JPH0399022A - Medicine of bone cacochymia and evaluation of bone metabolism state - Google Patents

Abstract

PURPOSE:To provide the subject medicine of bone cacochymia containing beta2- microglobulin as the active component and excellent in bone formation promotion. CONSTITUTION:beta2-microglobulin (beta2-MG) alone or preferably in combination with a vitamin D3 is blended as the active component. As the vitamin D3, an active form vitamin D3 such as 1alpha-hydroxyvitamin D3, 1,25- or 1,24- dihydroxyvitamin D3, 1alpha-hydroxy- or 1,2-dihydroxy-26,27-hexafluorovitamin D3 is preferable and by using the compound in combination therewith, bone formation promotion of beta2-MG is improved. The concentration of beta2-MG in the body fluid collected from a subject is measured to evaluate the bone metabolism state of the subject in comparison with the concentration of beta2-MG in the body fluid collected from a normal person or past measured values of the subject as the standard.

Description

DETAILED DESCRIPTION OF THE INVENTION Industrial Field of Use The present invention relates to a bone metabolism treatment agent or bone formation promoting agent containing β2-microglobulin. Furthermore, the present invention relates to a method for evaluating the state of bone metabolism by measuring the concentration of β2-microglobulin.

Bone loss diseases include osteoporosis, renal osteodystrophy, rickets,
In addition to osteomalacia, secondary bone loss disease induced by the primary disease has also been observed to occur in patients taking steroids, anti-inflammatory drugs, diabetes, and rheumatic diseases. . Furthermore, it has been observed that post-operative bone metabolism disorder occurs even in patients who undergo gastrectomy. Maintaining bone mineral content at a normal level is necessary to maintain the strength of bone, which is a supporting tissue, and if bone mineral content decreases beyond physiological aging, it will lead to deformation of bone morphology and fracture. Since it is a risk factor, it is necessary to improve bone mineral density.

In order to improve bone mineral density, it is recommended to eat a diet with a high calcium content and take oral calcium supplements, and recently it has been shown that taking vitamin preparations, especially active vitamin preparations such as 1α-hydroxyvitamin preparations, is effective. ing.

Teijin ■ One Alpha ■ has been approved as an active vitamin preparation, and is recognized to be effective in increasing bone mineral density when taken internally in extremely small doses of 0.5 to 1 μg/day.

1α-Hydroxyvitamin cut, which is a kind of active vitamin cut, is a natural vitamin cut that has been hydroxylated at the 1α position in advance, and in the living body, it is converted to the final active form l,25-dihydride by hydroxylation at the 25th position in the liver. The vitamin is removed from the mouth and continues to be distributed throughout the body through the bloodstream.

1,25-dihydroxyvitamin binds to receptors with the small intestine, kidneys, parathyroid glands, and bones as the main target organs, promoting Ca absorption in the small intestine, promoting Ca reabsorption in the kidney, and suppressing secretion of parathyroid hormone in the parathyroid glands. function, serum Ca
resulting in an increase in

In bones, it also promotes bone turnover, from bone resorption to bone formation.

Problems to be Solved by the Invention> As a result of research aimed at developing a novel therapeutic agent for bone metabolic diseases, the present inventors found that β2-microglobulin (
It has been discovered that β2MG (hereinafter referred to as β2MG) has an excellent bone shape promoting effect, and in particular, this bone shape promoting effect is enhanced by synergistic action with other therapeutic agents for bone metabolic diseases such as vitamins, and the present invention has been reached.

Means for Solving the Problems> In general, bones are supporting tissues that support the skeleton of the limbs, and also act as a storehouse of calcium in the body.

Bone undergoes bone turnover, from the resorption of old bone by osteoclasts to the formation of new bone by osteoblasts.During skeletal growth, bone length is controlled by modeling, and skeletal structure is controlled. In the long term, the skeleton is maintained through remodeling.

During normal remodeling, a balance is maintained between resorbed bone mass and formal bone mass, and bone mineral content is maintained, but with age, the normal level of bone mineral content gradually decreases even in healthy individuals. There is.

On the other hand, when an abnormality occurs in bone turnover, bone mineral density decreases to a point that exceeds the above-mentioned physiological aging due to a state of excessive bone resorption or a continued state of decreased bone shape. A decrease occurs.

