于骨质疏松性骨折的诊治进展作以下综述。

ｌ骨质疏松性骨折的诊断１．１ＯＰ的危险因素，人种的差异（白种人和黄种人患骨质疏松的危险高于黑人）及遗传因素¨。

、老龄化、女性绝经¨１；低出生体重、性激素低下、吸烟、过度饮酒、咖啡或碳酸饮料等，体力活动缺乏，缺少阳光照射、饮食中钙或维生素Ｄ缺乏、同时合并影响骨代谢的疾病（如甲状旁腺功能亢进症、糖尿病、泌乳素瘤、甲状腺功能亢进症、结缔组织疾病、多种慢性肾脏疾病、慢性肝脏病、器官移植术后等）或影响骨代谢的药物（如糖皮质激素、免疫抑制剂、肝素、抗惊厥药、抗癌药、含铝抗酸剂等）。

１．２外伤暴力史和既往骨折史，骨质疏松性骨折的好发部位为脊柱、髋部和尺挠骨，长骨的骨折多有轻微暴力史，而椎体的骨折可由于身体自身的重力因素所导致，不一定有外加的暴力因素。

既往有过脆性骨折史（尤其是５０岁以后）对于诊断骨质疏松性骨折有蓖要价值，它代表着骨骼本身质与量的下降以及存在着骨骼系统以外的骨折危险因素，如体能的下降、营养不良、神经肌肉系统的协调能力下降、合并其他系统疾病等，这些患者再次发生骨折的风险明显增高ｐ。

- 180 -[44] GUAN J，WU L，XIAO Q，et al.Levels and clinicalsignificance of serum homocysteine (Hcy), high-density lipoprotein cholesterol (HDL-C), vaspin, and visfatin in elderly patients with different types of coronary heart disease[J].Ann Palliat Med，2021，10（5）：5679-5686.[45] MARKOVI Ć-BORAS M，ČAU ŠEVI Ć A，ĆURLIN M.Arelation of serum homocysteine and uric acid in Bosnian diabetic patients with acute myocardial infarction[J].Journal of Medical Biochemistry，2021，40（3）：261-269.[46] NEDELCU C，IONESCU M，PANTEA-STOIAN A，et al.Correlation between plasma homocysteine and first myocardialinfarction in young patients: case-control study in Constanta County, Romania[J].Exp Ther Med，2021，21（1）：101.[47] PSOTKA M A，SCHILLER N B，WHOOLEY M A，et al.Association of change in 5-year N-terminal fragment of the prohormone brain-type natriuretic peptide with left ventricular structure and function in stable coronary disease[J].J Cardiovasc Med (Hagerstown)，2018，19（2）：67-72.[48] GEMA M，CAROLINA G，F ÁCILA L，et al.Homocysteineand long-term recurrent infarction following an acute coronary syndrome[J].Cardiology Journal，2021，28（4）：598-606.（收稿日期：2023-09-11）　（本文编辑：陈韵）①德阳市人民医院口腔科　四川　德阳　618000通信作者：梁宇豪双膦酸盐类药物相关性颌骨坏死的研究及进展梁宇豪① 【摘要】　双膦酸盐类（bisphosphonates，BPs）在临床上广泛应用于预防和治疗骨质疏松症等疾病，取得了良好的治疗效果，但大量报道指出其可通过抗血管生成及抑制骨吸收等作用引发药物相关性颌骨坏死（medication-related osteonecrosis of the jaw，MRONJ）。

种植术后双膦酸盐相关性颌骨坏死处理体会李阳;高永波【摘要】双膦酸盐相关性颌骨坏死(bisphosphonate-related osteonecrosis of the jaw,BRONJ)近年来呈现逐渐增多的趋势,本文详细报道了种植术后发生的双磷酸盐相关性颌骨骨坏死病例的临床表现、诊断与治疗,并结合文献讨论了可能的发病机制、治疗方案及对口腔种植的影响,以提高口腔医师对这一疾病的防治意识.%Recently, an increasing number of cases of jaw necrosis associated with oral bisphosphonates has been re-ported. Herein we describe a case of BRONJ after dental implant. The definitive diagnosis was derived from the medical history, clinical features, orthopantomography/computed tomography (CT). The systemic status of the patient was relatively compromised. A review of the literature provides answers to key clinical questions for dentists in the care of patients who are receiving oral bisphosphonates.【期刊名称】《口腔颌面外科杂志》【年(卷),期】2016(026)006【总页数】4页(P427-430)【关键词】牙种植;双膦酸盐;骨坏死;并发症【作者】李阳;高永波【作者单位】遵义医学院附属龙岗中心医院口腔科,广东深圳 518116;遵义医学院附属龙岗中心医院口腔科,广东深圳 518116【正文语种】中文【中图分类】R782.4双膦酸盐(bisphosphonates,BPs)是用于治疗各种骨代谢疾病的一类药物，能有效地治疗和控制骨质疏松、减轻疼痛[1]。

