WO2010104079A1 - Composition for reducing bone fracture risk and/or preventing bone fracture - Google Patents

Abstract

Disclosed is a medicinal composition, a food composition or a feed composition which is efficacious for reducing bone fracture risk or preventing bone fractures in adult and geriatric human males or male mammals. The aforesaid compositions were developed based on the finding that, due to the administration of an effective amount of zinc to a human female or female mammal during the periods when the female is fertile, pregnant or lactating, the risk of bone fractures in a human male or male mammal born to the human female or female mammal can be significantly reduced when the human male or male mammal reaches adulthood or later.

Description

Composition for reducing fracture risk and / or preventing fracture

The present invention relates to a composition for reducing fracture risk and / or preventing fracture. More specifically, the present invention relates to a pharmaceutical composition or a food composition (oral ingestion agent) that can be taken orally effective in reducing fracture risk and / or preventing fracture.

In recent years, with the aging of the population, fractures are attracting attention as a threat to the elderly's independent life and healthy life. One of the biggest causes of elderly people becoming bedridden is a fracture. Moreover, osteoporosis is mentioned as one of the causes which increase a fracture. In order to lead a healthy elderly life, reducing fracture risk and preventing fractures will be extremely important in advanced countries where aging continues.

骨 A fracture is a fracture or a crack in the bone. Increasing the bone strength can reduce the risk of fracture and prevent a fracture. The main determinants of bone strength include (1) bone mass and density, and (2) bone quality. The characteristics indicating bone quality include structural characteristics and material characteristics. Structural characteristics include macroscopic bone structure and size, microcancellous trabecular structure and cortical bone (compact bone) morphology and porosity. The material characteristics include mineralization degree, crystal size, collagen, and micro damage (Non-Patent Document 1).

Osteoporosis is divided into several modes, for example, (1) secondary osteoporosis caused by a specific disease or drug, and (2) primary osteoporosis that is thought to occur due to various causes overlapping. Can do. The main ones of primary osteoporosis can include osteoporosis and senile osteoporosis in postmenopausal women.

Osteoporosis in postmenopausal women is caused by a decrease in estrogen. Estrogen is a major regulator of bone metabolism, and it is supposed that osteoporosis is caused by a decrease in bone mass due to a decrease in estrogen.

On the other hand, the cause of senile osteoporosis in men and postmenopausal women after the menopause is considered to be caused by a combination of factors, such as decreased sex hormones, changes in systemic hormones and cytokine actions. Yes. The proliferative ability and function of osteoblast progenitor cells and mature osteoblasts decrease at the cellular level as a result of aging. In addition, it is said that bone resorption increases with aging and bone formation declines. Furthermore, the endocrine system changes due to aging, and the concentration of growth hormone and IGF-I decreases, which reduces bone formation. It is said that the decrease in sex hormones causes bone loss even in men.

For some time, estrogen has been given to osteoporosis in postmenopausal women. However, estrogen has problems such as that it has side effects such as uterine bleeding and breast swelling, and that it may induce endometrial cancer and breast cancer (Non-patent Document 2). Active vitamin D, bisphosphate, magnesium, calcium, casein phosphopeptide, and the like are also used for the treatment of osteoporosis.

Moreover, recently, the use of vitamin K _2, vitamin K ₂ and the combination of zinc is known as an improvement agent or preventive agent for osteoporosis (Patent Document 1). In addition, as a composition with the effect of increasing bone mass and muscle mass, which helps prevent falls and fractures in the elderly, creatine and vitamin D, glucosamines, glycosaminoglycans are active ingredients, bone and muscle strengthening Food compositions have been developed (Patent Document 2).

JP 10-036256 JP 2008-237070

In the present invention, a pharmaceutical composition or (health) food composition effective for reducing fracture risk and / or preventing fracture, particularly for improving or preventing adult male, elderly male, and male adult osteoporosis and senile osteoporosis Development is the first issue.

