201105332 六、發明說明： 【發明所屬之技術領域】 本發明係有關於含有艾爾骨化醇（eldecalcitol )( ED-7 1 )而成之用以抑制前臂部骨折之醫藥組成物、包含 投予有效量之艾爾骨化醇而成之前臂部骨折之抑制方法以 及艾爾骨化醇於該醫藥組成物之製造中之用途。 【先前技術】 高齡者之骨折「由於若成爲高齡則骨骼變脆故而自然 爲難以避免者」，不僅亦間接影響高齡者之生命預後，亦 由於生存期間之自立降低，直接使QOL (生活品質）惡化 ，故而期望對其之抑制或預防。尤其是隨著高齡者顯著增 加及平均壽命之顯著延長，高齡者之骨折增加亦顯著變多 ，而強烈要求對其之抑制或預防。 作爲高齡者幾乎或完全無外傷之骨折（脆弱性骨折） 基礎疾病之一有骨質疏鬆症。骨質疏鬆症係因骨強度降低 使骨折危險性易增大之骨骼疾病。日本之骨質疏鬆症患者 於20〇2年之時點推估約有11〇〇萬人，其中80%以上爲女性 。隨後，由於人口高齡化急遽增高，推測骨質疏鬆症患者 將急遽增加。 骨質疏鬆症由於骨脆弱化，主要於脊椎（椎體）、大 腿骨附近部位 '前臂部容易骨折，尤其大腿部及前臂部骨 折，不用說是由交通事故等高度外力引起，即使是由於一 般曰常生活引起之跌倒等輕微外力亦會引起。 S· -5- 201105332 該等骨折之發生頻率，於大腿骨頸部爲155人/10萬人 ，於前臂部則比其高而爲196人/10萬人左右。再者，於日 本國之女性中前臂部骨折時，自50歲開始急遽增加，於55 歲以後成爲每年3 00~400人/10萬人，於80歲以後有更增加 之傾向。 雖然有關於前臂部骨折之預後對生命預後的影響較小 ，但由與大腿骨頸部骨折爲同等以上之骨折發生數以及骨 折期間顯著之ADL( Activities of daily living:日常生活 動作）及QOL ( Quality of life ;生活品質）之降低觀之， 其骨折之預防極其重要。 另一方面，依據2006年骨質疏鬆症之預防及治療GL作 成委員會編著之基準，於日本中骨質疏鬆症之治療時，主 要使用鈣製劑、女性激素製劑、回性型維他命D製劑、維 他命K製劑、雙磷酸酸酯製劑、SERM製劑、抑鈣素（ Calcitonin )製劑、異黃酮製劑、蛋白同化激素製劑等。 於日本以外地區之治療，除了該等以外，亦有使用PTH及 其類似物、RANKL阻礙劑、緦製劑等。 該等現行治療中，最被高頻率使用者爲雙磷酸酯製劑 。爲雙磷酸酯之一的阿倫磷酸酯（alendronate )藉由以 1 〇mg/天連續治療可減少停經後之骨質疏鬆症患者之椎骨 骨折危險性，增加BMD。且近幾年來，亦報導有非椎體骨 折之危險性減少及大腿骨頸部骨折後二次骨折之預防或減 低化之效果（專利文獻1、專利文獻2 )。201105332 VI. Description of the Invention: [Technical Field] The present invention relates to a pharmaceutical composition comprising eldecalcitol (ED-7 1 ) for inhibiting fracture of the forearm, including administration An effective amount of Alcoholic Alcohol is used to inhibit the formation of an arm fracture and the use of Alec made alcohol in the manufacture of the pharmaceutical composition. [Prior Art] The fracture of an elderly person "is naturally difficult to avoid if the bone becomes brittle," which not only indirectly affects the prognosis of the elderly, but also directly reduces QOL (quality of life) due to the decrease in self-reliance during the survival period. It is deteriorating, so it is expected to inhibit or prevent it. In particular, with the significant increase in the elderly and the significant increase in the average life expectancy, the increase in the fracture of the elderly is also significantly increased, and it is strongly required to inhibit or prevent it. Osteoporosis, one of the underlying diseases that is almost or completely free of trauma in elderly people (vulnerability fracture). Osteoporosis is a bone disease in which the risk of fracture is easily increased due to a decrease in bone strength. Japanese osteoporosis patients estimated that there were about 110,000 people at 20:2, of which more than 80% were women. Subsequently, due to the rapid increase in population aging, it is speculated that patients with osteoporosis will increase rapidly. Osteoporosis is caused by bone fragility, mainly in the spine (vertebral body) and the vicinity of the thigh bone. The forearm is easily fractured, especially in the thigh and forearm. It is not necessary to be caused by a high external force such as a traffic accident, even if it is due to general A slight external force such as a fall caused by a normal life can also be caused. S· -5- 201105332 The frequency of these fractures is 155/100,000 in the thigh bone neck and 196/100,000 in the forearm. Furthermore, in the case of a fracture of the forearm in a woman in Japan, it has increased rapidly since the age of 50. After the age of 55, it has become 300 to 400 people per 100,000 people per year, and there is a tendency to increase after the age of 80. Although the prognosis of the forearm fracture has little effect on the prognosis of life, the number of fractures equal to or greater than the fracture of the thigh and neck and the significant ADL (Analysis of daily living) and QOL during the fracture. The quality of life is reduced, and the prevention of fractures is extremely important. On the other hand, according to the 2006 GL preparation committee for the prevention and treatment of osteoporosis, in the treatment of osteoporosis in Japan, mainly used calcium preparations, female hormone preparations, vitamin D preparations, vitamin K preparations , a bisphosphate preparation, a SERM preparation, a calcitonin preparation, an isoflavone preparation, a protein anabolic hormone preparation, and the like. In addition to these, treatments other than Japan also use PTH and its analogs, RANKL inhibitors, sputum preparations and the like. Among these current treatments, the most frequently used users are diphosphate preparations. Alen phosphate, one of the diphosphates, can reduce the risk of vertebral fractures in patients with osteoporosis after menopause and increase BMD by continuous treatment at 1 〇mg/day. In recent years, there has been reported a reduction in the risk of non-vertebral fractures and the prevention or reduction of secondary fractures after fractures of the thigh and neck (Patent Document 1 and Patent Document 2).
然而，雙磷酸酯作爲骨質疏鬆症之治療藥雖可使BMD -6- 201105332 上升，但同時暗示有具有微小骨損傷累積等之骨質降低之 可能性。再者’阿倫磷酸酯由於其嚴格之服用規則及副作 用，故亦有患者順應性差之報導。一般，雙磷酸酯由於與 飲食中之鈣形成螯合物而阻礙其吸收，故必須於空腹時服 用’且爲了預防食道炎或食道潰爛而有必需以站姿或坐姿 與大量水一起服用且服用後3 0分鐘以上不可橫躺等之嚴格 服藥限制。目前雖已開發該等限制較少之新穎雙磷酸酯劑 ’但近幾年來’以精密觀察到雙磷酸酯服用時於牙科治療 時有顎骨壞死問題，此外，亦報導有骨關節疼痛等之肌肉 骨骼系統副作用，有安全上的問題。 關於除此之外之骨質疏鬆症治療藥，爲SERM製劑之 有效成分之鹽酸雷洛昔分（raloxifene hydrochloride)亦 有靜脈血栓栓塞症發作或梗塞之血管運動症狀危險性增加 之報告，於PTH則有於動物骨肉腫發生危險性增加之報告 ’各均有嚴重的安全性問題。再者，PTH及RANKL阻礙劑 係皮下或靜脈內注射劑，亦有不適合長期投藥等之順應性 方面的問題。 另一方面，除雙磷酸酯以外，作爲確認有非椎體骨折 預防效果之藥劑有維他命D化合物，由Metab分析已報導抑 鈣素與阿法骨化醇（Alfacalcidol )均對非椎體骨折顯示有 意義之抑制效果（非專利文獻1 )。維他命D化合物並無其 他同藥效所見之順應性降低或嚴重副作用等之問題，於必 須長期服用之骨質疏鬆症治療劑中可謂爲非常優異之藥劑However, as a therapeutic drug for osteoporosis, bisphosphonate can increase BMD-6-201105332, but it also suggests a possibility of bone loss with accumulation of minute bone damage. Furthermore, 'Allen's phosphate esters are reported due to poor patient compliance due to their strict rules of administration and side effects. In general, since the bisphosphonate inhibits its absorption by forming a chelate with calcium in the diet, it must be taken on an empty stomach. In order to prevent esophagitis or esophageal ulceration, it is necessary to take it with a large amount of water in a standing or sitting position. After 30 minutes or more, you should not be able to lie on a strict medication limit. At present, these novel biphosphates have been developed with less restriction. However, in recent years, there has been a problem of osteonecrosis in dental treatment when the diphosphate is taken accurately. In addition, muscles such as bone and joint pain have also been reported. Side effects of the skeletal