201105333 六、發明說明： 【發明所屬之技術領域】 本發明係關於一種醫藥組成物，係含艾爾骨化醇（ ED-7 1 )而成，用於抑制重症骨質疏鬆症患者的非外傷性 椎體骨折；一種抑制重症骨質疏鬆症患者的非外傷性椎體 骨折之方法，係包含投予有效量之艾爾骨化醇而成；及用 於製造該醫藥組成物之艾爾骨化醇之使用。 【先前技術】 骨質疏鬆症是被定義爲「以骨強度降低爲特徵，骨折 之風險變得容易增高之骨骼疾病」（非專利文獻1 )，伴 隨著骨密度之減少，骨構造發生變化，在椎體、撓骨遠位 端、股骨頸部等各種部分變得容易發生骨折。 曰本骨質疏鬆症患者，在2002年的時間點估計有大 約1 1 00萬人。骨質疏鬆症，係以女性壓倒性地占多數， 而8 0%以上爲女性。女性之中，從40多歲〜50多歲停經 期之後骨量急劇減少，60多歲的情況在2人之中會有1 人，而到了 70歲以上的情況則在1 0人之中會有7人發現 患有骨質疏鬆症的狀態。男性之中，在超過6 0歲以後， 骨質疏鬆症徐緩地增加，在70歲以上的情況1 0人之中有 4人左右。由於人口高齡化急劇發生，因此予測骨質疏鬆 症患者人數在今後會急劇增加。 骨質疏鬆症，會因爲骨骼的脆弱化，而主要在脊椎（ 椎體）、股骨附近部位、前腕部位等容易骨折。其中發生 -5- 201105333 頻率最高的椎體骨折，認爲在70到75歲有25%、80歲 以上有43 %的機會發生，由其引起疼痛或脊柱變形、姿 勢異常，不僅會對日常生活造成障礙，還發現伴隨於此發 生的消化系統或呼吸系統之機能障礙等會造成生活品質（ QOL ; Quality of Life )大幅降低。甚至使生命預後（ vital prognosis)變差，而成爲使看護的必要性增加的原 因（非專利文獻2 )。 此外，骨質疏鬆症造成之脆弱性骨折，在很多情形還 會伴隨著稱爲"Fracture Cascade"的短期間持續發生骨折 的現象。印證此現象的報告是由Siris等人所作的報告， 指出了新的椎體骨折發生頻率會依隨現存的椎體骨折數目 而定，其中可知在股骨之骨密度T分數降低2SD的情況 下，椎體骨折的絕對風險，在沒有現存椎體骨折的情況爲 2.4%，有一個現存椎體骨折情況爲7.2%，2個的情況爲 13.3%，3個的情況爲20.7%，骨折風險會與現存椎體骨 折數成比例地提高（非專利文獻3 )。認爲此傾向在骨密 度値愈低的情況會愈爲顯著。在北美以及歐洲、澳洲實施 的骨質疏鬆症藥臨床測試數據之解析結果之中，椎體骨折 在1年內的發生比例，在測試開始時已經具有椎體骨折的 患者爲未具有的患者之5.1倍（95%信賴區間：3.1，8·4 )。此解析結果看來，可知在新的椎體骨折發生的患者群 中，1年以內再發生新的骨折的相對風險，與未發生新的 椎體骨折的患者群相比，增大爲9 · 3倍（9 5 %信賴區間： 1.2 > 7 1.6)。 -6- 201105333 另外也有報告指出，帶有疼痛的椎體骨折的累積所造 成的機能降低爲股骨頸骨折的5 0〜62 %，而且會成爲到 75歲爲止脊椎骨折患者不健康的原因，椎體骨折的發生 及其續發，爲高齡期前期機能降低的主要原因（非專利文 獻4)。因此，防止骨質疏鬆症患者之椎體骨折發生，不 僅在醫療領域，在社會方面也正成爲極重要的課題。 另一方面，根據2006年骨質疏鬆症之預防與治療GL 製作委員會所編著的準則，在日本國內骨質疏鬆症的治療 ，主要是使用鈣製劑、女性荷爾蒙製劑、活性型維生素D 製劑、維生素K製劑、雙膦酸酯製劑、S ERM製劑、降鈣 素製劑、異黃酮製劑、蛋白同化荷爾蒙製劑等。在日本以 外的治療，除了該等以外還加上使用PTH以及其類似物 、RANKL阻礙劑、緦製劑等。 該等現行治療劑之中，現在使用頻率最高的是雙膦酸 酯製劑。雙膦酸酯其中之一的阿侖膦酸鹽，以l〇mg/天進 行持續治療，能夠使停經後的骨質疏鬆症患者椎骨骨折之 危險性減少而使BMD增加。另外近年來還有文獻報告出 ，會有降低脊椎骨折之風險，或預防脊柱變形及身高減少 的效果（專利文獻1 )。 然而，雙膦酸酯作爲骨質疏鬆症之治療藥雖然使 BMD上昇，但是也提示了同時會有導致微小骨骼損傷的 累積等、骨質降低的可能性。甚至有報告指出，阿侖膦酸 鹽由於有嚴苛的服用規則或副作用，因此患者的順從性會 變差。一般而言，雙膦酸酯由於與食物中的鈣形成螯合使 201105333 得其吸收受到阻礙，因此應於空腹時服用，或者 食道炎或食道潰瘍，而有以立姿或坐姿並與足量 服用’服用後不能橫躺30分鐘以上等嚴苛的服 現在’減少該等限制新的雙膦酸酯劑正在開發之 近年來’在服用雙膦酸酯時，牙科治療時的顎骨 特別引起注意，此外還有報告指出骨關節痛等肌 統副作用，而會有安全上的問題。 關於其他骨質疏鬆症治療藥，亦有報告指出 劑中有效成分的鹽酸雷洛昔芬會增加靜脈血拴栓 或梗塞這種血管運動症狀風險，PTH會增加動物 發生風險等，各個藥物在安全上各自有嚴重的問 ，PTH以及RANKL阻礙劑爲皮下或靜脈內注射 有不適合長期投予等順從性方面的問題。 另一方面，有文獻報告出除了雙膦酸酯之外 有骨質疏鬆症治療效果的藥劑，還有維生素D 根據在日本以外進行的綜合分析，將通常的維兰 經過氫氧化的維生素D之製劑總合與安慰劑進 情況，相對於安慰劑的相對風險（RR : Relative 95%信賴區間）爲0.63 ( 0.45〜0.88)，抑制椎 發生頻率約3 7 % (非專利文獻5 )。另外還有文 ，在75歲以上之高齡者與現存具有骨折之患者 投予維生素D衍生物其中之一的阿法骨化醇， 體骨折抑制效果（非專利文獻6)。維生素D化 不會發生其他同效藥物所觀察到的順從性減低或 爲了預防 的水一起 藥限制。 中，然而 壞死問題 肉骨骼系 SERM 製 塞症發作 的骨肉腫 題。再者 劑，也會 ，認爲具 化合物， .素D或 行比較的 Risk)( 體骨折的 獻揭示出 中，藉由 明顯有椎 合物，在 嚴重的副 -8 - 201105333 作用等問題的觀點上，作爲有必要採長期服用方式的骨質 疏鬆症治療劑，堪稱非常優異的藥劑。 ia種維生素D化合物其中一種的艾爾骨化醇，自 1 9 8 5年被申請物質發明以來，已有多數的專利、非專利 文獻被報告出來’其中之一是日本特許第3789956號（專 利文獻2)的關於一種「骨癒合促進劑」，係含有艾爾骨 化醇作爲有效成分。此處提及的骨癒合促進，是指在骨延 長、骨切斷、骨折、骨移植等之後，伴隨必要的骨骼再接 合的骨骼修復過程的促進，因此與不伴隨這種再接合的骨 折抑制或預防相異。另外，關於「以新的維生素D 3衍生 物爲有效成分的醫藥」的日本特許第1974453號（專利文 獻3)揭示了一種隨著維生素D代謝異常而發生的疾病之 治療劑’係含有艾爾骨化醇作爲有效成分。該疾病包含骨 質疏鬆症。 [先前技術文獻] [專利文獻] [專利文獻1]日本特表平11-501906 [專利文獻2]日本特許第3789956號 [專利文獻3]日本特許第1974453號 [非專利文獻] ’ [非專利文獻 1] JAMA，2001，285，785.201105333 VI. Description of the Invention: [Technical Field of the Invention] The present invention relates to a pharmaceutical composition comprising Alecbolic Alcohol (ED-7 1 ) for inhibiting non-traumaticity in patients with severe osteoporosis Vertebral body fracture; a method for inhibiting a non-traumatic vertebral body fracture in a patient with severe osteoporosis, comprising administering an effective amount of ergocalciferol; and ergocalciferol for use in the manufacture of the pharmaceutical composition Use. [Prior Art] Osteoporosis is defined as "a bone disease characterized by a decrease in bone strength and an increased risk of fracture" (Non-Patent Document 1), and bone structure changes with a decrease in bone density. Various parts such as the vertebral body, the distal end of the curved bone, and the femoral neck become prone to fracture. In the case of sputum osteoporosis, an estimated 11 million people were estimated at the time of 2002. Osteoporosis is dominated by women overwhelming, and more than 80% are women. Among women, the bone mass has decreased drastically since the menopause period in the 40s to 50s. In the 60s, there will be 1 in 2 people, and in the case of 70 years old or older, it will be among 10 people. Seven people found a state of osteoporosis. Among men, osteoporosis has increased slowly after more than 60 years of age, and about 4 out of 10 people are over 70 years old. As the population ages rapidly, the number of patients with osteoporosis will increase dramatically in the future. Osteoporosis is easily broken due to the fragility of bones, mainly in the spine (vertebral body), the vicinity of the femur, and the anterior wrist. Among them, the highest frequency of vertebral fractures occurred from -5 to 201105333. It is believed that there are 25% of the 70-75 years old and 43% of the 80-year-old or older. It causes pain or spinal deformity and abnormal posture, not only for daily life. As a result of the obstacles, it has also been found that the digestive system or the dysfunction of the respiratory system accompanying this causes a significant decrease in quality of life (QOL; Quality of Life). Even the vital prognosis is deteriorated, which is a cause of increasing the necessity of care (Non-Patent Document 2). In addition, fragility fractures caused by osteoporosis, in many cases, are accompanied by a continuous fracture called short-term “Fracture Cascade”. The report confirming this phenomenon is a report by Siris et al., which indicates that the frequency of new vertebral fractures will depend on the number of existing vertebral fractures. It can be seen that in the case of a decrease in bone mineral density T score of 2SD in the femur, The absolute risk of vertebral fractures was 2.4% in the absence of existing vertebral fractures, 7.2% in one existing vertebral fracture, 13.3% in two, and 20.7% in three, and the risk of fracture was The number of existing vertebral fractures is proportionally increased (Non-Patent Document 3). It is considered that this tendency becomes more pronounced in the case where the bone density is lowered. Among the results of clinical trial data on osteoporosis drugs implemented in North America and Europe and Australia, the proportion of vertebral fractures within 1 year, the patients who had vertebral fractures at the beginning of the test were 5.1 patients who did not have Times (95% confidence interval: 3.1, 8. 4). From this analysis, it can be seen that in the patient population with new vertebral fractures, the relative risk of recurrence of new fractures within 1 year is increased to 9 compared with the group of patients without new vertebral fractures. 