Further, in the present invention, the risk of fracture of a male male and / or prevention of fracture is reduced. In particular, the male of a grown mammal, the male of an old mammal, and the male grown male osteoporosis and old osteoporosis Development of a pharmaceutical composition or feed composition effective for improving or preventing the above is a second problem.

Furthermore, in the present invention, the risk of fracture and / or prevention of fractures in male or mammalian males born by administration to mothers from the time of pregnancy to pregnancy or from pregnancy to pregnancy and breastfeeding. Development of a pharmaceutical composition or a (health) food composition or a feed composition is a third problem.

In addition, conventional anti-fracture agents or preventive or therapeutic agents for osteoporosis have been developed using bone mass and bone density as indicators, and it is not sufficient to confirm and demonstrate whether bone strength has actually improved. There wasn't. Therefore, in the present invention, a fourth problem is to develop a pharmaceutical composition or a food composition that can reduce the risk of fracture, which has been confirmed or verified to actually improve bone strength.

The inventor of the present application can administer an effective amount of zinc to a woman or a mother of a mammal by giving it an effective amount of zinc to a woman or a mammal mother during the period before pregnancy and during pregnancy and breastfeeding, or at least during pregnancy. Alternatively, the present invention was completed by finding that the risk of fracture when a boy or male offspring born from an animal mother reached adulthood was significantly reduced.

This specification includes the contents described in the specification and / or drawings of Japanese Patent Application No. 2009-061838, which is the basis of the priority of the present application.

In the present invention, when zinc is administered to a woman, a boy born from the woman reaches adulthood (hereinafter also referred to as “adult”, “adult”, “after growth”, etc.) or old age In addition, the male has a particularly excellent effect of reducing fracture risk and / or preventing fracture.

Furthermore, the present invention provides a method for administering a fracture to a male when a male offspring born from the mother grows (hereinafter also referred to as an “adult”) or reaches an old age by administering zinc to a mammalian mother. It has a particularly excellent effect of enabling risk reduction and / or prevention of fractures.

Cortical bone thickness (cm) of the pup mouse by X-ray CT imaging * p <0.05 mm, there is a significant difference Cortical bone area ratio (%), which is the ratio of cortical bone area to total bone area * p <0.05 mm, there is a significant difference Minimum moment of inertia (mg · cm) showing the bone strength against bending * p <0.05mm, there is a significant difference Cross-sectional second-order moment (mg · cm) showing bone strength against torsion * p <0.05 mm, significant difference Maximum bending energy (mJ) from the three-point fracture test of the right femur Tissue volume of cancellous bone (mm ³ ) * p <0.05, significant difference Total bone mass of cortical bone (mg) * p <0.05 mm with significant difference 25 (OH) vitamin D3 concentration in blood (nmol / L) * p <0.05, there is a significant difference

1. 1. Introduction Osteoporosis has conventionally been regarded as a disease involving a fracture caused by a decrease in bone mass, but is now regarded as a disease with an increased risk of fracture. And it has been widely recognized that therapeutic agents for osteoporosis require preventive treatment of fractures.

In osteoporosis associated with postmenopausal estrogen reduction, the cause is elucidated and treatment methods are being established, but in fractures associated with decreased bone strength in men, the cause is considered to be due to multiple factors and is still fundamental. No practical treatment or prevention method has been developed.

By the way, in recent years, it has become known that there is a correlation between nutrition during pregnancy and the health of the born child. For example, it has been found that there is a correlation between folic acid intake during pregnancy and neural tube closure disorder, which is a congenital anomaly that occurs in neural tubes such as the brain and spinal cord. Pregnant women are said to be able to reduce the risk of neural tube closure problems in their babies by ingesting folic acid, because the fetal neural tube is created in the early stages of pregnancy. Adequate folic acid intake before and after conception is recommended.

Including this viewpoint, research is being conducted on the relationship between nutrition during pregnancy and the subsequent growth and health of the baby.