system have security problems. Regarding the treatment of osteoporosis other than this, raloxifene hydrochloride, which is an active ingredient of the SERM preparation, also reports an increase in the risk of venous symptoms of venous thromboembolic episodes or infarction, in PTH. Reports of increased risk of osteosarcoma in animals have serious safety concerns. Further, PTH and RANKL inhibitors are subcutaneous or intravenous injections, and there are also problems in compliance with long-term administration and the like. On the other hand, in addition to the bisphosphonate, vitamin D compounds have been identified as agents for the prevention of non-vertebral fractures. Metab analysis has reported that both calcitonin and Alfacalcidol show non-vertebral fractures. A significant inhibitory effect (Non-Patent Document 1). Vitamin D compounds have no other problems associated with reduced efficacy or serious side effects, and are excellent in osteoporosis treatments that must be taken for a long time.
S 201105332 因此爲維他命D化合物之一種之艾爾骨化醇自1985年 申請物質發明以來，已有眾多專利、非專利文獻的報告， 其一有關於含有艾爾骨化醇作爲有效成分之「骨癒合促進 劑」之日本特許第3 78 9956號（專利文獻3 )»此處所謂之 骨癒合促進爲促進在骨延長、骨切除、骨折、骨移植等之 後所必要的骨再接合所伴隨之骨修復過程，故與未伴隨再 接合之骨折抑制或預防並不相同。又，關於「以維他命D3 衍生物爲有效成分之醫藥」之日本特許第19744 53號（專 利文獻4)揭示含有艾爾骨化醇作爲有效成分之伴隨維他 命D代謝異常之疾病之治療劑。此疾病包含有骨質疏鬆症 〇 前臂部爲人在跌倒時最先接觸地面或地板而承受最大 身體荷重的部位，因此於高齡者或骨質疏鬆症患者等之骨 骼變脆的人容易因跌倒而骨折，其若未骨折而可充分承受 因跌倒引起之身體荷重，則不僅前臂部，因跌倒而致之身 體全體損傷將亦可減少至最小限度。 [先前技術文獻] [專利文獻] [專利文獻1]特表平10-504839 [專利文獻2]特表2006-500402 [專利文獻3]特許第3789956號 [非專利文獻] [非專利文獻 1] Bone Miner. Metab.，2008，26，531 201105332 【發明內容】 [發明欲解決的課題] 因此，本發明之目的在於提供可預防前臂部骨折之提 高既有藥劑效果之醫藥組成物。 [用以解決課題之手段] 本發明提供含有艾爾骨化醇所成之用以抑制前臂部骨 折之醫藥組成物或前臂部骨折抑制劑。較好，本發明之醫 藥組成物係對原發性骨質疏鬆症患者投予，更好係對大腿 骨骨密度爲小於年幼者平均骨密度（Young Adult Mean， YAM )之80%，較好小於70%，更好小於60%之人類投予。 較好對原發性骨質疏鬆症患者以0.75 μ£/天之用量經口投予 〇 如上述，骨折之抑制或預防就未伴隨骨再接合方面與 骨癒合促進不同，故艾爾骨化醇抑制前臂部骨折之用途， 爲本發明人等首次所發現者。又，上述之以艾爾骨化醇作 爲骨質疏鬆症之治療劑，並未提示於前臂部之特定部位之 骨折抑制用途，故艾爾骨化醇抑制前臂部骨折之用途，仍 是本發明人等首次所發現者。 [發明效果] 藉由本發明，可比以往所使用之醫藥品更大地抑制前 臂部骨折。本發明之前臂部骨折抑制效果，比同種同藥效 之阿法骨化醇更有意義地提高，爲超過熟知本技藝之一般 -9- 201105332 知識所能預測到之程度者。 【實施方式】 本說明書及申請專利範圍全部中，使用以下定義。 所謂艾爾骨化醇（eldecalcitol)爲開發碼「ED-71」 之化合物，爲具有化學名：（1R，2R，3R，5Z，7E ) -2-( 3-經基丙氧基）-9，10-開環膽留（86£：〇(；11〇16313)-5,7，10( 19)-三烯-1，3,25-三醇之化合物。 前臂部係由橈骨與尺骨構成。 用以抑制骨折之醫藥組成物由於可預防骨折，故亦可 謂爲用以預防骨折之醫藥組成物。抑制或預防意指對未罹 患骨質疏鬆症者以及骨質疏鬆症患者均不發生新的骨折。 骨質疏鬆症分類爲原發性骨質疏鬆症及續發性骨質疏 鬆症。原發性骨質疏鬆症進而包含特發性骨質疏鬆症、I 型骨質疏鬆症及Π型骨質疏鬆症。 特發性骨質疏鬆症出現於兒童或有正常性腺機能之男 女青年，I型骨質疏鬆症（停經後之骨質疏鬆症）則發生 於5 1~75歲之間，女性易發生率約爲男性之6倍，但亦發生 於性腺摘除後或血清中雄性激素濃度低的男性。II型骨質 疏鬆症（退化性或老人性骨質疏鬆症）與老化正常過程等 有關，一般發病於60歲以上之患者。高齡女性經常同時出 現I型及II型。 本發明之醫藥組成物的投予對象爲高齡者，較好爲骨 質減少患者或骨質疏鬆症患者，更好爲骨質疏鬆症患者， -10- 201105332 又更好爲原發性骨質疏鬆症患者。 所謂高齡意指年齡60歲以上。 本發明之醫藥組成物欲投予之對象的骨密度較好低於 YAM之80%，更好低於YAM之70%，最好低於YAM之60% 〇S 201105332 Therefore, Alcoholic Alcohol, a kind of vitamin D compound, has been reported in many patents and non-patent literatures since its application for material invention in 1985, and one of them has "Bone" containing Al-calcitol as an active ingredient. Japanese Patent No. 3 78 9956 (Patent Document 3) of the "Healing Promoter" is a bone that promotes bone re-engagement necessary for bone elongation, bone resection, fracture, bone graft, and the like. The repair process is not the same as fracture inhibition or prevention without re-engagement. Further, Japanese Patent No. 19744 53 (Patent Document 4), which is a "medicine having a vitamin D3 derivative as an active ingredient", discloses a therapeutic agent containing a disease in which vitamin A is abnormally metabolized by containing Alcohol. This disease involves osteoporosis. The forearm is the part of the person who is exposed to the ground or the floor to the greatest body load when falling. Therefore, people who are brittle in the elderly or osteoporosis are vulnerable to falls due to falls. If it is not fractured and can fully withstand the body load caused by the fall, not only the forearm, but also the total body damage caused by the fall can be reduced to a minimum. [Prior Art Document] [Patent Document 1] Japanese Patent Application Laid-Open No. Hei. No. Hei. No. Hei. No. Hei. No. Hei. [Brief Description of the Invention] [Problems to be Solved by the Invention] Therefore, an object of the present invention is to provide a pharmaceutical composition which can prevent the forearm fracture and improve the effect of the existing medicament. [Means for Solving the Problem] The present invention provides a pharmaceutical composition or a forearm fracture inhibitor which comprises an Alkali alcohol and which is used for inhibiting the fracture of the forearm. Preferably, the pharmaceutical composition of the present invention is administered to a patient with primary osteoporosis, and it is better that the bone density of the thigh bone is less than 80% of the Young Adult Mean (YAM) of the young child. Less than 70%, more preferably less than 60% of humans are administered. It is better to orally administered to patients with primary osteoporosis at a dose of 0.75 μ£/day. For example, the inhibition or prevention of fracture is not associated with bone healing in bone re-engagement, so Alcohol The use of the forearm fracture was first discovered by the inventors. Moreover, the above-mentioned use of Algonhydrin as a therapeutic agent for osteoporosis does not suggest the use of fracture prevention in a specific part of the forearm, and therefore the use of Alec made alcohol to suppress the fracture of the forearm is still the present inventor. Waiting for the first time. [Effect of the Invention] According to the present invention, it is possible to suppress the fracture of the forearm more than the conventionally used medical product. The effect of inhibiting the fracture of the arm prior to the present invention is more meaningfully improved than that of the same pharmacologically effective alfacalcidol, which is beyond the knowledge of the knowledge of the general art -9-201105332. [Embodiment] The following definitions are used throughout the specification and the claims. The so-called eldecalcitol is a compound of the development code "ED-71" and has the chemical name: (1R, 2R, 3R, 5Z, 7E) -2-(3-pyridyloxy)-9 , 10-ring-opened bile retention (86 £: 〇 (; 11〇16313)-5,7,10( 19)-triene-1,3,25-triol compound. The forearm is composed of the tibia and ulna The medical composition for inhibiting fracture can be said to be a pharmaceutical composition for preventing fracture because it can prevent fracture. Inhibition or prevention means that no new fracture occurs