3 times (9 5 % confidence interval: 1.2 > 7 1.6). -6- 201105333 There are also reports that the accumulation of vertebral fractures with pain is reduced by 50 to 62% of femoral neck fractures and may be an unhealthy cause of vertebral fractures until the age of 75, vertebral bodies The occurrence of fractures and their continuation are the main reasons for the decline in early-stage function (Non-Patent Document 4). Therefore, prevention of vertebral fractures in patients with osteoporosis is becoming a very important issue not only in the medical field but also in society. On the other hand, according to the guidelines compiled by the GL Production Committee for the Prevention and Treatment of Osteoporosis in 2006, the treatment of osteoporosis in Japan mainly uses calcium preparations, female hormone preparations, active vitamin D preparations, and vitamin K preparations. , bisphosphonate preparations, S ERM preparations, calcitonin preparations, isoflavone preparations, protein assimilation hormone preparations, and the like. In addition to these, treatments other than Japan include the use of PTH and its analogs, RANKL inhibitors, sputum preparations and the like. Among the current therapeutic agents, the most frequently used one is the bisphosphonate formulation. One of the bisphosphonates, alendronate, which is continuously treated at 10 mg/day, can reduce the risk of vertebral fractures in postmenopausal osteoporosis patients and increase BMD. In addition, in recent years, there have been reports in the literature that there is a risk of reducing the risk of spinal fracture or preventing the deformation of the spine and the reduction of the height (Patent Document 1). However, bisphosphonate, as a therapeutic agent for osteoporosis, has increased BMD, but it has also been suggested that there is a possibility that bone mass damage may occur due to accumulation of minute bone damage. There are even reports that alendronate has poor patient compliance due to harsh rules or side effects. In general, bisphosphonates are chelated in combination with calcium in foods, which hinders the absorption of 201105333. Therefore, it should be taken on an empty stomach, or esophagitis or esophageal ulcers, and taken in a standing or sitting position with sufficient dose. 'After taking it, you can't lie down for more than 30 minutes, and the harsh clothes are now. 'Reducing these restrictions. New bisphosphonate agents are being developed in recent years.' When taking bisphosphonates, the tibia during dental treatment is particularly noticeable. In addition, there are reports of muscular side effects such as bone and joint pain, and there are safety problems. Regarding other osteoporosis treatments, it has also been reported that raloxifene hydrochloride, an active ingredient in the agent, increases the risk of venous blood stasis or infarction, and the risk of vasomotor symptoms, PTH increases the risk of animals, etc., and each drug is safe. Each has serious questions that PTH and RANKL inhibitors are subcutaneous or intravenous injections with problems that are not suitable for long-term administration and the like. On the other hand, there are reports on the treatment of osteoporosis in addition to bisphosphonates, as well as vitamin D. According to a comprehensive analysis conducted outside Japan, the usual vitamins are treated with vitamin D. In the case of total and placebo, the relative risk relative to placebo (RR: Relative 95% confidence interval) was 0.63 (0.45 to 0.88), and the frequency of inhibition of vertebral formation was approximately 37% (Non-Patent Document 5). In addition, there is also a method for inhibiting the body fracture of Alfacalcitol, which is one of vitamin D derivatives, in an elderly person over 75 years old and a patient with a fracture (Non-Patent Document 6). Vitamin D does not cause a reduction in compliance observed with other co-effect drugs or a water-based restriction for prevention. However, the problem of necrosis is the osteosarcoma of the SERM of the meat skeleton. Further, it is also considered to have a compound, a protein D or a line of comparison of the Risk) (the disclosure of the body fracture revealed by the obvious vertebral compound, in the role of the severe -8 - 201105333 In view of the fact that it is a therapeutic agent for osteoporosis that is necessary for long-term administration, it is a very excellent drug. One of the vitamin D compounds, ercocalcitol, has been invented since 1985. A large number of patents and non-patent documents have been reported. One of them is Japanese Patent No. 3789956 (Patent Document 2), which relates to a "bone healing promoter" containing Alcoholic Alcohol as an active ingredient. The promotion of bone healing refers to the promotion of a bone repair process with necessary bone re-engagement after bone elongation, bone fracture, fracture, bone graft, etc., and therefore fracture inhibition or prevention without such re-engagement In addition, Japanese Patent No. 1974453 (Patent Document 3), which discloses "medicine with a new vitamin D 3 derivative as an active ingredient", discloses an abnormality in vitamin D metabolism. The present invention relates to a therapeutic agent for a disease which contains an osteocalcin as an active ingredient. The disease includes osteoporosis. [Prior Art Document] [Patent Document] [Patent Document 1] Japanese Patent Application No. 11-501906 [Patent Document 2 Japanese Patent No. 3789956 [Patent Document 3] Japanese Patent No. 1974453 [Non-Patent Document] [Non-Patent Document 1] JAMA, 2001, 285, 785.
[非專利文獻 2] Osteoporosis Int·，2000，11(7)，5 56. [非專利文獻 3] Osteoporosis Int., 2007，18(6)，761. 201105333 [非專利文獻4 ] h 11 p : / / www.ebm-library.jp/osteo/kanren/02/index.html [非專利文獻 5] Endocr. Rev.，2002，23(4)，560.[Non-Patent Document 2] Osteoporosis Int., 2000, 11(7), 5 56. [Non-Patent Document 3] Osteoporosis Int., 2007, 18(6), 761. 201105333 [Non-Patent Document 4] h 11 p : / / www.ebm-library.jp/osteo/kanren/02/index.html [Non-Patent Document 5] Endocr. Rev., 2002, 23(4), 560.