2. Intake of trace element zinc and its role Zinc is said to play catalytic, structural and regulatory functions in vivo. There are 300 to 500 types of zinc-dependent enzymes, and only typical ones include RNA polymerase and alkaline phatase. In addition, there are a large number of proteins in the living body whose structure is maintained by zinc bonding, such as Zinc-finger protein. Specifically, it is estimated that there are as many as 2800 types of zinc-binding proteins in the human body.

Furthermore, although there are a wide variety of regulatory functions of zinc, it is becoming clear that zinc is also involved in apoptosis and also works in intracellular signal transduction substances.

Thus, due to the various roles of zinc in the body, it is known that zinc deficiency includes growth disorder, hypogonadism, taste / olfactory disturbance, hair loss, immune decline, and the like.

According to the “2005 dietary standard for Japanese dietary intake”, the recommended amount of zinc consumed by Japanese is 3 mg per day for pregnant women, compared to the recommended amount of 7 mg per day at the age of pregnancy. In the period, the recommended amount per day is 10 mg. However, according to the 2005 National Health and Nutrition Survey, about 90% of pregnant women do not meet the daily required intake of zinc, which includes additional amounts.

In addition, according to the “2005 Japanese Dietary Intake Standard”, the daily intake of zinc at the age of pregnancy is limited to 30 mg, but the oral toxicity of zinc is very low, too much It is said that hypertension will not occur if not consumed in large quantities.

On the other hand, “Dietary Reference Intakes for Vitamin A, Vitamin K, Arsenic, Boron, Chromium, Copper, Iodine, Iron, Manganese, Molybdenum, Nickel, Silicon, Vandium, and Zinc” According to Nutrition Board, Institute of Medicine, 2000), the recommended daily dose for pregnant women is 11-12 mg compared to the recommended daily dose of 8 mg at the age of pregnancy, and the daily dose for adult women The upper limit of intake is 40 mg.

3. Fracture risk and bone strength Osteoporosis is now characterized as a loss of bone strength and is defined as a bone disease that increases fracture risk. Bone strength is an integration of bone density and bone quality. In the past, particular attention has been directed to bone mass and bone density as an assessment of fracture risk. In bone mass measurement, the burden on the patient is small and clinically excellent, but there are various problems in evaluating the risk of fracture. For example, treatment with fluorine has little effect on preventing fractures despite an increase in bone mass. In addition, even with raloxifene treatment, it is said that the incidence of fracture is lower when the bone mass decreases than when the bone mass increases in the control group. In other words, the relationship between the increase in bone mass and the effect of inhibiting fractures does not necessarily match (Clinical Calcium Vol. 14, No. 12, pages 11-26). Thus, in bone mass measurement, it has become clear that there is a limit to the index of the therapeutic effect of fractures or osteoporosis, and the importance of evaluating bone strength and bone quality has recently been recognized.

Characteristics that represent bone quality include macroscopic bone structure and bone dimensions, microscopic trabecular bone trabecular structure and bone dimensions, microscopic trabecular bone trabecular structure and cortical bone morphology and porosity, etc. And “material properties” such as mineralization degree, crystal size, and micro damage. For example, as a macroscopic bone structure evaluation method, a method using dual-Xray-absorptiometry (eg, femoral neck length), a method using cross-sectional CT (eg, long bone), or a method using micro CT (A trabecular bone trabecular structure, fine bone). Bone material evaluation methods include quantitative backscattered electron imaging (quantative backscattered imaging qBEI), scanning electron microscope, and synchrotron radiation CT (Clinical). Calcium IV Vol.14, No.12, pages 27-32).