The inventors focused on examining the synergistic effect of active vitamin depletion and β2MG, or the correlation between β2MG and the degree of bone loss, regarding the disease group senile osteoporosis, which is a typical bone disease. We conducted a study on the influence of β2MG on bone metabolism.

As a result, we found for the first time in clinical research that β2MG has the effect of promoting bone formation, and that this effect is enhanced by cutting off the active vitamin. They found that there is a positive correlation between bone mineral density, bone mineral content, and bone density.

Until now, β2MG has been measured as a marker for renal function decline, malignant tumors (multiple myeloma, lymphocytic leukemia, malignant lymphoma, etc.), immune diseases, etc.;
They discovered that MG is useful as a marker of bone metabolic status.

In cases of chronic renal failure, the concentration of β2MG in the blood is at a high level that far exceeds the normal range for healthy individuals, which may cause amyloid fibrosis, and its elimination is desired.

First, the present invention provides a therapeutic agent for bone metabolic diseases characterized by containing β2MG as an active ingredient.

Furthermore, the present invention provides a therapeutic agent for bone metabolic diseases characterized by containing vitamin D3 as an active ingredient along with β2MG.

The present invention includes therapeutic agents for bone metabolic diseases using active vitamin D3s as vitamin D3s. Furthermore, in this invention, as active vitamin D3, 1α-
Included are therapeutic agents for bone metabolic diseases using hydroxyvitamin and/or 125-dihydroxyvitamin. Other vitamin D3s include 1,24-dihydroxyvitamin D3, 1α-hydroxy-26. 27-hexafluorovitamin D3, 125-dihydroxy-26
．． Also included are 27-hexafluorovitamin D3 and the like.

Furthermore, the present invention provides a therapeutic agent for bone metabolic diseases characterized by containing a calcium agent as an effective ingredient together with β2MG.

In addition, the present invention also provides for β2MG in body fluids collected from subjects.
The present invention provides a method for evaluating the bone metabolic state of a subject by measuring the concentration.

Furthermore, the present invention provides methods for evaluating bone metabolic status using various methods as described below.

That is, a method in which the bone metabolic state of a subject is evaluated based on the β2MG concentration in body fluids collected in advance from a healthy person, or a method in which the bone metabolic state of a subject is evaluated based on past measurements of the subject. This method is based on the value.

As the subject in the above, the present invention is useful in patients who have been confirmed to have a metabolic bone disease, and is particularly useful in patients undergoing treatment for a metabolic bone disease.

The β2MG in the present invention may be isolated from a living body, or may be synthesized by artificial means including methods such as genetic manipulation. In addition, if it is isolated from a living body, such as blood products,
It may be in a state where it coexists with components such as other proteins. Specific examples of substances isolated from living bodies include those isolated from serum, urine, etc.

β2MG is generally a low-molecular protein with a molecular weight of about 11,600 to 11,800, and is expressed on the crotches of nucleated cells as the L chain of class II antigen of the major histocompatibility complex (MHC).

Moreover, the vitamin D3s in the present invention may consist of only one type, or may be used in combination of two or more types depending on the case.

Among these vitamin D3 types, more preferable are:
Active vitamin D3 types are mentioned, and among them, 1α-hydroxyvitamin D3, 1,
25-dihydroxyvitamin D3, 1,24-dihydroxyvitamin and 1α-hydroxy-26. 27 hexafluorovitamin D3, 1,25-dihydroxy-2
6. Examples include 27-hexafluorovitamin.

As the calcium agent in the present invention, any calcium agent that is commonly used as a therapeutic agent for bone metabolic diseases may be used.

Further, β2MG to be contained in the therapeutic agent for bone metabolic diseases of the present invention
It is desirable to select the concentration as appropriate within the range that provides a therapeutic effect, depending on the form of administration such as an injection.

In addition, the method for evaluating bone metabolic status of the present invention uses body fluids collected from subjects such as patients with bone metabolic diseases as test subjects, and calculates the β2MG concentration in the body fluids through intensive analysis operations at an analysis center. It is characterized by measuring and evaluating the bone metabolic state of the subject from the measurement results. Specific examples of body fluids collected from such subjects include blood, serum, urine, ascites, and the like. For practical purposes, serum etc. are preferred.