[非專利文獻 6] J.Bone Mineral. Metab.，1992，10, 184. 【發明內容】 [發明所欲解決之課題] 因此，本發明目的爲提供一種醫藥組成物，可預防骨 折發生風險高之重症骨質疏鬆症患者的非外傷性椎體骨折 ，且效果高於現存之藥劑。 [用於解決課題之方法] 本發明提供一種醫藥組成物，係含艾爾骨化醇而成， 用於抑制重症骨質疏鬆症患者的非外傷性椎體骨折。宜將 本醫藥組成物投予至骨密度之T分數降低2.5SD以上，且 具有脆弱性骨折之重症骨質疏鬆症患者。宜對於原發性重 症骨質疏鬆症患者，以0.75 gg/天之用量口服投予艾爾骨 化醇。 如上述般骨折的抑制或預防，在並不會伴隨骨骼的再 接合這點上與先前技術的促進骨癒合相異，因此以艾爾骨 化醇抑制非外傷性椎體骨折之用途，爲本發明人等最先發 現。另外，如先前技術所述般，係以艾爾骨化醇作爲一般 骨質疏鬆症之治療劑，而並未提示抑制骨折風險大幅提高 -10- 201105333 的重症骨質疏鬆症之非外傷性椎體骨折之用途，因此以艾 爾骨化醇抑制重症骨質疏鬆症患者的非外傷性椎體骨折之 用途，仍然是由本發明人等最先發現。 [發明之效果] 藉由本發明，可預防骨折發生風險高之重症骨質疏鬆 症患者的非外傷性椎體骨折，而且效果高於現存藥劑。本 發明中之椎體骨折抑制效果，明顯高於同種類同效果藥物 的阿法骨化醇，遠超過由業界人士的常識所預測的層級。 【實施方式】 在本說明書及申請專利範圍全部內容，適用以下之定 義。 艾爾骨化醇（eldecalcitol )，是指開發代碼「ED-7 1 」之化合物，具有化學名：（lR，2R，3R，5Z，7E)-2-(3-_ 基丙氧基）-9，10-開環膽甾- 5,7,10 ( 19 )-三烯-1，3,25-三 醇（（1 R，2R，3R，5Z，7E ) -2- ( 3-hydroxypropyloxy )- 9，l〇-secocholesta-5,7，l〇 ( 19) -triene-l，3,25-triol)之化 合物。 骨質疏鬆症可分類爲原發性骨質疏鬆症與續發性骨質 疏鬆症。原發性骨質疏鬆症，係進一步包含特發性骨質疏 鬆症、I型骨質疏鬆症、以及II型骨質疏鬆症。 特發性骨質疏鬆症’發生於兒童或具有正常性腺機能 之青年男女，I型骨質疏鬆症（停經後骨質疏鬆症）」是 -11 - 201105333 發生在5 1〜7 5歲之間，女性容易罹患的機會爲男性的6 倍左右，而性腺摘除後或血清中睪固酮濃度低的男性也會 發生。II型骨質疏鬆症（退化性或老人性骨質疏鬆症）與 正常的老化過程等有關連，一般而言是60歲以上之患者 會發病。在高齡女性中，I型與Π型經常一起發生。 本發明之翳藥組成物之投予對象爲重症骨質疏鬆症患 者，若進一步加以限定，則爲重症原發性骨質疏鬆症患者 〇 依據世界衛生組織（WHO : World Health Organization)之診斷基準，骨質疏鬆症之重症度，係依 照骨密度以及脆弱性骨折數而定義。於此基準之中，「正 常」定義爲相對於年輕成人基準之平均（Young Adult Mean，YAM)骨密度之T分數在-1SD以內，以下將「低 骨量（骨量減少）」定義爲骨密度之T分數爲-1〜-2.5 SD ，「骨質疏鬆症」定義爲骨密度之T分數爲-2.5SD以下 ，並且將「重症骨質疏鬆症」定義爲骨密度之T分數爲 -2.5 SD以下且具有1處以上之脆弱性骨折。此處，SD係 標準差値。 骨密度（BMD: Bone Mineral Density)是每單位面 積的骨量（骨重量），以g/cm2 (平方公分）表示。在骨 質疏鬆症診斷時，測定項目爲腰椎骨密度。其係藉由X 射線或超音波測定脊椎（腰椎）骨密度所得到，脊椎骨密 度是由YAM之比例（％ )數値化而得。在現今日本的診 斷基準中，YAM之70%以下則視爲「骨質疏鬆症」而爲 -12- 201105333 容易骨折的狀態，70〜80%而爲骨骼逐漸變脆弱的狀態則 視爲「骨減少症」，而80%以上則視爲「正常」。 對於骨密度之測定而言，有多種方法，具體地可列舉 DXA ( Dual Energy X-ray Absorptiometry)法：雙重能量 X 射線吸收法、QCT ( quantitative computed tomograghy )法：定量的電腦斷層攝影法、pQCT (peripheral quantitative computed tomograghy)法：末梢型定量的電 腦斷層法、QUS ( Quantitative ultrasound)法：定量的超 音波法等》其中DXA法，係使用兩個相異能量的X射線 束，藉由脈衝高的解析區別骨骼與軟部組織，並測定骨鹽 量（單位：g )。進一步測量由照射X射線方向觀察到的 骨骼投影面積（cm2)，將該骨鹽量除以投影的骨骼面積 ，藉此可得到DXA法之骨密度（g/cm2 )。本發明中之骨 密度，宜以DXA法、QCT法、pQCT法、QUS法、 RA/MD法、較佳爲藉由DXA法、QUS法測定。測定部位 可列舉腰椎、股骨、全身骨、撓骨、踵骨、脛骨、手骨、 指骨等’宜爲軀幹骨，以DXA法測定腰椎、股骨、全身 骨’以末梢骨D X A法測定撓骨、踵骨，或以q u s法測定 踵骨。 T分數是指骨密度的所謂「偏差値」，以γ A M之骨 密度爲基準時’表示偏離基準至何種程度的標準差値（ SD) 。丁分數如以下方式計算： -13- 201105333 [數1] τ分數=(受試者之測定骨密度値-100%YAM値） /100%YAM値之標準差 100% YAM骨密度値與其標準差（SD )，分別由測定 所使用之機器決定。在本發明中，對於股骨附近部位骨作 密度測定時，在使用Hologic公司之密度測定器QDR的 情況，分別將100% YAM値採用0.8 63 g/cm2，標準差採用 0.1 1 0 (任一者皆記載於，原發性骨質疏鬆症之診斷基準 (2 000年度改訂版）折茂肇；林泰史以及其他人等：曰 本骨代謝學會雜誌18 (3) : 76-82，2001)代入上式而計 算T分數。另一方面，在使用Lunar公司之骨密度測定器 DPX的情況，只要將藉由該測定器所得到之値，代入同樣 是原發性骨質疏鬆症之診斷基準（2000年度改訂版）折 茂肇；林泰史以及其他人等：日本骨代謝學會雜誌18(3 ):76-8 2, 2 00 1所記載之下式，即可轉換爲QDR測定近 似値。將其代入上式即可得到T分數。以下實施例1中， T分數係從使用QDR或DPX之任一者所得到之骨密度算 出。 [數2] QDR測定近似値= (DPX測定骨密度値+ 〇.〇92)/1 .294 如前述般，在日本YAM之70%以下則定義爲「骨質 -14- 201105333 疏鬆症」，而且爲容易骨折的狀態，而日本蕋準的「YAM 之70%」，相當於日本以外基準的「骨密度之τ分數爲 相對於YAM値而言的約-2.5SD」’對於日本基準骨密度 以YAM的多少％表示，與日本以外的基準差別是以由 YAM降低多少SD單位表示，而基本上沒有多大差異（ http://www. ebm-library.jp/osteo/guideline/guide02.html ) 〇 本發明之重症骨質疏鬆症患者，比照日本以外的診斷 基準，是表示在股骨附近部位骨密度之T分數爲-2.5SD 以下且具有脆弱性骨折之患者，進一步加以限定，則表示 股骨附近部位骨密度之T分數爲-2.5 SD以下且具有2處 以上脆弱性骨折之患者，而關於骨密度若利用日本的診斷 基準，則亦可置換爲股骨附近部位骨密度爲YAM之70% 以下且具有脆弱性骨折之患者，進一步加以限定，則爲股 骨附近部位骨密度爲YAM之70%以下且具有2處以上脆 弱性骨折之患者。 脆弱性骨折是指以低骨量（骨密度未達YAM之80% 、或在脊椎X射線影像有骨質疏鬆化的情況）爲原因， 由輕微外力所造成的非外傷性骨折。在本發明中，脆弱性 骨折宜爲椎體骨折。因此，以Genant等的SQ grade爲基 準（HARRY K. GENANT，et al : J Bone Miner Res 1 993 ; 8 : 1 1 3 7 - 1 1 4 8 ) ’由內科醫師、矯形外科醫師、放射線科 醫師這二位判定委員中至少兩位，獨立地對於由椎體正面 以及側面拍攝到的胸、腰椎X射線照片中第4胸椎至第4 -15- 201105333 腰椎合計1 3椎體進行讀片，使用所得到之照片而進行脆 弱性骨折之計數。另外，獨立進行的判定之中有2位以上 的被認爲是不一致的情況，由上述3位再度進行協議，而 決定是否有椎體骨折。 非外傷性骨折，意指因爲跌倒等一般在曰常生活發生 的輕微外力所造成的骨折。相反地，外傷性骨折意指因爲 交通事故等較大的外力所造成的骨折。 骨強度是由骨密度與骨質這兩個主要因素所構成，每 單位體積骨量的骨密度能說明骨強度大槪70%的要素， 殘餘30%的要素是由微細構造、骨代謝循環、微小骨折 、石灰化的因子所構成的骨質來說明。 用於抑制骨折之醫藥組成物，是指可預防骨折，因此 亦可稱爲預防骨折用之醫藥組成物。本發明中之抑制或預 防，意指在骨質疏鬆症罹患者之中，不會發生新的骨折。 含有本發明之化合物作爲有效成分之醫藥組成物，係 使用在該領域之中通常所使用的藥劑用添加劑，可藉由通 常所使用的各種製劑之調製方法而調製。就上述添加劑而 言，可列舉一般醫藥所使用之賦形劑、結合劑、滑澤劑、 崩壞劑、著色劑、矯味矯臭劑、乳化劑、界面活性劑、溶 解補助劑、懸浮化劑、等張化劑、緩衝劑、防腐劑、抗氧 化劑、安定化劑、吸收促進劑等，亦可將該等適當地組合 使用。劑形可爲錠劑、九劑、膠囊劑、顆粒劑、藥粉、液 劑等口服投予所適合的劑形，或者注射劑、外用劑、吸入 劑等、關節內、靜脈內、肌肉內等非口服投予所適合的劑 -16- 201105333 形之任一者皆可。 就口服投予所用的固體組成物而言，可使用錠劑、藥 粉、顆粒劑等。在如此的固體組成物之中，係一種或兩種 以上之有效成分與至少一種不活性賦形劑，例如乳糖、甘 露醇、葡萄糖、白糖、蔗糖等糖類、結晶纖維素、澱粉、 碳酸鈣、矽酸鋁、偏矽酸鋁鎂等無機物等混合。本醫藥組 成物’依據常法亦可進一步含有添加劑，例如硬脂酸鎂般 的滑澤劑或羧甲基纖維素鈣，或如海藻酸鈉等般的崩壞劑 、安定化劑、聚乙二醇等溶解補助劑、聚乙烯醇等結合劑 、可可粉等矯味矯臭劑、如月桂基硫酸鈉般的乳化劑或界 面活性劑等。錠劑或九劑亦可依照必要以糖衣或胃溶性或 腸溶性物質之薄膜加以包膜。口服投予所用的液體組成物 包含藥學上所容許之乳濁劑、溶液劑、懸浮劑、糖漿劑或 酏劑等，一般而言所使用的不活性稀釋劑，包含例如精製 水或乙醇。液體醫藥組成物除了不活性稀釋劑以外，亦可 含有如可溶化劑、濕潤劑'懸浮劑般的補助劑、甘味劑、 風味劑、芳香劑、防腐劑。 非口服投予所用的注射劑，係含有無菌之水性或非水 性溶液劑'懸浮劑或乳濁劑。就水性溶劑而言，包含例如 注射用蒸餾水或生理食鹽水。就非水性之溶劑而言，有例 如丙二醇'聚乙二醇或如橄欖油般的植物油、如乙醇般的 醇類、或Polysorbate 80 (藥方名）等。如此的醫藥組成 物亦可進一步含上述添加物，例如等張化劑、防腐劑、濕 潤劑、乳化劑、分散劑、安定化劑、抗氧化劑、緩衝劑、 -17- 201105333 吸收促進劑或溶解補助劑。該等係藉由例如通過細菌截留 過濾器進行過濾、殺菌劑之摻合或照射而無菌化。另外， 還可將該等製造成無菌之固體組成物，於使用前溶解或懸 浮於無菌水或無菌注射用溶劑而後使用。亦可將可含該等 補助劑等的溶液收納於容器後，藉由冷凍乾燥等製成固體 製劑，而成爲使用時調製之製劑。另外，可將一次的投予 量收納於一個容器，另外還可將多次的投予量收納於一個 容器。 外用劑包含栓劑、經皮膚用液劑、經皮膚用貼附劑、 經黏膜貼附劑、軟膏劑、硬膏劑、乳霜劑、凝膠劑、巴布 劑、噴霧劑、洗劑、點眼劑、眼軟膏等。含有一般所使用 之軟膏基劑、洗液基劑、水性或非水性之液劑、懸浮劑、 乳劑等。例如就軟膏或洗液基劑而言，可列舉聚乙二醇、 丙二醇 '白色凡士林、石蠟、白蜜蠟、聚氧乙烯硬化蓖麻 油、單硬脂酸甘油、硬脂醯醇、鯨蠟醇、聚桂醇（ Lauromacrogol )等 〇 吸入劑或經鼻劑等經黏膜劑，係使用固體、液體或半 固體狀之物，可依照以往周知的方法而製造。可適當地添 加例如周知的賦形劑，或進一步亦可適當地添加pH調整 劑、防腐劑、界面活性劑、滑澤劑、安定劑或增黏劑等。 投予可使用適當的吸入或吹送所用的裝置。例如可使用計 量投予吸入裝置等周知的裝置或噴霧器、以單獨化合物或 配方的混合物粉末的形式，或與醫藥上可容許之載體組合 ，以溶液或懸浮液的形式投予。乾燥粉末吸入器等可爲單 -18- 201105333 &或多次的投予用，或可利用乾燥粉末或粉末含有膠囊。 $者亦可採用以適當的氣體將其驅出的加壓氣溶膠噴霧等 形態。 本發明之化合物可使用於哺乳類（特別是人）的骨折 防。投予量及投予間隔，因應於包含患者之身高、體重 '年齡、性別或醫學上的症狀、欲治療症狀之嚴重程度、 投:予途徑、患者的肝腎機能、病歴，以及所使用之特定化 合物或其鹽等各種要素，經由醫師的判斷適當地選擇。 通常對人體口服投予之情況、1天的投予量係以0.01 〜l.Ogg爲適當（宜爲0.5〜l.Opg、更佳爲0.75pg)，將 其以1次或分成2至4次投予。非口服投予之情況、1天 的投予量，係以0.01〜1.0 pg爲適當（宜爲0.25〜l.Opg) ’投予量係考慮症狀、年齡、性別等，因應各別的情況而 適當地決定，其中亦包含在一定期間之中改變用量》或者 以低使用量長期間投予，亦可得到相同的治療效果。 爲了得到能夠觀測到的效果，患者在相當期間，實際 上每天接受艾爾骨化醇的投予爲佳。考慮到患者在持續至 少8週（宜爲24週、較佳爲96週、更佳爲更長的144週 以上）期間的治療期間中，有時候也可能會有未接受艾爾 骨化醇的投予的期間，然而由該期間所測量到的修正血清 鈣値及修正尿中鈣値，在停藥中也能確認艾爾骨化醇之效 果充分地持續，因此包含如此的停藥期間的情形亦屬於本 發明之範圍內。 有效量意指至少使骨折的風險機率減少所必要的量， -19 - 201105333 但是未達毒性量的艾爾骨化醇量。 相當期間意指爲了使患者的骨密度及骨強度增加，難 以發生骨折所需要的足夠長的時間量。本發明中之相當期 間是指至少24週以上，較佳爲48週以上，更佳爲丨44週 以上。 實際上每天’係意指投予以每天爲原則，而認爲全效 果與患者每天接受投予的情況沒有差異的程度，患者不小 心漏掉投予的日子亦可包含在內。 本發明之化合物，可與認爲前述本發明之化合物會表 現出有效性的各種疾病治療劑或預防劑倂用或循環使用。 倂用是指同時服用兩種以上的藥劑，與在相同服用期間之 中，將時間錯開而服用兩種以上的藥劑，這兩種情況皆包 含在內。循環使用是指患者在既定期間接受艾爾骨化醇的 投予’接下來在第二期停止艾爾骨化醇的投予（接受追加 的骨形成促進劑或骨吸收抑制劑以及/或荷爾蒙療法或不 接受皆可），然後返回艾爾骨化醇療法。一般而言，骨質 疏鬆症的病因涉及的範圍很廣，因此難以解析某患者由於 何種病因而產生何種病況的情形很多。另外，骨質疏鬆症 病期也很多種，現在還是採用集團的形式對各種狀態的患 者一起實施治療。因此，在臨床上，也有進行將作用機制 相異的兩劑或三劑以上加以組合的多劑倂用療法或循環使 用療法的情形。該倂用療法或循環使用療法，其目的爲將 作用機制相異的藥劑加以組合，以使副作用減輕或骨折抑 制作用增強。該倂用或循環使用，亦可隔著所希望的時間 -20- 201105333 間隔。同時投予的製劑，可爲混合劑或者可各別製劑化。 就可倂用或循環使用的藥劑而言，可列舉由雌激素或 雌激素衍生物、雙膦酸酯、抗雌激素或選擇的雌激素受體 調節子、α V Θ 3整合素阻礙劑、組織蛋白酶K阻礙劑、 HMG-CoA還原酵素阻礙劑、破骨細胞液胞型ΑΤΡ酶阻礙 劑、破骨細胞受體的VEGF結合的拮抗劑、過氧化小體增 殖因子活性化受體r、降鈣素、鈣受體拮抗劑、副甲狀腺 荷爾蒙或副甲狀腺荷爾蒙衍生物、成長荷爾蒙分泌促進物 質、人類成長荷爾蒙、胰島素樣成長因子、P-3 8蛋白質 激酶阻礙劑、骨形態形成蛋白質、BMP拮抗作用之阻礙 劑、前列腺素衍生物、維生素K或維生素K衍生物、依 普黃酮、氟化物鹽、鈣營養補助食品及雄性素受體調節子 選擇一種或其以上之藥劑，具體而言，可列舉L-天冬胺 酸鈣、磷酸氫鈣、雌三醇、17卢雌二醇、四烯甲萘醌（ Menatetrenone )、阿侖膦酸鹽（Alendronate)、依替膦 酸鹽（Etidronate)、利塞膦酸鹽（Risedronate)、伊班 膦酸鹽（Ibandronate )、鹽酸雷洛昔芬、依降鈣素、鮭魚 降鈣素、依普黃酮、癸酸諾龍、特立帕肽（Teriparatide )等藥劑。其中特別適合的藥劑，係雙膦酸酯、抗雌激素 或選擇的雌激素受體調節子、降鈣素，具體而言阿侖膦酸 鹽、依替膦酸鹽、利塞膦酸鹽、伊班膦酸鹽、鹽酸雷洛昔 芬、依降鈣素、鮭魚降耗素。 藉由臨床測試數據之解析，顯示出若在相當期間實際 上每日投予有效量之艾爾骨化醇，則能夠使重症骨質疏鬆 -21 - 201105333 症患者的非外傷性椎體骨折之風險減少。 