4). Male fracture risk or senile osteoporosis and intake of zinc in pregnant women / mammalian male fracture risk or senile osteoporosis and intake of mammalian mother's zinc By giving a sufficient amount of zinc to a mammalian mother, including humans, during pregnancy, from the time when she can conceive, and during breastfeeding, a male born from that mother or a male male offspring, The present inventors have found that the risk of fracture can be reduced, and that the risk of fracture in adulthood and senile can be significantly reduced. All conventional osteoporosis drugs are administered to osteoporosis patients or cases where there is a risk of suffering from osteoporosis. This is an epoch-making invention that reduces the risk of fractures in adult male pups after adulthood or in old age.

The present invention is a composition containing zinc as an active ingredient, and is administered to a pregnant woman or a mammal mother to reduce the risk of fracture of a male or male offspring that the pregnant woman or mammal mother gave birth. Includes effective compositions.

Furthermore, the present invention relates to a composition containing zinc as an active ingredient, which is administered to a pregnant woman or a mother of a mammal so that the pregnant woman or the mother of the mammal gives birth to a male or mammalian male adult osteoporosis And compositions effective for improving or preventing senile osteoporosis.

The above composition may be any of a pharmaceutical (for) composition, a food (for) composition, or a feed (for) composition. Mammals include humans, but also include livestock, pets, and laboratory animals.

By the way, in the examples described later, the effect of taking zinc during pregnancy and breastfeeding from the time when the mother can become pregnant is the effect of reducing the risk of fracture and improving the prevention of fracture in boys born from that mother. As it appeared prominently. In other words, when the mother ingested and did not ingest the zinc experimentally, the mother was born with a significant difference in the effectiveness in reducing fracture risk and preventing fracture. When zinc was ingested, it was excellent.

On the other hand, in the examples described later, the effect of taking zinc during pregnancy and breastfeeding from the time when the mother can become pregnant is effective in reducing fracture risk and preventing fracture even in girls born from the mother. There was also an improvement. In other words, when the mother took and did not take zinc experimentally, there was no significant difference in the effectiveness of reducing fracture risk and preventing fracture among girls born to the mother. However, there was also a tendency for mothers to take zinc.

In other words, the effect of taking zinc during pregnancy and breastfeeding from the time when the mother can become pregnant is not only for boys but also for girls, as it reduces the risk of fracture and improves the effectiveness of fracture prevention. It can be expected.

Needless to say once again, the sex of the baby is unknown unless the gender of the baby is clarified through ultrasonography during pregnancy, except in special cases where males and females can be born. However, any pregnant woman, as well as any pregnant woman, does not substantially impair the effectiveness of zinc administration. It is also apparent that livestock, pets, laboratory animals and the like do not substantially impair the effectiveness of zinc administration as described above.

4-1. Pharmaceutical composition In the present invention, a pharmaceutical composition containing zinc as an active ingredient, and a male or a male born from a pregnant woman or a mother of a mammal has become an adult by administering to the mother of the pregnant woman or a mammal. And a pharmaceutical composition that is effective in reducing fracture risk and improving or preventing adult osteoporosis and senile osteoporosis.

The pharmaceutical composition of the present invention may be any zinc composition including zinc-containing compounds and compositions, such as zinc sulfate, zinc chloride, inorganic zinc, zinc gluconate, chelate zinc, and picolinic acid. Zinc etc. are mentioned, Furthermore, zinc binding protein, a zinc binding peptide, etc. are mentioned.

The pharmaceutical composition of the present invention can be made into appropriate dosage forms such as powders, granules, tablets, capsules, and liquids. For formulation, adjuvants commonly used for formulation, such as excipients, binders, disintegrants, and lubricants, can be added. Examples of excipients include starch, lactose, sucrose, methylcellulose, carboxymethylcellulose, sodium alginate, calcium hydrogen phosphate, synthetic aluminum silicate, microcrystalline cellulose, polyvinylpyrrolidone (PVP), and hydroxypropyl starch (HPS). .結合 Binders include aqueous solutions of starch, microcrystalline cellulose, sodium carboxymethylcellulose, polyvinylpyrrolidone (PVP), gum arabic powder, gelatin, glucose, sucrose, or water / ethanol solutions thereof. Disintegrants include starch, carboxymethylcellulose, carboxymethylcellulose calcium, microcrystalline cellulose, hydroxypropyl starch, calcium phosphate and the like. For lubricants, carnauba wax, light anhydrous silicic acid, synthetic aluminum silicate, natural aluminum silicate, synthetic magnesium silicate, hardened oil, hardened vegetable oil derivative (Sterotex HM), sesame oil, white beeswax, titanium oxide, dry hydroxide Aluminum gel stearic acid, calcium stearate, magnesium stearate, talc, calcium hydrogen phosphate, and sodium lauryl sulfate.