in patients with osteoporosis and osteoporosis. Osteoporosis is classified as primary osteoporosis and persistent osteoporosis. Primary osteoporosis further includes idiopathic osteoporosis, type I osteoporosis and spastic osteoporosis. Osteoporosis occurs in children or young men and women with normal glandular function. Type I osteoporosis (osteoporosis after menopause) occurs between 51 and 75 years old, and the prevalence of women is about 6 times that of men. But also occurs in men after gonadectomy or serum with low concentrations of androgen. Type II osteoporosis Symptoms (degenerative or senile osteoporosis) are related to normal aging processes, etc., and generally occur in patients over 60 years old. Older women often have both type I and type II. The pharmaceutical composition of the present invention is administered to senior citizens. Preferably, it is a patient with osteopenia or osteoporosis, preferably a patient with osteoporosis, and -10-201105332 is more preferably a patient with primary osteoporosis. The so-called advanced age means age 60 or older. The bone mineral density of the target to be administered by the pharmaceutical composition is preferably lower than 80% of YAM, preferably lower than 70% of YAM, preferably lower than 60% of YAM.
所謂骨密度（BMD: Bond Mineral Density)爲藉由 X 光或超音波測定之於骨中沉積之鈣與年少成人（骨密度達 最大之 20~44 歲）之平均（Young Adult Mean，YAM)相 比或多或少經數値化（％)者。 以現在曰本骨質疏鬆症之診斷基準，無脆弱性骨折時 ，骨密度爲YAM之80%以上則爲「正常」，若爲70~80%則 爲骨易脆化狀態之『骨質減少症」，因此若爲70%以下則 爲「骨質疏鬆症」之骨易折斷之狀態（骨質疏鬆症之預防 及治療基準製作委員會編，代表：折茂肇）。 又，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由骨 密度與脆弱性骨折數加以定義。於該基準中，相對於YAM 之骨密度T評分在-1SD以內定義爲「正常」，骨密度T評分 爲-1〜-2.5SD則定義爲「低骨質量（骨量減少）」，骨密 度T評分爲-2.5 SD以下則定義爲「骨質疏鬆症」，因此骨 密度之T評分爲-2.5SD以下，且具有一處以上之脆弱性骨 折定義爲「重症骨質疏鬆症」。此處，SD爲標準偏差値。 骨密度之測定有數種方法，具體舉例有DXA ( Dual Energy X-ray Absorptiometry)法：雙能量 X射線吸收法； £. -11 - 201105332 QCT ( quantitative computed tomograghy)法：定量電腦 斷層攝影法；pQCT ( peripheral quantitative computed tomograghy )法：末梢型定量電腦斷層法；QUS ( Quantitative ultrasound )法：定量超音波法等。其中， DXA法係使用兩個不同能量的X射線束，藉由脈衝高解析 ，區別骨與軟骨組織，而測定骨鹽量（單位：g )。進而 計算自X射線照射方向所見之骨投影面積（cm2 )，將該骨 鹽量除以投影的骨面積藉此獲得獲得DXA法之骨密度（ g/cm2 )。本發明之骨密度較好藉由DXA法、QCT法、 pQCT法、QUS法、RA/MD法測定，更好藉由DXA法、QUS 法測定。測定部位舉例有腰椎、大腿骨、全身骨、橈骨、 跟股、脛骨、手骨、指骨等，較好以軀幹骨DXA法測定腰 椎、大腿骨；全身骨，以末梢骨DXA法測定橈骨、跟骨， 或以QUS法測定跟骨。 所謂T評分爲骨密度之所謂「偏差値」，爲以YAM之 骨密度作爲基準時，顯示某程度與其偏差之標準偏差値（ SD) 。T評分係如下計算而得： 〔數1〕 T評分=(被檢者之測定骨密度値-1 〇〇 % YAM値） /100% YAM値之標準偏差 100% YAM骨密度値與其標準偏差（SD )係依據測定 所使用之設備分別制定。於本發明中測定大腿骨附近部位 骨密度時，於使用Hologic公司的骨密度測定器的QDR時， 使用〇.8 6 3 g/cm2作爲100%YAM値，使用0.110作爲標準偏 -12- 201105332 差（均記載於原發性骨質疏鬆症之診斷基準（ 2000年度修 訂版），折茂肇；林泰史等：日本骨代謝學會雜誌18(3 ):76-8 2，200 1 )，利用上式計算T評分。另一方面，使 用Lunar公司的骨密度測定器的DPX時，將由該設備所得之 値，仍然依據原發性骨質疏鬆症之診斷基準（2000年度修 訂版），折茂肇；林泰史等：日本骨代謝學會雜誌18(3 ):76-8 2，2 001所記載之下式，變換成QDR測定近似値。 此若套用至上述式則可獲得T評分。 如前述，於日本，骨密度爲YAM之80%以上定義爲「 正常」，若爲YAM之70%以下則定義爲「骨質疏鬆症」之 骨容易折斷之狀態，但爲日本基準的「YAM之80%以上」 以及「Y A Μ之7 0 %」分別相當於日本以外地區基準的「骨 密度之Τ評分爲相對於YAM値之約-1SD」以及「骨密度之 T評分爲相對於YAM値之約-2.5SD」，相對於日本基準的 以YAM的多少％表示骨密度，日本以外地區之基準之以比 YAM降低多少SD單位表示雖有不同，但基本上並無太大差 異 （http://www_ebmlibrary_jp/〇steo/guideline/guide02. html )。 本發明之所謂的重症骨質疏鬆症患者’依據日本以外 地區的診斷基準，係表示大腿骨附近部位骨密度之T評分 爲-2.5 SD以下且具有脆弱性骨折之患者’進一步限定爲表 示大腿骨附近部位骨密度之T評分爲- 2.5SD以下且具有2處 以上脆弱性骨折之患者，但與骨密度相關而利用日本的診 斷基準，亦可替換爲大腿骨附近部位骨密度爲YAM之7 0% S- -13- 201105332 以下且具有脆弱性骨折之患者，進一步限定爲大腿骨附近 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。 所謂外傷性骨折表示因交通事故等之較大外力所發生 之骨折，所謂非外傷性骨折表示因跌倒等之一般日常生活 發生之輕微外力所發生之骨折。所謂脆弱性骨折意指原因 爲低骨質量（骨密度小於YAM之80%或脊椎X射線照相有 骨質疏鬆化之情況）而因輕微外力所發生之非外傷性骨折 〇 所謂骨強度係由骨密度與骨質兩種要因所構成，爲每 單位體積之骨量的骨密度被認爲是說明骨強度的大約70% 的要素，剩餘3 0%的要素則認爲是說明由微細構造、骨代 謝率、微小骨折、石灰化之要因所構成之骨質。 含有本發明化合物作爲有效成分之醫藥組成物可使用 本技藝者通常所用之藥劑用添加劑，以通常使用之各種製 劑之調製方法予以調製。作爲上述添加劑，可舉例有一般 醫藥所使用之賦形劑、結合劑、滑澤劑、崩解劑、著色劑 、矯味矯臭劑、乳化劑、界面活性劑、溶解助劑、懸浮劑 '等張化劑、緩衝劑、防腐劑、抗氧化劑、安定化劑、吸 收促進劑等，亦可適當組合該等而使用。劑型可爲錠劑、 九劑、膠囊劑、顆粒劑、粉劑、液劑等之視於經口投予之 劑型，亦可爲注射劑' 外用劑、吸入劑等之適於關節內、 靜脈內、肌肉內等之非經口投予之劑型之任一種。 至於用以經口投予之固體組成物，係使用錠劑、粉劑 -14- 201105332 、顆粒劑等。該種固體組成物係將一種或兩 成分與至少一種惰性賦形劑例如乳糖、甘露 白糖、蔗糖等之糖類、結晶纖維素、澱粉、 鋁、偏矽酸鋁酸鎂等無機物混合。本醫藥組 —般方法，含有其他添加劑例如如硬脂酸鎂 羧甲基纖維素鈣或褐藻酸鈉等之崩解劑、安 二醇等之溶解助劑、聚乙烯醇等之結合劑、 味矯臭劑、如月桂硫酸鈉等之乳化劑或界面 劑或九劑亦可依據需要以糖衣或胃溶性或腸 衣被膜。用以經口投予之液體組成物含有藥 濁劑、溶液劑、懸浮劑、糖漿劑或酊劑等， 之惰性稀釋劑例如純化水或乙醇。液體醫藥 性稀釋劑以外，亦可含有如可溶化劑、濕潤 輔助劑、甜味劑、風味劑、芳香劑、防腐劑 用以非經口投予之注射劑含有無菌的水 液劑、懸浮劑或乳濁劑。水性溶劑含有例如 或生理食鹽水。非水性溶劑有例如丙二醇、 橄欖油之植物油、如乙醇之醇類或聚〇_ Polysorbate ) 8 0 (藥典名）等。該種醫藥組 含有上述添加劑例如等張化劑、防腐劑、濕 、分散劑、安定化劑、抗氧化劑、緩衝劑、 溶解助劑。該等係例如藉由通過保留細菌之 、配合殺菌劑或藉由照射而無菌化。又，該 菌固體組成物而於使用前溶解或懸浮於無菌 種以上之有效 糖、葡萄糖、 碳酸鈣、矽酸 成物亦可依據 之滑澤劑或如 定化劑、聚乙 可可粉等之矯 活性劑等。錠 溶性物質之膜 劑可容許之乳 包含一般所用 組成物除了惰 劑、懸浮劑之 〇 性或非水性溶 注射用蒸餾水 聚乙二醇或如 丨梨糖醇酯（ 成物亦可進而 潤劑、乳化劑 吸收促進劑或 過濾器而過濾 等亦可製造無 水或無菌注射 -15- 201105332 用溶劑中而使用。亦有將包含該等輔助劑等之溶液收納於 容器後，藉由凍結乾燥等作成固形製劑而作爲使用時調製 之製劑亦可。又，亦可將一次投予量收納於一個容器中， 亦可將複數次投予量收納於一個容器中。 外用劑包含栓劑、經皮用液劑、經皮用貼附劑、經黏 膜貼附劑、軟膏劑、硬膏劑、乳霜劑、凍膠劑、外敷軟膏 劑、噴霧劑、洗劑、點眼劑、眼軟膏等。包含一般所用之 軟膏基劑、洗劑基劑、水性或非水性液劑、懸浮劑、乳劑 等》例如作爲軟膏或洗劑基劑，舉例有聚乙二醇、丙二醇 、白色凡士林、石蠟、白色密蠟、聚氧乙烯硬化蓖麻油、 單硬脂酸甘油酯、硬脂醇、鯨蠟醇、聚乙二醇硬脂酸酯（ Lauromacrogol )等 ° 吸入劑或經鼻劑等之經黏膜劑可使用固體、液體或半 固體狀者，可依據以往公知方法製造。例如亦可適當添加 公知之賦形劑或進而添加pH調整劑、防腐劑、界面活性劑 、滑澤劑、安定劑或增黏劑等。投予可使用用以適當吸入 或吹送之裝置。例如使用計量投予吸入裝置等之公知裝置 或噴霧器，化合物可單獨或作爲經處方之混合物之粉末或 與醫藥容許之擔體組合作爲溶液或懸浮液投予。乾燥粉末 吸入器等可爲單次或多次投予用者，亦可利用乾燥粉末或 含有粉末之膠囊。或者，亦可使用適當氣體而驅出之加壓 氣溶膠噴霧器等之形態。 本發明之化合物可用於預防哺乳類尤其是人類之前臂 部骨折。投予量及投予間隔係對應於包含患者身高、體重 •16· 201105332 '年齡、性別或醫學症狀、欲治療症狀之嚴重度、投予路 徑、患者腎肝機能、病歷以及所用之特定化合物或其鹽之 多種要素，由醫師判斷而適當選擇。 通常對人類經口投予時，1日投予量爲0.01〜1.0μ§，較 好爲0.5~1.0pg，更好爲0.75pg爲適當，其可投予—次或分 兩次至四次投予。非經口投予時，1日投予量爲0.01 q.Opg ，較好爲〇.25~1.0pg爲適當，投予量係考慮症狀、年齡、 性別等因應各情況適宜決定，其亦包含在一定期間改變其 用量。或持續更長期投予低用量亦可獲得同樣效果》 爲獲得所觀測之效果，患者較好接受實質上相當於每 曰期間之艾爾骨化醇之投予。可認爲有患者在至少24週， 更好48週，又更好更長之144週以上之期間繼續治療期間 ，有偶爾未接受艾爾骨化醇之投予之期間，但此期間由於 可自所測量之修正血清鈣値以及修正尿中鈣値，確認停藥 中亦具有充分之艾爾骨化醇之效果，故包含此種停藥期間 之療程亦包含於本發明範圍。 所謂有效量意指至少使骨折危險率減少之必要量，但 未達毒性量之艾爾骨化醇之量。 所謂相當期間’意指患者之骨密度及骨強度增大而不 易骨折之充分長的時間量。本發明中所謂相當時間，較好 爲24週以上，更好爲48週以上，又更好爲144週以上。 所謂實質上每日意指投予雖以每日爲原則，但亦包含 在患者每日接受投予時所確認之總體效果並未變化之程度 下，患者不留神而忘記投予之日。 -17- 201105332 本發明之化合物可與認爲前述本發明化合物顯示有效 性之疾病之各種治療劑或預防劑並用或循環使用。所謂倂 用包含兩種藥劑同時服用以及共同服用期間中錯開時間服 用之兩種。所謂循環使用，爲患者於特定時間，接受艾爾 骨化醇之投予’接著於第二期停止艾爾骨化醇之投予（可 接受亦可不接受追加骨形成促進劑或骨吸收抑制劑及/或 激素療法），接著回到艾爾骨化醇療法。通常由於骨質疏 鬆症之病因分歧，故大多難以由某患者之何種病因，而解 析獲得何種病態。且，病期亦爲多樣，骨質疏鬆症尙未有 以多種狀態之病患之集體一起被受理而進行治療。因此， 臨床上亦有組合作用機制不同之兩劑或三劑以上之多劑倂 用療法或循環使用療法之情況。此倂用療法或循環使用療 法藉由作用機制不同之藥劑組合，以減輕副作用或·增強骨 折抑制作用爲目的。該倂用或循環使用亦可間隔特定時間 。同時投予之製劑可爲調配劑亦可經個別製劑化。 倂用或循環使用之藥劑可舉例有自雌激素或雌激素衍 生物、雙磷酸酯、抗雌激素或選擇性雌激素壽體調控劑、 ανβ3整合素（integrin)阻礙劑、細胞自溶酶（cathepsin )K阻礙劑、HMG-CoA還原酶阻礙劑、破骨細胞液胞型 ATP酶阻礙劑、與破骨細胞受體之VEGF結合之拮抗劑、過 氧化體增生因子活性化受體γ、抑鈣素、鈣受體拮抗劑、 副甲狀腺激素或副甲狀腺激素衍生物、生長激素分泌促進 物質、人類生長激素、類胰島素成長因子、Ρ-38蛋白質激 酶阻礙劑、骨形態形成蛋白質、BMP拮抗機制之阻礙劑、 -18 - 201105332 前列腺素衍生物、維他命K或維他命K衍生物、異黃酮、 氟化物鹽、鈣營養補助食品以及雄激素受體調控劑所選擇 之一種或一種以上之藥劑，具體可舉例爲L-天冬胺酸鈣、 磷酸氫鈣、雌三醇、17β雌二醇、四烯甲萘醌（ menatetrenone )、阿倫磷酸酯、依替磷酸酯（etidronate )、利塞磷酸醋 （risedronate)、依班磷酸酯 （ ibandronate)、鹽酸洛烯吩（raloxifene)、依降鈣素（ Elcatonin)、鞋魚_抑銘素（salmon calcitonin)、異黃酮 、癸酸諾龍 （Nandrolone Decanoate)、特利帕肽（ teriparatide)等藥劑。