【摘要】 恶性肿瘤骨转移常引起疼痛、功能障碍、病理性骨折、脊髓压迫等症状，严重影响患者的生存质量。

双膦酸盐为破骨细胞强效抑制剂，可有效预防和减少相关症状，是治疗恶性肿瘤骨转移的主要措施之一。

因卡膦酸二钠是第3代双膦酸盐制剂，其对于恶性肿瘤转移导致的骨质疏松、疼痛、骨折等相关症状的治疗优于第1、2代双膦酸盐药物；并可调控肿瘤细胞的增殖与凋亡。

同时，研究资料表明因卡膦酸二钠药物相关发热、肾功能损害、颌骨坏死等不良反应的发生率低。

对于因卡膦酸二钠的剂量、用法、疗程及停药时机需要深入研究，不良反应和有效性需要长期追踪。

【关键词】 双膦酸盐；骨转移；因卡膦酸二钠；疗效；不良反应Clinical study and application of Bisphosphonate bicarbonate disodiumFENG Chen 1, LI Zhong-li 2, ZHANG Wen-xue 3 (1. Department of Radiotherapy, Shanxi Provincial Corp's Hospital, Xi'an 710054, China; 2. Department of Radiotherapy, the First Affiliated Hospital of Lishui College, Zhejiang, Lishui 323000, China; 3. Department of Radiotherapy, General Hospital of Tianjin Medical University, Tianjin 300052, China)Corresponding author: ZHANG Wen-xue, E-mail: 1035929104@ 【Abstract 】 Bone metastasis caused by cancer often cause significant symptoms, such as pain, impaired function, pathological fracture, spinal cord compression, etc. Bisphosphonate is a potent osteoclast inhibitor, which can effectively prevent and reduce related symptoms, and is standard therapeutic drug for cancer patients with bone metastasis. As the third-generation bisphosphonates, bicarbonate disodium is superior to the first-generation and second-generation bisphosphonates in the treatment of osteoporosis, pain, fracture and other related symptoms caused by malignant tumor metastasis, and can regulate the proliferation and apoptosis of tumor cells. Some study show that the incidence of adverse reactions such as pyretic renal function damage and osteonecrosis of jaw is low. The dosage, treatment course and timing of withdrawal of bicarbonate disodium require in-depth study, and adverse reactions and effectiveness require long-term follow-up.【Key words 】 Bisphosphonate; Bone metastasis; Bicarbonate disodium; Therapeutic effect; Adverse reactions双膦酸盐因卡膦酸二钠的临床研究与应用冯晨1，李中梨2，张文学3（1．陕西省武警总医院　放疗科，西安　710054；2．丽水学院第一附属医院　放疗科，浙江　丽水　323000；3．天津医科大学总医院　放疗科，天津　300052）通讯作者：张文学 E-mail ：1035929104@恶性肿瘤骨转移是晚期癌症患者的常见并发症，主要表现为骨痛、病理性骨折、高钙血症等，严重威胁患者的生存质量。

双膦酸盐作为辅助治疗方法降低四肢骨巨细胞瘤复发率的临床研究丁路;韩小平;黄涛;张华【摘要】目的对双膦酸盐(bisphosphonates,BPs)药物辅助治疗骨巨细胞瘤(giant cell tumors,GCT)的临床效果进行观察和评价.方法将2009年～2013年泰安市中心医院收治的37例经手术治疗的骨巨细胞瘤的患者纳入观察组22例和对照组15例,观察组给予双膦酸盐药物辅助治疗,随访24个月,观察比较两组患者的疼痛视觉模拟评分(VAS)疼痛评分,复发率和恢复情况等指标.结果观察组的术前、术后3个月和12个月的VAS疼痛评分均显著低于对照组(P＜ 0.05);在Ⅱ级骨巨细胞瘤和进行病灶刮除术患者中,观察组的复发率显著低于对照组(P＜0.05).结论双膦酸盐药物辅助治疗骨巨细胞瘤能够减少患者的痛苦,降低术后复发率,提高预后质量.【期刊名称】《中华保健医学杂志》【年(卷),期】2016(018)001【总页数】3页(P67-69)【关键词】双膦酸盐;骨巨细胞瘤;复发【作者】丁路;韩小平;黄涛;张华【作者单位】830011 新疆乌鲁木齐,新疆医科大学第五附属医院骨一科;830011 新疆乌鲁木齐,新疆医科大学第五附属医院骨一科;830011 新疆乌鲁木齐,新疆医科大学第五附属医院骨一科;830011 新疆乌鲁木齐,新疆医科大学第五附属医院骨一科【正文语种】中文【中图分类】R453骨巨细胞瘤（giant cell tumors，GCT）是一种常见的溶骨性骨肿瘤，好发于长管状骨的干骺端，以股骨远端和胫骨近端最为多见。

GCT占所有骨肿瘤的5%左右，但有研究表明，中国人群GCT发病率高于西方国家，GCT在中国人群占所有良性骨肿瘤的20%，而且发病呈年轻化的趋势［1］。

GCT的临床症状主要表现为不同程度的疼痛，可伴有肿胀、活动受限，病程从数周至数月不等，无特异性表现，早期GCT患者不易察觉。

病理检查可见大量的多核巨细胞、梭形的纤维母细胞样的基质细胞和圆形的类单核细胞。