The pharmaceutical composition of the present invention can take various forms of administration depending on the form of zinc, but can preferably be in the form of oral administration.

The pharmaceutical composition of the present invention contains an effective amount of zinc capable of reducing the risk of fractures during adulthood and old age, or reducing the risk of suffering from osteoporosis when a boy born from an administered mother is an adult. More specifically, it can be administered so that the intake amount is 7 to 40 mg per day in terms of zinc. Taking into account the intake of zinc by a method such as a meal, administration can be made so that the intake is 7 to 40 mg per day in terms of zinc. More specifically, it can be administered at an intake of 1 to 40 mg, preferably 4 to 30 mg, more preferably 6 to 30 mg, more preferably more than 10 mg and less than 30 mg per day in terms of zinc.

In addition, the pharmaceutical composition of the present invention can be administered during a period from the time when pregnancy is possible until pregnancy and breastfeeding. In addition, it is desirable to administer during the above-mentioned period, but administration during pregnancy is considered to be necessary at a minimum.

The pharmaceutical composition of the present invention is also referred to as a fracture risk reducing agent, an adult osteoporosis and senile osteoporosis improving agent or preventing agent.

4-2. Food composition: health food, food for specified health use, food for special use for pregnant woman or dietary supplement In the present invention, a food composition containing zinc as an active ingredient, which is administered to a pregnant woman or a mother of a mammal Thus, the present invention includes a food composition effective for reducing the risk of fracture when a male or male born from the pregnant woman or the mother of a mammal becomes an adult and for improving or preventing adult osteoporosis and senile osteoporosis.

The food composition of the present invention may be any zinc composition including zinc-containing compounds and compositions, such as zinc sulfate, zinc chloride, inorganic zinc, zinc gluconate, chelate zinc, and picolinic acid. Zinc etc. are mentioned, and also zinc binding protein, zinc binding peptide etc. are mentioned, and these zinc or a compound or composition containing zinc can be added to food in a required amount.

The food composition of the present invention can be prepared by adding a food containing a large amount of zinc, such as cheese, yeast, liver, meat, and natto, as it is or after processing it to other foods or food materials. Examples of the treatment include treatment that is easy to add to other food ingredients such as drying, pulverization, and cutting. The other foods or food materials may be any foods including processed foods, beverages, edible materials, and drinking materials.

The food composition of the present invention contains an effective amount of zinc capable of reducing the risk of fractures during adulthood and old age, or reducing the risk of suffering from osteoporosis when a boy born from an administered mother is an adult. More specifically, zinc is contained so that the intake amount is 7 to 40 mg per day in terms of zinc. In consideration of the amount of zinc intake by a method such as a meal, zinc is contained so as to be 7 to 40 mg per day in terms of zinc. More specifically, it can be contained in an amount of 1 to 40 mg, preferably 4 to 30 mg, more preferably 6 to 30 mg, more preferably more than 10 mg and less than 30 mg per day in terms of zinc.

In addition, the food composition of the present invention can be ingested during a period from the time when pregnancy is possible until pregnancy and breastfeeding. In addition, it is desirable to take it during the aforementioned period, but it is considered necessary to take it during pregnancy.

For example, the amount of zinc ingested by meals can be calculated using, for example, the 5th edition supplemented Japanese food standard ingredient table and the food composition table, or using the 5th edition Japanese food standard component table analysis manual. It is obtained by actually measuring the amount.