該等中，最好之藥劑爲雙磷酸酯' 抗雌激素或選擇性雌激素受體調控劑、抑鈣素，具體爲阿 倫磷酸酯、依替磷酸酯、利塞磷酸酯、依班磷酸酯、鹽酸 洛烯吩、依降鈣素、鮭魚抑鈣素。 由臨床試驗數據之解析，顯示若於相當期間實質上每 曰投予有效量之艾爾骨化醇，則可減少前臂部骨折之危險 性。 由以下顯示之實施例具體說明本發明，但本發明並不 受此等之限制。該等意義上無論如何不應解釋爲限定。 [實施例] 實施例1 以原發性骨質疏鬆症患者爲對象’以阿法骨化醇作爲 對照組，由隨機指派雙盲檢驗群間比較試驗，檢討艾爾骨 化醇之有效性。 -19 - 201105332 患者數： 艾爾骨化醇（ED-71)投予：526人 阿法骨化醇（ALF)投予：523人 診斷及包含基準：46〜92歲之原發性骨質疏鬆症患者 用量及投予： 艾爾骨化醇（ED-71) :0.75pg/日，經口投予 阿法骨化醇（ALF) : l.Opg/日，經口投予 試驗所使用之製劑分別基於W02005/074943及特許 4070459號調製。 投予期間：艾爾骨化醇（ED-71 )、阿法骨化醇（ ALF)—起連續投予144週（後觀察4週） 檢討方法：由X射線攝影測定既有椎體骨折個數，由 DXA法測定大腿部骨密度。患者大腿部骨密度以如下計算 並表示。亦即，大腿部骨密度測定使用Ho logic公司之骨 密度測定器的QDR時，使用原發性骨質疏鬆症診斷基準（ 2000年度修訂版），折茂肇；林泰史等：日本骨代謝學會 雜誌 1 8 ( 3 ) : 76-82，200 1 )中記載之 0.863g/cm2 作爲 100%YAM値。又，使用Lunar公司之骨密度測定器的DPX 時，由該測定器所得之値，仍然依據原發性骨質疏鬆症之 診斷基準（2000年度修訂版），折茂肇；林泰史等：曰本 骨代謝學會雜誌18 ( 3) : 76-82, 2001所記載之下式換算式 ，變換成使用QDR時之測定近似値後，使用0.863 g/cm2作 爲100%YAM値。該等患者測定値以0.8 63 g/cm2表示爲 100%YAM値，以下表1中相對於YAM所顯示之大腿骨骨密 -20- 201105332 度爲分別使用QDR或DPX所得者。 [數2] QDR測定近似値=(DPX測定骨密度値+0.092 ) /1.294 接著，由血液檢查測定25 (OH) D値及Ca攝取量。自 投予開始時至投予終了時對確認之前臂部、椎體部，進行 骨折時期、骨折原因等之面診、X射線攝影、發生頻率測 定，進行統計分析。又，發生頻率係由卡潘-麥爾（ Kaplan-Meier)推定。 表1爲顯不投予艾爾骨化醇/阿法骨化醇時，各投予群 患者背景者。 -21 - 201105332 [表i] 表1.艾爾骨化醇/阿法骨化醇投予群患者背景 ALF投予群 ED-71投予群 性別男性 15例 9例 女性 508例 517例 年齡（歲） 72.1±6.6 72.2±6.6 身高（cm) 148.8±6.0 148.9 土 5.7 體重（kg) 49.4±7.5 49.3±5.7 既存椎體骨折個數 1.2±1.4 1_2±1.3 大腿骨骨密度YAM <60% 39例 42例 60-70% 118例 140例 70-80% 169例 158例 >80% 142例 142例 25 (OH) D (ng/mL) 1 22.2±6.4 22.4±6.7 Ca攝取量（mg/日） 734.4±337.6 714.5+343.5 -22- 1 爲修正維他命D之營養學不足，投予開始前，對25 (OH )D値不足20ng/mL之患者補給400IU之維他命補充劑。艾 爾骨化醇投予期間，未變更維他命D補充劑之投予量，修 正sCa値爲ll.Omg/d L以上或超過10.4mg/d L，醫師判斷繼 續投予有問題之情況，停止艾爾骨化醇及維他命D補充劑 之投予，於修正sCa値爲10.4mg/d L，相當於修正sCa値爲 0.40mg/dL GF以下時，變更爲下述投予量再開始投予，未 進行其後投予量之變更。 201105332 艾爾骨化醇（ED-71) : 〇.5pg/日，經口投予 阿法骨化醇（ALF ) : 0.5pg/日，經口投予 除了交通事故等之因大的外力所引起之外傷性骨折以 外，因跌倒等非外傷性之前臂部骨折於3年內之發生頻率 ’於既存活性型維他命D3製劑之阿法骨化醇投予群523例 中發生17例（3.63% )，於艾爾骨化醇投予群526例中發生 5 例（1 . 0 7 % )。 表2爲利用層化對數等級（log-rank )檢定及層化Cox 回歸法比較藉由投予艾爾骨化醇/阿法骨化醇引起之非外 傷性前臂部骨折頻率者。 [表2] 表2 ·利用層化對數等級檢定及層化c ο X回歸之非外傷 性前臂部骨折之群間比較 層化對數等級檢定 層化Cox回歸 艾爾骨化醇相對阿法骨化醇 （P-値） 危險比 90%信賴區間 P-値 0.0096 0.29 Γ0.13:0.671 0.015 註1.危險比表示艾爾骨化醇相對於阿法骨化醇之前 臂部骨折危險率之比。 註2.使用兩個層化因子（血中25 (OH) D量：比 20ng/mL少之群、爲20ng/mL以上之群，椎體骨 折既往：〇個' 1個、2個以上） 所目b層化對數等級檢疋意指爲了防止對結果帶來影響 之因子（預後因子）偏頗而以比較之兩群以使該等因子均 -23- 201105332 等之方式分配者，以所用之預後因子計算層中群間差’ 由將其加權平均而調整層別，並進行對數等級檢定。所 對數等級檢定基本上係對所有曰之相對危險度予以平均 對此平均相對危險度（RR)是否爲統計學上有意義之卡 平方（Chi-square)檢定者。 所謂層化Cox回歸爲調查引起事故之前之期間帶來 種其他要因之效果所用之方法，對於以該等成爲基準之 體之危險度，假定成爲以比例常數之形式處理之比例危 性之方法。所謂危險表示某時點之前前臂部並未骨折者 於該時點之前臂部骨折之槪率（瞬間前臂部骨折槪率） 所謂危險比意指兩群危險之比値。亦即，以其中一方爲 準時，表示另一方有多少倍之前臂部骨折槪率。 層化對數等級檢定結果，確認相對於阿法骨化醇投 群，艾爾骨化醇投予群明顯較具優異性（危險比：0.2 9 90% 信賴區間（confidence interval (CI) ) : 0.13-0.67 單側p = 0.0048 )。亦即將阿法骨化醇投予群之骨折槪率 爲1時，艾爾骨化醇投予群之骨折槪率爲0.29，判定前 部骨折危險率減少7 1 %。 圖1係依據卡潘-麥爾（Kaplan-Meier)法表示藉由 予艾爾骨化醇/阿法骨化醇引起之經時非外傷性前臂部 折比例。此方法係自觀察開始至終點（前臂部骨折）之 ，計算每前臂部骨折發生時點對於風險集合之前臂部骨 者數並累計並計算前臂部骨折之累積發生率，從而解析 劑效果者。此處’所謂風險集合，係指在剛發生前臂部 藉 謂 氏 某 個 險 基 予 設 臂 投 骨 刖 折 藥 骨 -24- 201105332 折之前，未引起該事實時之個體數（患者數）。 依據圖1之經時解析，判定艾爾骨化醇之前臂部骨折 抑制效果由投予初期即已確認並持續至1 44週。 表3爲顯示圖1所示之未骨折患者數與前臂部骨折發生 數之數値比者。 -25- 201105332 [表3] 表3.由卡潘-麥爾所得之未骨折患者數與前臂部骨折 發生數 週 未骨折 骨折數 阿法骨化醇 基準 523 0 8週後 522 1 16週後 504 3 24週後 498 5 32週後 490 7 40週後 479 7 48週後 474 8 56週後 471 8 64週後 465 8 72週後 455 11 80週後 449 12 88週後 446 12 96週後 439 13 104週後 436 13 112週後 425 13 120週後 419 13 128週後 410 15 136週後 408 16 144週後 399 17 艾爾骨化醇 基準 526 0 8週後 526 0 16週後 514 0 24週後 504 2 32週後 498 2 40週後 494 2 48週後 491 2 56週後 484 2 64週後 478 2 72週後 473 2 80週後 469 2 8 8週後 465 2 96週後 455 3 104週後 451 3 112週後 442 4 120週後 438 4 128週後 433 5 13 6週後 430 5 144週後 425 5 -26- 201105332 表4爲於艾爾骨化醇/阿法骨化醇投予前大腿部骨密度 背景別對患者群分組化後之藥劑投予後前臂部骨折發生率 進行比較者。 [表4] 表4.藥劑投予前大腿部骨密度背景別之藥劑投予後 前臂部骨折發生件數 大腿骨骨密度 阿法骨化醇組 艾爾骨化醇組 進行大腿骨骨密度 測定之468例分佈 骨折發生 件數 進行大腿骨骨密度 測定之482例分佈 骨折發 生件數 低於60% 39例 2例 42例 0例 60%以上低於70% 118例 5例 140例 〇例 70%以上低於80% 169例 7例 158例 2例 80%以上 142例 2例 142例 2例 依據表4之藥劑投予前大腿骨骨密度背景別之前臂部 骨折發生件數比較，艾爾骨化醇之前臂部骨折抑制效果， 獲得大腿骨骨密度低於70%之群中比阿法骨化醇更顯著較 高之結果。亦即，阿法骨化醇投予群157例中，7例見到前 臂骨骨折，相反地，於艾爾骨化醇投予群1 8 2例中完全未 見到前臂部骨折發生。 比較例 針對非外傷性椎體骨折進行層化對數分級檢定及層化 Cox回歸之結果，相對於阿法骨化醇投予群之艾爾骨化醇 投予群之椎體骨折發生之危險性，並非前臂部骨折發生危 -27- 201105332 險性低者（層化對數等級檢定：Ρ = 〇·〇46，危險比：0.74， 90 %信賴區間（Cl :0.56-0.97))。亦即將阿法骨化醇投予 群的骨折槪率作爲1，艾爾骨化醇投予群的骨折槪率爲 〇 . 7 4，判定椎體骨折之危險率停留在減少2 6 %。 【圖式簡單說明】 圖1顯示依據卡潘-麥爾（Kapian-Meier)法所得之艾 爾骨化醇/阿法骨化醇投予時之非外傷性前臂部骨折發生 頻率之經時推移。 -28-BMD (BMD: Bond Mineral Density) is the average (Young Adult Mean, YAM) phase of calcium deposited in bone by X-ray or ultrasonography and young adults (20 to 44 years old with the highest bone density). More or less than the number of people (%). Based on the current diagnostic criteria for osteoporosis, when there is no fragility fracture, the bone density is more than 80% of YAM, which is "normal". If it is 70-80%, it is "osteopenia". Therefore, if it is 70% or less, it is a state in which the bone of "osteoporosis" is easily broken (edited by the Prevention and Treatment Standards Committee for Osteoporosis, representative: 折茂肇). Moreover, according to the World Health Organization (WHO) World Health Organization, the severity of osteoporosis is defined by the number of bone fractures and fragility fractures. In this benchmark, the bone density T score relative to YAM is defined as "normal" within -1 SD, and the bone density T score of -1 to -2.5 SD is defined as "low bone mass (bone reduction)", bone density A T-score of -2.5 SD is defined as "osteoporosis", so the T-score of bone density is -2.5 SD or less, and one or more vulnerable fractures are defined as "severe osteoporosis". Here, SD is the standard deviation 値. There are several methods for determining bone density. For example, DXA (Dual Energy X-ray Absorptiometry) method: dual energy X-ray absorption method; £. -11 - 201105332 QCT (quantified computed tomograghy) method: quantitative computed tomography; pQCT (peripheral quantitative computed tomograghy) method: peripheral quantitative computed tomography; QUS (Quantitative ultrasound) method: quantitative ultrasound method. Among them, the DXA method uses two X-ray beams of different energies, and the bone mass and cartilage tissue are distinguished by high pulse analysis, and the amount of bone salt (unit: g) is determined. Further, the bone projection area (cm2) seen from the X-ray irradiation direction was calculated, and the bone mineral amount (g/cm2) obtained by the DXA method was obtained