藉由在以下所揭示之實施例，對本發明作具體說明， 而本發明並不受到該等所限定，該等在任何意義方面的解 釋皆不受到限定。 [實施例] 實施例1 以原發性骨質疏鬆症患者爲對象，藉由隨機分配雙盲 檢測群間比較測試（randomized double blind Between-group comparison )對於艾爾骨化醇之有效性與阿法骨化 醇對照而作檢討。 患者群：將平均年齡72.1歲（46〜92歲）之原發性 骨質疏鬆症患者之重症患者依照以下方式分群： A群：股骨附近部位骨密度之T分數爲-2.5 S D以下 且脆弱性椎體骨折； B群：股骨附近部位骨密度之T分數爲-2.5SD以下且 脆弱性椎體骨折2處以上。 用量以及投予： 艾爾骨化醇（ED-71) : 0.75pg/天，口服投予 阿法骨化醇（ALF) : l.Ogg/天，口服投予。 分別基於W02005/074943、日本特許第4070459號， 調製出測試所使用的製劑。 投予期間：艾爾骨化醇（ED-71)與阿法骨化醇（ ALF)—起持續投予144週（後觀察4週） -22- 201105333 新的椎體骨折之評估：以S Q g r a d e爲基準，由內科 醫師、矯形外科醫師、放射線科醫師這3位判定委員中至 少2位獨立地對於在投予開始時、6個月、1年、2年、3 年或隨時由椎體的正面以及側面拍攝到的胸、腰椎X射 線照片中第4胸椎至第4腰椎合計1 3椎體進行讀片，在 與投予開始時相比認爲有發生變形的情況，測量椎體之前 緣高度、中央高度、後緣高度，將與投予前相比認爲有 1 5 %且4mm以上減少的椎體，評爲新的椎體骨折。另外 ’在獨立進行的判定之中有2位以上的判定被認爲是不一 致的情況’係由上述3位再度進行協議，而決定是否有新 的椎體骨折。 爲了校正維生素D營養學上的不足，對於在開始投 予則25(OH) D値未達20ng/mL的患者補充400IU之維 生素D補給劑。艾爾骨化醇投予期間中、維生素〇補給 劑之投予量不作變更，而修正sCa値超過1丨.Omg/dL以上 或10.4mg/dL ’醫師判斷持續投予會有問題的情況，則停 止艾爾骨化醇及維生素D補給劑之投予，符合補正sCa 値爲10.4mg/dL以下，且修正uCa値爲0.40mg/dL GF以 下的情況’變更爲下述投予量再度開始投予，其後不進行 投予量之變更。 艾爾骨化醇（ED-71) : 〇.5pg/天，口服投予 阿法骨化醇（ALF ) : 〇.5pg/天，口服投予。 表1及表2分別揭示艾爾骨化醇/阿法骨化醇投予時 之A群以及B群患者的非外傷性新的椎體骨折在〗4 4週 -23- 201105333 期間之發生數。表3揭示了包含重症以及輕症可收集數據 的全體原發性骨質疏鬆症患者（股骨骨密度之平均T分數 在艾爾骨化醇群爲-2.27±0.79、阿法骨化醇群爲-2.2 6±0.82 ，而脆弱性骨折在艾爾骨化醇群爲1.2± 1.3個，阿法骨化 醇群爲1.2±1.4個）之非外傷性新的椎體骨折之144週發 生頻率。 [表1] 表1. 藥劑投予時A群之非外傷性新的椎體骨折之144 週發生頻率 ALF投予群(132例） ED-71投予群(141例） 非外傷性新的椎體骨折發生數 41件 23件 [表2] 表2. 藥劑投予時B群之非外傷性新的椎體骨折之1 44 週發生頻率 ALF投予群C75例） ED-71投予群(73例） 非外傷性新的椎體骨折發生數 34件 18件 [表3] 表3 .藥劑投予時全體原發性骨質疏鬆症患者之非外傷性 新的椎體骨折之144週發圭 ALF投予群(523例） ED-71投予群(526例） 非外傷性新的椎體骨折發生數 80件 64件 表4係藉由對數秩（logrank)檢定及COX迴歸’對 -24- 201105333 於全部患者、A群、B群，投予艾爾骨化醇/阿法骨化醇所 產生之非外傷性新的椎體骨折頻率之抑制效果之差異進行 評估。 [表4] 表4. 藉由對數秩檢定、分層C OX迴歸進行的非外傷性 新的椎體骨折之群間比較 艾爾骨化醇 對數秩檢定 cox迴歸 VS 阿法骨化醇 (P値） 危險比 90%信賴區間 非外傷性新的椎體骨折 0.046 0.74 [0.56 ： 0.97] 骨密度爲τ分數-2.5SD以下 且有脆弱性骨折的患者群 0.0032 0.495 [0.323 ： 0.761] 骨密度爲T分數12.5SD以下 且有椎體骨折2個以上的患者群 0·⑻ 52 0.477 [0.295 ： 0.771] 注1.危險比表示艾爾骨化醇對阿法骨化醇之非外傷性新的 椎體骨折危險率比。 對數秩檢定，基本上是指將整個期間的相對危險度加 以平均，對於此平均相對危險度（RR )在統計學上是否 爲有意義的，進行卡方檢驗（chi square test)。 COX迴歸，是指欲調查某些其他因素在事件發生爲 止的期間所產生的效果時所使用的方法，且係假定比例危 險性（以比例常數的形式，乘以當作基準個體的危險）的 方法。危險是指至某時間點爲止，並未發生新的非外傷性 椎體骨折，而表示在該時間點非外傷性椎體骨折的機率（ 新的非外傷性椎體骨折的瞬間機率）。危險比係意指兩群 -25- 201105333 的危險比。亦即表示以其中一群作爲基準的情況下， 群會有多少倍的非外傷性新的椎體骨折機率。 對數秩檢定的結果可知，關於全原發性骨質疏鬆 者中非外傷性新的椎體骨折發生爲止的時間，艾爾骨 (ED-71 )投予群與阿法骨化醇（ALF )投予群相比 顯著水準（significance level)單側5%有明顯的差j =0.046 )。另外還確認了在COX迴歸之中，關於非 性新的椎體骨折發生爲止的時間，ED-7 1投予群比 投予群更具有效果（危險比：0.74，90 %信賴區 confidence interval，CI: 0.56〜0.97)。由危險比之 判明，若將ALF投予群的骨折機率定爲1，則ED·: 予群的機率爲0.74，非外傷性新的椎體骨折的發生危 減少2 6 % » 再者，此骨折抑制效果，根據WHO之診斷基準 定義爲重症骨質疏鬆症（骨密度之T分數爲-2.5SD 且有脆弱性骨折）的集團中，從對數秩檢定與分層 迴歸之任一分析看來，皆可確認相對於阿法骨化醇而 艾爾骨化醇的有效性具有更大的差異。亦即，在重症 疏鬆症（骨密度之T分數爲-2.5 SD以下且有脆弱性 )群之中，對數秩檢定之Ρ値爲〇.〇〇32，在新的椎體 發生上觀察到了明顯的差異。另外，由危險比之値看 骨折發生危險率約減少5 0 %，並偵測到較顯著的差 危險比：0.495，90%CI :0.323 〜0.761)。[Non-Patent Document 6] J. Bone Mineral. Metab., 1992, 10, 184. [Disclosure] [Problems to be Solved by the Invention] Accordingly, an object of the present invention is to provide a pharmaceutical composition which can prevent a high risk of fracture Non-traumatic vertebral fractures in patients with severe osteoporosis, and the effect is higher than the existing agents. [Means for Solving the Problems] The present invention provides a pharmaceutical composition comprising Alcoholic Alcohol for inhibiting non-traumatic vertebral fractures in patients with severe osteoporosis. It is advisable to administer this pharmaceutical composition to patients with severe osteoporosis with a T-score reduction of bone mineral density of 2.5 SD or more and a fracture. It is advisable to orally administer Alcohol in 0.75 gg/day for patients with primary severe osteoporosis. As described above, the inhibition or prevention of fractures is not related to the promotion of bone healing in the prior art, and is not related to the promotion of bone healing in the prior art. Therefore, the use of Algonhydrin to inhibit non-traumatic vertebral fractures is The inventors first discovered. In addition, as described in the prior art, Algonhydrin is used as a therapeutic agent for general osteoporosis, and does not suggest a significant increase in the risk of fracture prevention. -10-201105333 Non-traumatic vertebral fracture of severe osteoporosis The use thereof, and therefore, the use of Algonhydrin to inhibit non-traumatic vertebral fractures in patients with severe osteoporosis is still first discovered by the present inventors. [Effect of the Invention] According to the present invention, a non-traumatic vertebral fracture of a patient with severe osteoporosis with a high risk of fracture can be prevented, and the effect is higher than that of an existing medicament. The inhibitory effect of the vertebral body fracture in the present invention is significantly higher than that of the same type of drug, and far exceeds the level predicted by the common sense of the industry. [Embodiment] The following definitions apply to the entire contents of the specification and the patent application. Eldecalcitol is a compound of the development code "ED-7 1" with the chemical name: (lR, 2R, 3R, 5Z, 7E)-2-(3-_propoxy)- 9,10-open-loop cholesteric - 5,7,10 ( 19 )-triene-1,3,25-triol ((1 R,2R,3R,5Z,7E ) -2- ( 3-hydroxypropyloxy ) - 9,l〇-secocholesta-5,7,l〇( 19)-triene-l,3,25-triol). Osteoporosis can be classified into primary osteoporosis and persistent osteoporosis. Primary osteoporosis further includes idiopathic osteoporosis, type I osteoporosis, and type II osteoporosis. Idiopathic osteoporosis' occurs in children or young men and women with normal glandular function, type I osteoporosis (osteoporosis after menopause)" is -11 - 201105333 occurs between 5 1 and 7 5 years old, female is easy The chance of suffering is about 6 times that of men, and it can occur in men after gonadectomy or in patients with low concentrations of testosterone in serum. Type II osteoporosis (degenerative or senile osteoporosis) is associated with normal aging processes, and is generally common in patients over 60 years of age. In older women, type I and sputum often occur together. The drug composition of the present invention is administered to a patient with severe osteoporosis, and if it is further limited, it is a patient with severe primary osteoporosis, according to the diagnostic criteria of the World Health Organization (WHO): The severity of the looseness is defined by the bone density and the number of fractures. In this benchmark, "normal" is defined as the T-score of the Young Adult Mean (YAM) bone mineral density within -1 SD. The following is defined as "low bone mass (bone reduction)" as bone. The T score of density is -1 to -2.5 SD, "osteoporosis" is defined as the T-score of bone density is -2.5 SD or less, and "severe osteoporosis" is defined as the T-score of bone density is -2.5 SD or less. And has more than one vulnerable fracture. Here, the SD standard is 値. Bone Mineral Density (BMD) is the amount of bone per unit area (bone weight) expressed in g/cm2 (square centimeters). In the diagnosis of osteoporosis, the measurement item was lumbar spine bone mineral density. It is obtained by measuring the bone density of the spine (lumbar spine) by X-ray or ultrasonic wave, and the density of the spine is obtained by subtracting the ratio (%) of YAM. In the current diagnostic criteria, 70% or less of YAM is considered to be "osteoporosis" and is -12-201105333. It is easy to fracture. 