The food composition of the present invention can be a health food, a food for specified health use, a special use food for pregnant women, or a dietary supplement. The food composition may be solid (powder, granule, etc.), paste, liquid or suspension. For example, in the case of a drink, sweetener, acidulant, vitamin Other additives that are commonly used in the manufacture of drinks can also be added. In the case of health foods, foods for specified health use, special-purpose foods for pregnant women or dietary supplements, powders, granules, tablets, capsules It is also possible to use supplements in appropriate dosage forms such as agents and liquids.

It should be noted that the food composition of the present invention is also described as a fracture risk reducing agent, an adult osteoporosis and senile osteoporosis improving agent or preventive agent.

Furthermore, the present invention can also be used as a food additive for preparing health foods, foods for specified health use, special-purpose foods for pregnant women or dietary supplements containing zinc as an active ingredient.

[Example]

In this example, an age-related osteoporosis model SAM (Senescence-Accelerated Mouse) P6 was used. It has been reported that SAMP6 (mouse) is about 16 weeks of age and significantly decreases bone mass compared to the control SAMR1. SAMP6 (mouse) is about 20 weeks old and can sufficiently evaluate osteoporosis in the elderly. Further, in this example, a zinc level of 7 ppm was set as an intermediate zinc deficiency state in the case of rodents with zinc deficiency. In the past, a number of experiments with extremely low zinc levels such as 1 ppm have been reported as zinc-deficient conditions, but if you continue to consume such extremely low zinc levels, your intake will be significantly reduced, Daily fluctuations in food intake increase. In the experiment with intake of extremely low zinc levels, we simply observed (confirmed) the phenomenon (effect) due to a decrease in calorie intake and abnormal eating, and it was completely a test to confirm the effect of pure zinc deficiency. Is inappropriate.

SAMP6 female (8 weeks old) containing 7 ppm zinc (medium low zinc level feed, hereinafter also referred to as “low level group”) or 35 ppm feed (appropriate zinc level feed, below) (Also called “appropriate level group”). Two weeks after ingestion of these zinc diets, the female mice were mated with syngeneic male mice to become pregnant.

The female mice were fed the same feed as before mating during pregnancy. The female mice (mother mice) were fed a diet with an appropriate zinc level after giving birth, and the pups were fed a diet with an appropriate zinc level after weaning.

In this example, the following items were measured.

(1) X-ray CT imaging was performed on Lacita LCT-100A (Aloka) at 4, 8 and 12 weeks of age of the pups, and bone-related parameters were measured.

(2) The 20-week-old mouse was dissected and the left and right femurs and blood were collected.

(2-1) For the right femur, bone strength was measured by a three-point bending test method using a model hardness tester ModelCTK-252C (Muromachi Kikai Co., Ltd.).

(2-2) For the left femur, micro-CT imaging was performed using TDM1000 (Yamato Scientific Co., Ltd.), and detailed morphological parameters of cortical bone and cancellous bone in the vicinity of the growth plate were calculated using the image analysis software TRI. Analyzed by / 3D-BON (Ratok System Engineering).

(2-3) For blood, about 25-hydroxy ergocalciferol (hereinafter also referred to as “25 (OH) vitamin D ₃ ”) in serum, commercially available kit 25-Hydroxy Vitamin D EIA (Immunodiagnostic Systems Ltd) And measured.

Since it is a well-known fact that bone metabolism behaves differently depending on gender, each measurement value is statistically analyzed by student t-test for each gender, and p <0.05 is considered statistically significant. did. For statistical analysis, commercially available software StatView Ver5.0 (SAS Institute Inc.) was used.