by dividing the bone salt amount by the projected bone area. The bone density of the present invention is preferably measured by the DXA method, the QCT method, the pQCT method, the QUS method, the RA/MD method, and more preferably by the DXA method or the QUS method. Examples of the measurement site include lumbar vertebrae, thigh bone, whole body bone, tibia, heel, tibia, hand bone, phalanx, etc. The lumbar spine and thigh bone are preferably measured by the DXA method of the trunk bone; the whole body bone is measured by the DXA method of the distal bone. Bone, or the calcaneus by the QUS method. The T-score is the so-called "deviation" of bone density. When the bone density of YAM is used as a reference, the standard deviation SD (SD) of a certain degree and its deviation is displayed. The T-score is calculated as follows: [Number 1] T-score = (measurement of bone density 被-1 〇〇% YAM値) /100% standard deviation of YAM値 100% YAM bone density 値 and its standard deviation ( SD) is based on the equipment used for the measurement. When measuring the bone density in the vicinity of the thigh bone in the present invention, when using the QDR of the Hologic BMD, 〇.8 6 3 g/cm 2 was used as 100% YAM値, and 0.110 was used as the standard deviation -12-201105332. Poor (both in the diagnostic criteria for primary osteoporosis (2000 revision), 折茂肇; Lin Taishi et al: Journal of the Society for Bone Metabolism 18(3): 76-8 2,200 1 ), using the above formula Calculate the T score. On the other hand, when using the DPX of Lunar's Bone Densitometer, the sputum obtained from the device is still based on the diagnostic criteria for primary osteoporosis (2000 revision), and Lin Taishi et al.: Japanese bone The following equations are described in the Journal of Metabolism Society 18(3):76-8 2,2 001, and converted to QDR to determine the approximate 値. If this is applied to the above formula, a T score can be obtained. As described above, in Japan, 80% or more of the bone density of YAM is defined as "normal", and if it is 70% or less of YAM, the bone of "osteoporosis" is easily broken, but it is the Japanese standard "YAM". "80% or more" and "70% of YA 」" are equivalent to the "Bone density Τ score of about -1 SD relative to YAM 」" and the "T-score of bone density is relative to YAM". About -2.5SD", the bone density is expressed as % of YAM relative to the Japanese standard. The SD unit of the benchmark outside Japan is lower than YAM. Although there are differences, there is basically no difference (http:/ /www_ebmlibrary_jp/〇steo/guideline/guide02. html ). The so-called severe osteoporosis patient of the present invention is based on the diagnostic criteria outside Japan, and indicates that the T-score of the bone density near the femur is -2.5 SD or less and the patient with the fragility fracture is further limited to the vicinity of the thigh bone. The T-score of the site bone density is -2.5SD and has more than 2 vulnerable fractures. However, it can be replaced with the Japanese diagnostic criteria based on bone mineral density. It can also be replaced with 70% of the bone density in the vicinity of the thigh bone. S- -13- 201105332 The following patients with fragility fractures are further limited to patients with a bone density near the femur that is less than 70% of YAM and have more than two fragility fractures. A so-called traumatic fracture indicates a fracture that occurs due to a large external force such as a traffic accident. A so-called non-traumatic fracture indicates a fracture that occurs due to a slight external force such as a fall. The so-called fragility fracture means that the cause is low bone mass (bone density is less than 80% of YAM or osteoporosis of the spine) and non-traumatic fractures due to slight external force. The so-called bone strength is determined by bone density. Bone mineral density per unit volume is considered to be about 70% of the bone strength, and the remaining 30% of the elements are considered to be explained by the fine structure and bone metabolic rate. The bones formed by the causes of tiny fractures and calcification. The pharmaceutical composition containing the compound of the present invention as an active ingredient can be prepared by using a pharmaceutical additive commonly used by those skilled in the art, in a preparation method of various preparations which are usually used. Examples of the above additives include excipients, binders, slip agents, disintegrators, colorants, flavoring agents, emulsifiers, surfactants, dissolution aids, and suspending agents used in general medicines. The agent, the buffer, the preservative, the antioxidant, the stabilizer, the absorption enhancer, and the like may be used in combination as appropriate. The dosage form may be a dosage form of a lozenge, a nine-part, a capsule, a granule, a powder, a liquid, or the like, which may be administered orally, or may be an injection, an external preparation, an inhalant, or the like suitable for intra-articular, intravenous, Any of the dosage forms administered intramuscularly orally. As for the solid composition for oral administration, a tablet, a powder, -14-201105332, granules, and the like are used. The solid composition is one or two components mixed with at least one inert excipient such as saccharide such as lactose, mannose, sucrose or the like, crystalline cellulose, starch, aluminum, magnesium metasilicate aluminate or the like. The pharmaceutical group generally contains other additives such as a disintegrant such as calcium stearate carboxymethylcellulose calcium or sodium alginate, a dissolution aid such as diol, a binder such as polyvinyl alcohol, and a taste. A odorant, an emulsifier such as sodium lauryl sulfate or an interfacial agent or nine agents may also be coated with a sugar-coated or gastric-soluble or enteric coating as needed. The liquid composition for oral administration contains a turbid agent, a solution, a suspending agent, a syrup or an elixir, and the like, and an inert diluent such as purified water or ethanol. In addition to liquid pharmaceutical diluents, such as solubilizing agents, moisturizing agents, sweeteners, flavoring agents, flavoring agents, preservatives for parenteral injections containing sterile aqueous solutions, suspensions or Opacifying agent. The aqueous solvent contains, for example, or physiological saline. The non-aqueous solvent is, for example, propylene glycol, a vegetable oil of olive