70 to 80% of the bones are gradually weakened. "80" is considered "normal". For the determination of bone density, there are various methods, specifically DXA (Dual Energy X-ray Absorptiometry) method: dual energy X-ray absorption method, QCT (quantified computed tomograghy) method: quantitative computed tomography, pQCT (peripheral quantitative computed tomograghy) method: peripheral quantitative computer tomography, QUS (Quantitative ultrasound) method: quantitative ultrasonic method, etc." DXA method, using two different energy X-ray beams, by pulse high The analysis distinguishes between bone and soft tissue and determines the amount of bone salt (unit: g). Further, the bone projection area (cm2) observed by the irradiation X-ray direction is measured, and the bone salt amount is divided by the projected bone area, whereby the bone density (g/cm2) of the DXA method can be obtained. The bone density in the present invention is preferably measured by the DXA method, the QCT method, the pQCT method, the QUS method, the RA/MD method, or preferably by the DXA method or the QUS method. The measurement site may be a lumbar vertebra, a femur, a whole body bone, a bone, a tibia, a tibia, a hand bone, a phalanx, etc., which is preferably a trunk bone, and the DXA method is used to measure the lumbar vertebrae, the femur, and the whole body bone. The tibia, or the tibia is measured by the qus method. The T score refers to the so-called "deviation" of the bone density, and when the bone density of γ A M is used as a reference, it indicates the degree of standard deviation SD (SD) from the reference. The Ding score is calculated as follows: -13- 201105333 [Number 1] τ score = (subject measured bone density 値 -100% YAM 値) / 100% YAM 値 standard deviation 100% YAM bone density 値 and its standard deviation (SD), which is determined by the machine used for the measurement. In the present invention, when density measurement is performed on the bone near the femur, in the case of using Hologic's density measuring device QDR, 100% YAM値 is used as 0.8 63 g/cm 2 and standard deviation is 0.1 1 0 (either All are documented in the diagnosis of primary osteoporosis (2 000 annual revised edition); Lin Taishi and others: Sakamoto Bone Metabolism Society Journal 18 (3): 76-82, 2001) substituted into the above formula And calculate the T score. On the other hand, in the case of using the bone mineral density measuring device DPX of Lunar, the sputum obtained by the measuring instrument is substituted for the same diagnostic criteria (2000 revised edition) of primary osteoporosis; Lin Taishi and others, etc.: Japanese Journal of Bone Metabolism, 18(3): 76-8 2, 2 00 1 can be converted to QDR to determine the approximate 値. Substituting it into the above formula gives a T score. In the following Example 1, the T score is calculated from the bone density obtained using either QDR or DPX. [Number 2] QDR measurement approximate 値 = (DPX measurement of bone density 値 + 〇. 〇 92) / 1.294 As mentioned above, 70% or less of YAM in Japan is defined as "bone-14-201105333 looseness", and In order to be in a state of easy bone fracture, Japan’s "70% of YAM" is equivalent to the "traditional τ score of bone density is about -2.5 SD relative to YAM" for the Japanese benchmark. The percentage of YAM indicates that the difference from the benchmark outside Japan is expressed by how many SD units are reduced by YAM, and there is basically no significant difference (http://www.ebm-library.jp/osteo/guideline/guide02.html) 〇 The patient with severe osteoporosis of the present invention is a patient who has a T-score of -2.5 SD or less and has a fragility fracture in the vicinity of the femur in comparison with a diagnostic criterion other than Japan, and further defines a bone near the femur. A patient whose density has a T-score of -2.5 SD or less and has two or more fragile fractures, and if the bone mineral density is based on the Japanese diagnostic criteria, the bone density in the vicinity of the femur can be replaced by 70% or less of the YAM and is fragile. Sexual bone For patients who have been discounted, it is further defined as a patient with a bone density near the femur that is less than 70% of YAM and has two or more fragile fractures. Vulnerable fracture refers to a non-traumatic fracture caused by a slight external force due to low bone mass (80% of bone density is not reached, or osteoporosis in the spine X-ray image). In the present invention, the fragility fracture is preferably a vertebral fracture. Therefore, based on the SQ grade of Genant et al. (HARRY K. GENANT, et al : J Bone Miner Res 1 993 ; 8 : 1 1 3 7 - 1 1 4 8 ) 'by a physician, orthopedic surgeon, radiologist At least two of the two judges independently read the 4th thoracic vertebrae of the thoracic and lumbar X-rays of the vertebral body and the 4th-15th 201105333 lumbar vertebrae total of 13 vertebral bodies. The resulting photograph was used to count the number of fragility fractures. In addition, two or more of the independently determined determinations are considered to be inconsistent, and the above three digits are re-agreed to determine whether or not there is a vertebral fracture. A non-traumatic fracture refers to a fracture caused by a slight external force such as a fall that usually occurs in a normal life. Conversely, a traumatic fracture means a fracture caused by a large external force such as a traffic accident. Bone strength is composed of two main factors: bone density and bone mass. The bone density per unit volume of bone mass can explain the factor of 70% of bone strength. The remaining 30% of the elements are composed of fine structure, bone metabolism cycle, and tiny The bones formed by the factors of fracture and calcification are explained. The pharmaceutical composition for suppressing fracture refers to a preventable