(result)
(1) X-ray CT scan and bone-related parameter measurement results at 4, 8 and 12 weeks of age for pups (Figs. 1-4)
Cortical bone thickness by X-ray CT before dissection (Fig. 1) shows a statistically significant difference according to zinc level, specifically for males at 4 weeks of age, with low levels. There was a significant decrease in male mice in the group compared to male mice in the appropriate level group. Similarly, the cortical bone area ratio corresponding to the ratio of the cortical bone area to the total bone area (FIG. 2) was also significantly lower in the low level group male mice than in the appropriate level group male mice. . At 8 weeks of age, no significant difference was observed in the morphological parameters of the pup mice (born children).

Subsequently, at 12 weeks of age, the statistically significant difference according to the zinc level was recognized again specifically for males. Specifically, the cortical bone thickness was significantly decreased in the male mice in the low level group compared to the male mice in the appropriate level group. In addition, both the minimum cross-section secondary moment (Fig. 3) indicating bone strength against bending and the cross-section secondary polar moment (Fig. 4) indicating bone strength against torsion are low-level male pups and appropriate level groups. This was significantly lower than that of male mice. On the other hand, no statistically significant difference was observed between the two groups of female pups even when measured similarly at 4, 8, and 12 weeks of age.

As described above, pups born from low-zinc mother mice before and during pregnancy, after weaning, specifically, suppression of bone growth is observed for males, but in the middle After that, the cortical bone thickness decreased again and the bone strength decreased again after the adult period. Since mother mice and pups were fed a diet with an adequate zinc level filled with zinc even after the lactation period and after weaning, this phenomenon was observed once bone had recovered due to the zinc filling. It shows that the condition worsens again after growth.

(2-1) Bone strength measurement by a 3-point bending test of the right femur at 20 weeks of age in pups (Fig. 5)
Among the strength of the right femur extracted after dissection, the maximum bending energy leading to the bending was statistically significant depending on the zinc level, specifically for males. This was significantly lower than that of male mice in the appropriate level group (FIG. 5). On the other hand, in the female pup mice, no statistically significant difference was observed between the two groups in the parameter. The maximum bending energy leading to the fracture is data showing the brittleness of the bone, suggesting that the risk of fracture was actually increased in the male mice of the low level group in which the decrease was observed. Become.

(2-2) Results of measurement of bone mineral density and morphological parameters in the vicinity of the growth plate by micro-CT imaging of the left femur at 20 weeks of age in pups (FIGS. 6 and 7)
Among the morphological parameters of the fine bone of the left femur, cancellous bone tissue volume (hereinafter also referred to as “TV”) (FIG. 6) and total bone mass of cortical bone (hereinafter also referred to as “BMC”) (FIG. 7). ), The level of male mice in the low level group was significantly lower than that of male mice in the appropriate level group. On the other hand, in female pups, no statistically significant difference was observed between the two groups in any parameter. From these facts, at the age of 20 weeks, the femurs of the low-level pups (children) decreased specifically in both cortical and sea surface bones, and cortical bones. It was thought that it became fragile by the decrease in bone mineral content.

(2-3) Measurement results of serum 25 (OH) vitamin D ₃ concentration at 20 weeks of age of pups (FIG. 8)
In the measurement of blood 25 (OH) vitamin D ₃ concentration (FIG. 8), male mice in the low level group were statistically significantly lower than male mice in the appropriate level group. On the other hand, there was no statistically significant difference between the two groups in the female pups. 25 (OH) vitamin D ₃ is a precursor of 1,25-dihydroxyergocalciferol (hereinafter also referred to as “1,25 (OH) ₂ vitamin D ₃ ”), which is called active vitamin D ₃ . 1,25 (OH) ₂ vitamin D ₃ plays an important role in bone formation by affecting transcriptional control via vitamin D responsive elements present in the nucleus of osteoblasts. From this, the reduction of 25 (OH) vitamin D ₃ in the blood in male mice of the low level group contributes to the reduction of bone formation, reflecting the analysis results obtained by micro CT images It was considered a thing.