oil, an alcohol such as ethanol or poly-polysorbate 80 0 (Pharmacopoeia name). Such a pharmaceutical group contains the above additives such as an isotonic agent, a preservative, a wet, a dispersant, a stabilizer, an antioxidant, a buffer, and a dissolution aid. These are sterilized, for example, by retaining the bacteria, mixing the bactericide, or by irradiation. Further, the solid composition of the fungus may be dissolved or suspended in the above-mentioned effective sugar, glucose, calcium carbonate or citric acid before use, or may be based on a slip agent such as a tempering agent or a polyglycol powder. Active agent, etc. Membrane agent for insoluble substances: milk which can be used in general, except for inert or non-aqueous soluble injectable water, polyethylene glycol or sorbitol ester, which can be used in addition to an inerting agent or a suspending agent. Emulsifier absorption enhancer or filter for filtration, etc., can also be used for the production of anhydrous or sterile injection -15-201105332. Also, the solution containing the auxiliary agent or the like is stored in a container, and then freeze-dried, etc. The solid preparation may be prepared as a preparation prepared at the time of use. Alternatively, the single dose may be stored in one container, or the plurality of doses may be contained in one container. The external preparation contains a suppository and a transdermal substance. Liquid agent, transdermal patch, transmucosal patch, ointment, plaster, cream, gel, topical ointment, spray, lotion, eye drop, eye ointment, etc. Ointment base, lotion base, aqueous or non-aqueous liquid, suspending agent, emulsion, etc. used, for example, as an ointment or lotion base, exemplified by polyethylene glycol, propylene glycol, white petrolatum, paraffin, white Mild wax, polyoxyethylene hardened castor oil, glyceryl monostearate, stearyl alcohol, cetyl alcohol, polyethylene glycol stearate ( Lauromacrogol), etc., inhalation or nasal spray, etc. When a solid, liquid or semi-solid is used, it can be produced according to a conventionally known method. For example, a known excipient or a pH adjusting agent, a preservative, a surfactant, a slip agent, a stabilizer or a thickening may be added as appropriate. For administration, a device for proper inhalation or insufflation may be used. For example, using a known device or a nebulizer for metering an inhalation device or the like, the compound may be used alone or as a powder of a prescribed mixture or in combination with a medically acceptable carrier. The solution or suspension may be administered. The dry powder inhaler or the like may be administered as a single or multiple doses, or may be a dry powder or a capsule containing a powder. Alternatively, a pressurized aerosol may be expelled by using a suitable gas. The form of the nebulizer, etc. The compound of the present invention can be used for preventing the frontal arm fracture of mammals, especially humans. The dosage and the administration interval correspond to the height and weight of the patient. 6· 201105332 'The age, gender or medical symptoms, the severity of the symptoms to be treated, the route of administration, the renal function of the patient, the medical history, and the various compounds or salts used, are appropriately selected by the physician. Usually for humans In the case of oral administration, the administration amount per day is 0.01 to 1.0 μ§, preferably 0.5 to 1.0 pg, more preferably 0.75 pg, which may be administered once or twice to four times. In the case of non-oral administration, the dosage on the 1st is 0.01 q.Opg, preferably 〇25 to 1.0 pg, and the dosage is determined according to the circumstances, including the symptoms, age, sex, etc., which also includes It is possible to obtain the same effect by changing the dosage for a certain period of time, or by continuing to administer a low dose for a longer period of time. In order to obtain the observed effect, the patient preferably receives an administration of Alcoholic Alcohol substantially equivalent to each period. It can be considered that during the period of continuing treatment during the period of at least 24 weeks, better 48 weeks, and better and longer than 144 weeks, there is occasional period of no administration of Alcohol, but this period is due to Since the corrected serum calcium sputum is measured and the urinary calcium sputum is corrected, it is confirmed that the effect of escaping alcohol is also sufficient in the withdrawal, and the course of treatment including such a withdrawal period is also included in the scope of the present invention. By effective amount is meant the amount necessary to reduce at least the risk of fracture, but not to the amount of oleoflavone. The term "consistent period" means a sufficiently long amount of time that the patient's bone density and bone strength increase without being easily fractured. In the present invention, the equivalent time is preferably 24 weeks or longer, more preferably 48 weeks or longer, and still more preferably 144 weeks or longer. The term "substantially daily" means that the daily administration is based on the principle of daily, but also includes the fact that the patient's overall effect is not changed when the patient receives the daily dose, and the patient forgets the date of the injection. -17- 201105332 The compound of the present invention can be used in combination or in combination with various therapeutic or prophylactic agents which are considered to be effective for the aforementioned compounds of the present invention. The so-called 倂 contains two kinds of drugs taken at the same time and two times during the period of co-administration. The so-called recycling, for patients to receive Alcoholic alcohol at a specific time, 'Subsequent to the second phase of the discontinuation of Alcoholic Alcohol (can be accepted or not to accept additional bone formation enhancers or bone resorption inhibitors And/or hormonal therapy), then return to Algonhydrin therapy. Usually, due to the divergence of the causes of osteoporosis, it is difficult to determine which pathology is obtained from a patient. Moreover, the stage of the disease is also diverse, and osteoporosis is not treated with a group of patients in various states. Therefore, it is also clinically possible to combine two or more doses of therapy or recurrent therapy with different combinations of mechanisms. This therapy or