fracture, and therefore may also be referred to as a pharmaceutical composition for preventing fracture. Inhibition or prevention in the present invention means that no new fracture occurs in patients with osteoporosis. The pharmaceutical composition containing the compound of the present invention as an active ingredient is a pharmaceutical additive which is generally used in the field, and can be prepared by a preparation method of various preparations which are usually used. Examples of the above additives include excipients, binders, slip agents, disintegrating agents, coloring agents, flavoring agents, emulsifiers, surfactants, dissolution aids, and suspending agents used in general pharmaceuticals. An isotonic agent, a buffering agent, a preservative, an antioxidant, a stabilizer, an absorption enhancer, and the like may be used in combination as appropriate. The dosage form may be a dosage form suitable for oral administration of a tablet, a nine-part, a capsule, a granule, a powder, a liquid, or the like, or an injection, an external preparation, an inhalant, etc., intra-articular, intravenous, intramuscular, etc. Oral administration of any suitable agent-16-201105333 can be used. For the solid composition to be administered orally, a tablet, a powder, a granule, or the like can be used. Among such solid compositions, one or two or more active ingredients and at least one inactive excipient, such as sugars such as lactose, mannitol, glucose, white sugar, sucrose, crystalline cellulose, starch, calcium carbonate, An inorganic substance such as aluminum citrate or aluminum magnesium metasilicate is mixed. The pharmaceutical composition 'may further contain an additive according to a common method, such as a magnesium stearate-like slip agent or calcium carboxymethyl cellulose, or a disintegrating agent such as sodium alginate, a stabilizer, and polyethylene. A dissolution aid such as a glycol, a binder such as polyvinyl alcohol, a flavoring agent such as cocoa powder, an emulsifier such as sodium lauryl sulfate, or a surfactant. The lozenge or the nine doses may also be coated with a film of a sugar-coated or stomach-soluble or enteric material as necessary. The liquid composition to be administered orally comprises a pharmaceutically acceptable emulsion, solution, suspension, syrup or elixir, and the like, and generally used as an inactive diluent, for example, purified water or ethanol. The liquid pharmaceutical composition may contain, in addition to the inactive diluent, a solubilizing agent, a wetting agent's suspending agent, a sweetener, a flavoring agent, a flavoring agent, and a preservative. Injectables for parenteral administration include sterile aqueous or nonaqueous solutions, such as suspending or emulsifying agents. In the case of the aqueous solvent, for example, distilled water for injection or physiological saline is contained. As the nonaqueous solvent, there are, for example, propylene glycol 'polyethylene glycol or vegetable oil such as olive oil, alcohol such as ethanol, or Polysorbate 80 (prescription). Such a pharmaceutical composition may further contain the above additives, such as isotonic agents, preservatives, wetting agents, emulsifiers, dispersants, stabilizers, antioxidants, buffers, -17-201105333 absorption enhancers or dissolved Subsidy. These are sterilized by, for example, filtration through a bacteria-retaining filter, blending or irradiation of a bactericide. Alternatively, these may be made into a sterile solid composition which is dissolved or suspended in sterile water or a sterile injectable solvent before use. A solution containing the above-mentioned auxiliary agent or the like may be stored in a container, and then a solid preparation may be prepared by freeze-drying or the like to prepare a preparation prepared at the time of use. Further, it is possible to store the dose in one container in one container, and to store the plurality of doses in one container. The external preparation comprises a suppository, a transdermal solution, a transdermal patch, a transmucosal patch, an ointment, a plaster, a cream, a gel, a cataplasm, a spray, a lotion, and an eye drop. Agent, eye ointment, etc. It contains an ointment base, a lotion base, an aqueous or non-aqueous liquid, a suspending agent, an emulsion, and the like which are generally used. For example, in the case of an ointment or a lotion base, polyethylene glycol, propylene glycol 'white petrolatum, paraffin wax, white beeswax, polyoxyethylene hardened castor oil, glyceryl monostearate, stearyl alcohol, cetyl alcohol, A mucosal agent such as an inhalant or a nasal spray such as a sulphate or a transnasal agent can be produced by a conventionally known method using a solid, a liquid or a semi-solid. For example, a well-known excipient can be added as appropriate, or a pH adjuster, a preservative, a surfactant, a slip agent, a stabilizer or a tackifier can be added as appropriate. The device used for proper inhalation or insufflation can be administered. For example, it may be administered in the form of a solution or suspension by using a known device such as a metered inhalation device or a nebulizer, in the form of a mixture of a single compound or a formulation, or in combination with a pharmaceutically acceptable carrier. The dry powder inhaler or the like may be used as a single -18-201105333 & or multiple times, or may be a dry powder or a powder containing capsules. The $ can also be in the form of a pressurized aerosol spray that is driven out by a suitable gas. The compounds of the invention are useful for the prevention of fractures in mammals, particularly humans. The dose and the interval of administration are based on the patient's height, weight 'age, gender or medical symptoms, the severity of the symptoms to be treated, the route of administration, the liver and kidney function of the patient, the disease, and the specific use Various elements such as a compound or a salt thereof are appropriately selected by a physician's judgment. Usually, when the human is administered orally, the dosage for one day is suitably 0.01 to 1.0 gg (preferably 0.5 to 1.0 gp, more preferably 0.75 pg), and it may be divided into 1 or 2 to 4 Sub-going. In the case of non-oral administration, the dosage for one day is 0.01 to 1.0 pg (preferably 0.25 to 1.0 gp). The dosage is considered in terms of symptoms, age, sex, etc., depending on the individual circumstances. Appropriately determined, which also includes the amount of change during a certain period of time or when administered for a long period of low use, the same therapeutic