(Discussion)
From the above, it was suggested that male offspring mice are affected by bone after growth depending on their mother's intake of zinc before and during pregnancy. Reported that the effects of pre-pregnancy and pregnancy nutrition on the long-term prognosis of the bones of the offspring suggest long-term prognostic bone weakness in a rat model with reduced protein intake during pregnancy (Lanham et al. (2008) Osteoporosis Int 19: 147-156 and 157-167). Also, epidemiologically, it has been pointed out that there is an association between low growth in fetal and infancy and increased risk of fracture in adulthood (Cooper et al. (1995) J Bone Miner Res 10: 940-947, Cooper (1997) Ann Rheum Dis 56: 17-21, Cooper et al. (2002) Calcif Tissue Int 70: 391-394, Fall et al. (1998) J Clin Endocrinol Metab 83: 135-139). However, the long-term effect of zinc before and during pregnancy on the bone after growth of the offspring (child) has not been reported so far, and this example is a novel finding.

The specific effect on male pups (male pups) in this example is a phenomenon that transcends generations, and cannot be explained only by conventional genetic effects, but DNA methylation and histone acetylation. Or other epigenetic phenomena may occur before or during pregnancy. More specifically, due to the low zinc state of the female (mother) before and during pregnancy, it is unique to male pups (male pups) as epigenetic phenomena such as active vitamin D and bone metabolism Is expected to have an impact.

Zinc is taken in unconsciously on a daily basis because there are very few foods that can be consumed in large doses, and the use of cereals, vegetables, beans, etc. that are often consumed in daily diets decreases. That itself is difficult. According to the 2005 National Health and Nutrition Survey, about 90% of pregnant women do not meet the daily intake of zinc, which includes additional amounts. In addition, about 80% of pregnant women in the world are not satisfied with zinc (Caulfield et al. (1998) Am J Clin Nutr 68 (Suppl): 499S-508S).

As a qualitative interpretation, there is no debate about extrapolating the phenomenon of zinc deficiency in laboratory animals to humans, and in terms of effects on bones in male adulthood, zinc intake during maternal pregnancy Proved to be very important.

In this example, it was confirmed that female mice can prevent osteoporosis in male offspring mice and reduce the risk of fractures by ingesting a diet with an appropriate zinc level before and during pregnancy. In this example, taking a diet with an appropriate zinc level before and during pregnancy may specifically avoid the risk of fractures in adults and older adults due to insufficient zinc intake for birth males. Was newly found.

The present invention relates to the field of pharmaceutical manufacturing for reducing or preventing osteoporosis in male male mammals, including humans, as well as food production for reducing or preventing male male fracture risk. It can be used in the field of industry or beverage manufacturing industry or the field of feed manufacturing industry.

All publications, patents and patent applications cited in this specification shall be incorporated into the present specification as they are.

Claims (10)

1. ● A pharmaceutical composition containing zinc as an active ingredient and effective in reducing fracture risk and / or prevention of fracture.
2. The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition is administered to the male mother during pregnancy and breastfeeding from the time when the male can become pregnant.
3. The pharmaceutical composition according to claim 1, which is effective in reducing fracture risk and / or preventing fracture in adult and / or elderly men.
4. A pharmaceutical composition containing zinc as an active ingredient and effective for reducing the risk of male fracture and / or preventing fracture.
5. The pharmaceutical composition according to claim 4, which is administered to a mother of the male mammal.
6. The pharmaceutical composition according to claim 4, wherein the pharmaceutical composition is administered to a mother of the male mammal during pregnancy and lactation from the time when the male mammal can become pregnant.
7. 7. The pharmaceutical composition according to any one of claims 1 to 6, which contains zinc so that the intake amount is 7 to 40 mg per day in terms of zinc.
8. ¡A male fracture risk reducing agent and / or fracture prevention agent containing zinc as an active ingredient.
9. The agent according to claim 8, which is administered to the male mother before and during pregnancy.
10. The agent according to claim 8 or 9, which contains zinc so that the intake amount is 7 to 40 mg per day in terms of zinc.

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