recurrent therapy is intended to reduce side effects or enhance bone fracture inhibition by a combination of agents having different mechanisms of action. The use or recycling can also be separated by a specific time. The preparations to be administered at the same time may be formulated as individual preparations. The agents to be used or recycled may be exemplified by estrogen or estrogen derivatives, diphosphates, antiestrogens or selective estrogen spleen regulators, ανβ3 integrin inhibitors, and cellular autolytic enzymes ( Cathepsin) K inhibitor, HMG-CoA reductase inhibitor, osteoclast liquid cell type ATPase inhibitor, antagonist of VEGF binding to osteoclast receptor, peroxisome proliferator-activated receptor gamma, inhibition Calcium, calcium receptor antagonist, parathyroid hormone or parathyroid hormone derivative, growth hormone secretion promoting substance, human growth hormone, insulin-like growth factor, Ρ-38 protein kinase inhibitor, bone morphogenetic protein, BMP antagonism mechanism Obstruction agent, -18 - 201105332 Prostaglandin derivative, vitamin K or vitamin K derivative, isoflavone, fluoride salt, calcium nutrient supplement, and one or more agents selected by androgen receptor modulators, specifically For example, L-aspartate calcium, dibasic calcium phosphate, estriol, 17β estradiol, menatetrenone, alen phosphate, etidron phosphate (etidronate), risedronate, ibandronate, raloxifene, elcatonin, salmon calcitonin, isoflavones, Agents such as Nandrolone Decanoate and teriparatide. Among these, the best agent is a diphosphate ester anti-estrogen or selective estrogen receptor modulator, calcitonin, specifically alen phosphate, etidron phosphate, riser phosphate, and Iban phosphate Ester, roptenol hydrochloride, lysocalcin, salmon calcitonin. Analysis of clinical trial data shows that the risk of forearm fractures can be reduced if an effective amount of ergocalciferol is administered per sputum during a substantial period of time. The invention is specifically illustrated by the examples shown below, but the invention is not limited thereto. These terms should not be construed as limiting in any way. [Examples] Example 1 A patient with primary osteoporosis was treated with Alfacalcidol as a control group, and the effectiveness of Alcoholic Alcohol was evaluated by a randomized double-blind test between groups. -19 - 201105332 Number of patients: Alcohol (ED-71) administration: 526 patients with Alfacalcidol (ALF): 523 patients with diagnosis and inclusion criteria: primary osteoporosis 46 to 92 years old The dosage and administration of patients: Alcohol (ED-71): 0.75pg/day, oral administration of Alfacalcidol (ALF): l.Opg/day, oral administration test The formulations were prepared based on WO2005/074943 and No. 4070459, respectively. During the administration period: Alecbolic alcohol (ED-71) and Alfacalcidol (ALF) were administered continuously for 144 weeks (after 4 weeks of observation). Review method: X-ray examination of existing vertebral fractures Number, the bone density of the thigh was measured by the DXA method. The patient's thigh bone density is calculated and expressed as follows. That is, when the bone density of the thigh is measured using the QDR of the bone density tester of Ho Logic, the diagnostic criteria for primary osteoporosis (2000 revision) are used, and the sputum is used; Lin Taishi et al.: Journal of the Japanese Society of Bone Metabolism 0.83 g/cm2 as described in 1 8 (3): 76-82,200 1 ) is taken as 100% YAM値. In addition, when using the DPX of Lunar's Bone Densitometer, the sputum obtained from the tester is still based on the diagnostic criteria for primary osteoporosis (2000 revision), and the 泰 骨 肇; In the Journal of Metabolism, 18 (3): 76-82, 2001, the conversion formula is converted to the approximate measurement using QDR, and 0.863 g/cm2 is used as 100% YAM値. The sputum was determined to be 100% YAM 0.8 at 0.8 63 g/cm 2 in these patients, and the femur bone density -20-201105332 degrees shown in Table 1 below was obtained using QDR or DPX, respectively. [Number 2] QDR measurement approximate 値 = (DPX measurement bone density 値 + 0.092 ) / 1.294 Next, 25 (OH) D 値 and Ca intake amount were measured by blood test. From the start of the administration to the end of the administration, the face, the vertebral body, the face of the fracture, the cause of the fracture, the X-ray imaging, and the frequency of occurrence were measured and statistical analysis was performed. Again, the frequency of occurrence is presumed by Kaplan-Meier. Table 1 shows the background of the patients who were administered to each group when the Alecbolic Alcohol/Alfacalcidol was not administered. -21 - 201105332 [Table i] Table 1. Alecbolic alcohol/Alfacalcitol active group patients Background ALF administration group ED-71 administered to groups of males 15 cases 9 women 508 cases 517 cases ( Year) 72.1±6.6 72.2±6.6 Height (cm) 148.8±6.0 148.9 Soil 5.7 Weight (kg) 49.4±7.5 49.3±5.7 Number of existing vertebral fractures 1.2±1.4 1_2±1.3 Bone bone density YAM <60% 39 Case 42 cases 60-70% 118 cases 140 cases 70-80% 169 cases 158 cases > 80% 142 cases 142 cases 25 (OH) D (ng / mL) 1 22.2 ± 6.4 22.4 ± 6.7 Ca intake (mg / Day) 734.4±337.6 714.5+343.5 -22- 1 To correct the nutritional deficiency of vitamin D, 400 IU of vitamin supplement was replenished to patients with 25 (OH )D値 less than 20 ng/mL before the start of the administration. During the administration of Alcoholic Alcohol, the dosage of vitamin D supplement was not changed, and the sCa値 was corrected to ll.Omg/d L or more or more than 10.4 mg/d L. The physician judged to continue to cast the problem and stop. The administration of Alcohol and Vitamin D supplements is based on the correction of sCa値 of 10.4 mg/d L, which corresponds to the correction of sCa値 of 0.40 mg/dL GF or less, and is changed to the following dosage and then started to be administered. There was no change in the amount of the subsequent dose. 201105332 Algonhydrin (ED-71): 〇.5pg/day, oral administration of Alfacalculated alcohol (ALF): 0.5pg/day, orally administered in addition to traffic accidents In addition to traumatic fractures, the frequency of non-traumatic pre-arm fractures within 3 years due to falls was observed in 17 of the 523 cases of Alpha-calcinol-administered group of viable vitamin D3 preparations (3.63%). 