effect can be obtained. In order to obtain an observable effect, it is preferable that the patient actually receives the administration of Alecbolic Alcohol daily for a considerable period of time. In view of the patient's treatment period during a period of at least 8 weeks (preferably 24 weeks, preferably 96 weeks, more preferably longer than 144 weeks), sometimes there may be unacceptable Al-calcitol During the administration period, however, the corrected serum calcium sputum and the corrected urinary calcium strontium measured during the period were confirmed, and the effect of the esculinated alcohol was confirmed to be sufficiently sustained during the withdrawal, and thus the period of withdrawal was included. The situation is also within the scope of the invention. An effective amount means the amount necessary to reduce at least the risk of a fracture, -19 - 201105333 but the amount of escaping alcohol that does not reach the toxic amount. A comparable period means that in order to increase the bone density and bone strength of the patient, it is difficult to generate a sufficient amount of time for the fracture. The equivalent period in the present invention means at least 24 weeks or more, preferably 48 weeks or more, more preferably 44 weeks or more. In fact, every day is meant to be a daily basis, and the full effect is considered to be no different from the patient's daily acceptance. The days when the patient is not careful to miss the investment can be included. The compound of the present invention can be used or recycled together with various disease therapeutic or prophylactic agents which are considered to be effective for the aforementioned compounds of the present invention. Ingestion means taking two or more kinds of medicines at the same time, and taking two or more medicines by staggering the time during the same taking period, both of which are included. Recycling refers to the patient receiving the administration of Alecbolic Alcohol for a given period of time. Next, the administration of Alec made Alcohol is stopped in the second phase (accepting additional bone formation enhancers or bone resorption inhibitors and/or hormones) Therapy may or may not be accepted, and then return to Algondiol Therapy. In general, the causes of osteoporosis involve a wide range, and it is therefore difficult to analyze the condition of a patient due to which disease. In addition, there are many types of osteoporosis, and it is now practiced in groups of patients in various states. Therefore, clinically, there are also cases in which a plurality of doses of therapy or circulatory therapy are used in which two or more doses differ in the mechanism of action. Therapeutic or recurrent therapy is intended to combine agents with different mechanisms of action to reduce side effects or enhance fracture inhibition. This can be used or recycled, or separated by the desired time -20-201105333. The formulations to be administered at the same time may be a mixture or may be separately formulated. Examples of the agent that can be used or recycled include estrogen or estrogen derivatives, bisphosphonates, antiestrogens or selected estrogen receptor modulators, α V Θ 3 integrin inhibitors, Cathepsin K inhibitor, HMG-CoA reductase inhibitor, osteoclast liquid cell type chymase inhibitor, VEGF-binding antagonist of osteoclast receptor, peroxisome proliferator-activated receptor r, descending Calcium, calcium receptor antagonist, parathyroid hormone or parathyroid hormone derivative, growth hormone secretion promoting substance, human growth hormone, insulin-like growth factor, P-3 8 protein kinase inhibitor, bone morphogenetic protein, BMP antagonism a blocking agent, a prostaglandin derivative, a vitamin K or a vitamin K derivative, an ipriflavone, a fluoride salt, a calcium nutritional supplement, and an androgen receptor modulator, one or more agents selected, specifically, Listed as L-aspartate calcium, dibasic calcium phosphate, estriol, 17 lux estradiol, menatetrenone, alendronate (Alendronate), etidron Etidronate, Risedronate, Ibandronate, Raloxifene Hydrochloride, Calcitonin, Salmon Calcitonin, Epstein Flavonoids, Nandrolone Citrate, Trinity An agent such as eriparatide. Particularly suitable agents are bisphosphonates, antiestrogens or selected estrogen receptor modulators, calcitonin, in particular alendronate, etidronate, risedronate, Ibandronate, raloxifene hydrochloride, lyreocalcin, and squid. Analysis of clinical test data shows that the risk of non-traumatic vertebral fractures in patients with severe osteoporosis-21 - 201105333 can be achieved by administering an effective amount of ergocalculated alcohol daily for a considerable period of time. cut back. The present invention is specifically described by the following examples, which are not intended to be limited thereby, and are not limited in any sense. [Examples] Example 1 For patients with primary osteoporosis, the effectiveness of Algonized Alcohol and Alpha Alcohol by randomized double blind Between-group comparison Calcium alcohol was reviewed for comparison. Patients: Severe patients with primary osteoporosis patients with an average age of 72.1 years (range, 46-92 years) were grouped as follows: Group A: T-scores of bone density near the femur were below -2.5 SD and vulnerable vertebrae Body fractures; Group B: The T-score of bone density near the femur is below -2.5 SD and more than 2 fractures of the vertebral body. Dosage and administration: Alecbolic alcohol (ED-71): 0.75 pg/day, orally administered Alfacalcidol (ALF): l.Ogg/day, orally administered. The formulations used in the test were prepared based on WO2005/074943 and Japanese Patent No. 4070459, respectively. During the administration period: Alecbolic alcohol (ED-71) and Alfacalcidol (ALF) were continuously administered for 144 weeks (after 4 weeks of observation) -22- 201105333 Evaluation of new vertebral fractures: SQ Based on grade, at least 2 of the three judges, including physicians, orthopedic surgeons, and radiologists, independently from the vertebral body at the start of the administration, 6 months, 1 year, 2 years, 3 years, or at any time. The front and side of the thoracic and lumbar X-ray photographs of the thoracic and lumbar spine were read from the 4th thoracic vertebrae to the 4th lumbar vertebrae, and the vertebral body was observed to be deformed before the vertebral body was measured. The height of the rim, the height of the center, and the height of the trailing edge were evaluated as a new vertebral fracture with a vertebral body that was considered to have a decrease of 15% and