5 cases (1.07%) occurred in 526 cases of Alcoholic Alcohol. Table 2 compares the frequency of non-traumatic forearm fractures caused by administration of Alecbolic Alcohol/Alfacalcidol using a stratified log-rank assay and a stratified Cox regression. [Table 2] Table 2 • Comparison of stratified logarithmic scales and stratification c ο X-regression of non-traumatic forearm fractures stratified logarithmic scale stratified Cox regression Alec made alcohol relative Alpha ossification Alcohol (P-値) Hazard ratio 90% confidence interval P-値0.0096 0.29 Γ0.13:0.671 0.015 Note 1. The hazard ratio indicates the ratio of the risk of arm fracture in the previous osteocalcin relative to alfacalcidol. Note 2. Two stratification factors (25 (OH) D in blood: less than 20 ng/mL, 20 ng/mL or more, vertebral fractures: 1 ', 2 or more) The logarithmic level check indicates that the factors (prognostic factors) that are influential to the results are biased, and the two groups are compared so that the factors are all distributed in the manner of -23-201105332, etc. The difference between the groups in the prognostic factor calculation layer is adjusted by weighted averaging, and the logarithmic level is checked. The logarithmic scale test basically averages the relative risk of all ticks. Is this average relative risk (RR) a statistically significant Chi-square tester. The stratified Cox regression is a method used to investigate the effects of other factors in the period before the accident is caused, and it is assumed that the risk of such a target is a proportional hazard. The so-called hazard indicates the rate of fracture of the arm before the forearm is not fractured at a certain point in time (instantaneous forearm fracture rate) The so-called hazard ratio means the ratio of the two groups of hazards. That is, when one of them is correct, it indicates how many times the other side has a lower arm fracture rate. The results of the stratified logarithmic scale test confirmed that the Alcoholic Alcohol Administration Group was significantly superior to the Alfacalcitol Alcohol Group (hazard ratio: 0.2 9 90% confidence interval (CI)): 0.13 -0.67 unilateral p = 0.0048). Also, when the rate of fracture of the Alfacalcitol group was 1, the rate of fracture of the Alcoholic Alcohol Group was 0.29, and the risk of anterior fracture was reduced by 71%. Figure 1 shows the time-dependent non-traumatic forearm fold ratio caused by Alcohol/Alphacalculated Alcohol according to the Kaplan-Meier method. This method is performed from the beginning of the observation to the end point (fracture of the forearm). The number of bones before the risk of the forearm fracture is calculated and the cumulative incidence of the forearm fracture is calculated and calculated to resolve the effect of the agent. Here, the so-called risk set refers to the number of individuals (number of patients) that did not cause this fact before the forearm was borrowed from a certain risk base to the arm. According to the time-lapse analysis of Fig. 1, the effect of suppressing the arm fracture before the determination of Algonhydrin was confirmed from the initial stage of administration and continued until 1 44 weeks. Table 3 shows the number of unbroken patients shown in Figure 1 and the number of occurrences of forearm fractures. -25- 201105332 [Table 3] Table 3. Number of unbroken patients obtained from Capan-Mal and number of fractures in the forearm fracture for several weeks. Alphacalculated alcohol baseline 523 0 8 weeks later 522 1 16 weeks later 504 3 24 weeks later 498 5 32 weeks later 490 7 40 weeks later 479 7 48 weeks after 474 8 56 weeks after 471 8 64 weeks after 465 8 72 weeks after 455 11 80 weeks after 449 12 88 weeks after 446 12 96 weeks later 439 13 104 weeks after 436 13 112 weeks after 425 13 120 weeks after 419 13 128 weeks after 410 15 136 weeks after 408 16 144 weeks after 399 17 Aer bone alcohol benchmark 526 0 8 weeks after 526 0 16 weeks later 514 0 After 24 weeks, 504 2 32 weeks later 498 2 40 weeks later 494 2 48 weeks later 491 2 56 weeks later 484 2 64 weeks later 478 2 72 weeks later 473 2 80 weeks later 469 2 8 8 weeks later 465 2 96 weeks later 455 3 104 weeks later 451 3 112 weeks later 442 4 120 weeks later 438 4 128 weeks later 433 5 13 6 weeks later 430 5 144 weeks later 425 5 -26- 201105332 Table 4 is the calcification of Al's bone alcohol / Alpha Before the administration of alcohol, the bone density of the thigh was compared. The incidence of forearm fracture was compared after the drug group was administered. [Table 4] Table 4. Bone mineral density in the thigh before administration of the drug. After the administration of the drug, the forearm fracture occurred in the thigh bone density. The Alfacalcitol group was treated with the Alcohol group to determine the bone density of the thigh bone. 468 cases of distributed fractures The number of fractures in 482 cases of femur bone density was less than 60%. 39 cases, 2 cases, 42 cases, 0 cases, 60% or more, less than 70%, 118 cases, 5 cases, 140 cases, 70 cases. % or less is less than 80% 169 cases, 7 cases, 158 cases, 2 cases, 80% or more, 142 cases, 2 cases, 142 cases, 2 cases, according to the agent of Table 4, before the administration of the bone density of the thigh bone, the number of previous arm fractures, Aier The inhibitory effect of bone fracture before calcitonin was more significant than that of alfacalcidol in the group with less than 70% bone density of the thigh bone. That is, among the 157 cases of Alfacalcidol administration group, 7 cases saw a fracture of the forearm bone. Conversely, no forearm fracture occurred in the 182 cases of Alcoholic Alcohol Administration. Comparative example of the results of stratified logarithmic stratification and stratified Cox regression for non-traumatic vertebral fractures, relative to the risk of vertebral fractures in the Alcoholic Alcoholic Group administered by Alfacalcitol , not the risk of forearm fracture -27- 201105332 low risk (stratification logarithmic level test: Ρ = 〇 · 〇 46, hazard ratio: 0.74, 90% confidence interval (Cl: 0.56-0.97)). The fracture rate of the Alfacalcidol group was also 1, and the fracture rate of the Alcoholic Alcohol Administration group was 〇. 7 4, the risk of vertebral fracture was determined to be reduced by 26%. BRIEF DESCRIPTION OF THE DRAWINGS Fig. 1 shows the temporal change of the frequency of non-traumatic forearm fractures when Alcoholic Alcohol/Alfacalcidol is administered according to the Kapian-Meier method. . -28-