a decrease of 4 mm or more before administration. Further, in the case where two or more judgments are judged to be inconsistent in the determination independently, the above three digits are re-agreed to determine whether or not there is a new vertebral fracture. To correct for the nutritional deficiencies of vitamin D, 400 IU of vitamin D supplement was added to patients who did not receive 20 ng/mL at 25 (OH) D値 at the start of the administration. During the administration of Alcoholic Alcohol, the dosage of the vitamin supplements was not changed, and the corrected sCa値 was more than 1丨.Omg/dL or 10.4mg/dL. Then, the administration of the escaping alcohol and the vitamin D supplement was stopped, and the corrected sCa 値 was 10.4 mg/dL or less, and the corrected uCa 値 was 0.40 mg/dL GF or less. The investment is not followed by the change in the amount of administration. Alecbolic alcohol (ED-71): 〇.5pg/day, orally administered Alfacalcidol (ALF): 〇.5pg/day, orally administered. Tables 1 and 2 respectively show the number of non-traumatic new vertebral fractures in Group A and group B patients during the administration of Alkali Alcohol/Alfacalcitol, and the number of occurrences of non-traumatic new vertebral fractures in the period of 4 4 weeks -23-201105333 . Table 3 reveals all patients with primary osteoporosis who have severe and mildly collectable data (the mean T-score of femoral bone mineral density is -2.77 ± 0.79 in the Aleurone group, and the alfacalcidol group is - The frequency of non-traumatic new vertebral fractures at 144 weeks was 2.2 ± 0.82, while fragility fractures were 1.2 ± 1.3 in the Aleurone group and 1.2 ± 1.4 in the alfacalcidol group. [Table 1] Table 1. Non-traumatic new vertebral fractures of Group A at the time of administration of 144 weeks Frequency of occurrence of ALF administration group (132 cases) ED-71 administration group (141 cases) Non-traumatic new The number of vertebral fractures was 41 pieces and 23 pieces [Table 2] Table 2. Non-traumatic new vertebral fractures of group B at the time of drug administration 1 44 weeks of frequency ALF administration group C75 cases) ED-71 group (73 cases) The number of non-traumatic new vertebral fractures was 34 pieces and 18 pieces [Table 3] Table 3. 144 weeks of non-traumatic new vertebral fractures in all primary osteoporosis patients at the time of drug administration Gui ALF group (523 cases) ED-71 group (526 cases) Non-traumatic new vertebral fractures occurred in 80 cases 64 pieces Table 4 by log rank (logrank) test and COX regression 'on- 24-201105333 Evaluate the difference in the inhibitory effect of non-traumatic new vertebral fractures produced by Aleurostatin/Alfacalcitol in all patients, Group A, and Group B. [Table 4] Table 4. Intergroup comparison of non-traumatic new vertebral fractures by log-rank stratification, stratified C OX regression, Alcoholic alcohol log rank test cox regression VS Alfacalcidol (P値) Hazard ratio 90% confidence interval non-traumatic new vertebral fracture 0.046 0.74 [0.56 : 0.97] Bone mineral density is below τ score -2.5SD and patients with fragility fractures 0.0032 0.495 [0.323 : 0.761] Bone mineral density A group of patients with a T score of 12.5 SD and less than 2 or more vertebral fractures 0·(8) 52 0.477 [0.295 : 0.771] Note 1. The hazard ratio indicates a non-traumatic new vertebrae of Alcoholic Alcohol on Alfacalcidol Body fracture risk ratio. The log-rank test basically consists of averaging the relative risk of the entire period, and whether the average relative risk (RR) is statistically significant, a chi square test is performed. COX regression refers to the method used to investigate the effects of certain other factors during the period of the event, and assumes the proportional hazard (in the form of a proportional constant, multiplied by the risk of being a reference individual) method. The risk is that no new non-traumatic vertebral fractures have occurred until a certain point in time, indicating the probability of a non-traumatic vertebral fracture at this time point (the immediate probability of a new non-traumatic vertebral fracture). The hazard ratio means the hazard ratio of the two groups -25- 201105333. That is to say, how many times of non-traumatic new vertebral fractures will occur in the group with one of them as a benchmark. The results of the log-rank test show that the time of the occurrence of non-traumatic new vertebral fractures in all primary osteoporosis, Aer bone (ED-71) administration group and Alfacalcidol (ALF) The group had a significant difference of 5% on one side compared to the significant level (j = 0.046). In addition, it was confirmed that in the COX regression, the time of the non-sexual new vertebral fracture occurred, the ED-7 1 administration group was more effective than the administration group (hazard ratio: 0.74, 90% confidence zone confidence interval, CI: 0.56~0.97). It is concluded from the hazard that if the fracture rate of the ALF-administered group is set to 1, the probability of ED·: group is 0.74, and the risk of new non-traumatic vertebral fracture is reduced by 26% » Furthermore, this The effect of fracture inhibition, defined by the WHO's diagnostic criteria as severe osteoporosis (T-score of bone density -2.5SD and fragile fractures), from any analysis of log-rank and hierarchical regression, It can be confirmed that there is a greater difference in the effectiveness of Alecbolic Alcohol relative to Alfacalcidol. That is, in the group of severe osteoporosis (the T-score of bone density is -2.5 SD and fragile), the logarithmic rank test is 〇.〇〇32, which is observed in the new vertebral body. The difference. In addition, the risk of fractures was reduced by about 50% from the hazard ratio, and a more significant difference was detected. Hazard ratio: 0.495, 90% CI: 0.323 to 0.761).
再進一步加以限定，骨密度之T分數爲-2.5SD 另一 症患 化醇 ，在 I ( p 外傷 ALF 間（ 値可 1投 險率 ，在 以下 COX 言， 骨質 骨折 骨折 來， 異（ 以下 -26- 201105333 且具有兩個以上現存椎I 値爲0.0052，從危險比;^ 率減少約52%，而具有 0.477 > 90% CI : 0.295 〜 !骨折的集團中，對數秩檢定的P :値看來，確認了骨折發生的危險 更高的骨折抑制效果（危險比： 0.77 1 )。 -27-Further limited, the T-score of bone density is -2.5SD. Another disease is alcohol, in the case of I (p trauma ALF (値1 can be risky, in the following COX words, bone fracture fractures, different (below - 26-201105333 and with more than two existing vertebrae I 値 is 0.0052, from the hazard ratio; ^ rate is reduced by about 52%, while in the group with 0.477 > 90% CI: 0.295 ~ ! fracture, the logarithmic rank of P: 値It appears that the risk of fracture is higher than the fracture inhibition effect (hazard ratio: 0.77 1 ). -27-