Preferred specific examples of methods for evaluating bone metabolic status include:
One example is a method that uses the β2MG concentration measured in advance in a body fluid collected from a healthy person as a standard. In this case, β2 in body fluids from healthy subjects obtained in advance
It is desirable to use the MG concentration as a standard. More specifically, there is a method of evaluating the bone metabolic state of a subject using the difference itself between the β2MG concentration of a healthy person and the β2MG concentration of a subject, or an index using the difference.

Another preferred method for evaluating the bone metabolic state is to use the measured value of β2MG concentration in body fluids in the past regarding the same subject as a standard, so that the β2MG concentration in the body fluids collected from the current subject is One example is a method of evaluating the current state of bone metabolism of a subject based on the measured value of concentration. For example, a method that uses the average value of past β2MG measurements in body fluids of the same subject as a standard, or
Examples include a method that uses a curve that captures the temporal change in the measured value as a periodic fluctuation as a reference.

If the evaluation method of the present invention is used, therapeutic drugs can be used to activate and suppress bone resorption, adjust bone shape, and treat the bone remodeling cycle obtained in this way. ADFR (Activa
tion, Depress, Free, R
epeat) therapy can be performed more easily and reliably.

Note that the bone metabolic state in the bone metabolic state evaluation method of the present invention is not particularly limited as long as it contributes to the treatment of bone metabolic disease. It is desirable to use an index to express the state of bone metabolism, and a specific example of this index is, for example, the so-called MD method (MD method) obtained using a microdensitometer or the like on an X-ray film image of bone. For example, “Bone Metabolism” Vol. 14, No. 2, pp. 91-104 (
(1981), etc.) MCI (metacarpal index) is an index that expresses the ratio of the bone cortex to the bone width, and is high in healthy subjects and middle-aged people, and low in osteopenic patients and elderly people. . Examples include those using the index as an indicator.

Examples> Examples will be described below, but the present invention is not limited to these in any way.

Example 1 Nine cases of senile osteoporosis (age 75 to 87 years, 1 male, 8 female) hospitalized for femoral fracture, spinal deformity, etc., serum β2MG before treatment and right second middle Bone mineral content and bone density were measured using the MD method of X-ray images of hand bones.Among the indicators that represent bone mineral content and bone density using MD/MS methods, these are indicators that indicate age-related decline and fracture risk factors. We looked at the correlation between serum β2MG concentration and MCI, which is considered important.

Serum β2MG concentration was 1.5 mg/. 11 2.5+n
g/. The distribution was within the normal range of 11, but in high cases MCI
The value is high, and in the case of low value, the MCI value is low, and the correlation coefficient is 0. 5
113, see Figure 1 to see the existence of a positive correlation at a risk rate of 15%.

This fact suggests that β2MG works to promote bone formation and that β2MG fi-degree measurement can be used to evaluate the progress of bone metabolic diseases.

? Example 2 5 parts by weight of human β2MG2 isolated from the urine of a healthy person and D
- A combination vial (hereinafter referred to as this drug vial) containing β2MG as a main component consisting of 0.5 parts by weight of mannitol and 1.12 parts by weight of aminoacetic acid was prepared.

Approximately 1,000 parts by weight of physiological saline was added to the main vial using a syringe, and after rotational shaking to prevent foaming, the solution was left to stand to dissolve, thus preparing the β2MG formulation solution.

Effects of the Invention> According to the therapeutic agent for bone metabolic diseases of the present invention, an excellent bone formation promoting effect can be obtained, and in particular, when β2MG is used in combination with vitamin D3, etc., an enhancing effect due to synergistic action can be obtained.

Furthermore, according to the method for evaluating the bone metabolic state of the present invention, the bone metabolic state of the subject can be determined very easily by measuring the β2MG concentration in body fluids that can be easily collected from the subject. can get.

[Brief explanation of drawings]

FIG. 1 shows the relationship between β2MG in the serum of patients with senile osteoporosis and the bone index MCI of subjects. Plasmid ΦB; zMG Nogi (mg/lノ

Claims (9)

[Claims] (1) A therapeutic agent for bone metabolic disease characterized by containing β_2-microglobulin as an active ingredient. (2) Vitamin D_3 along with β_2-microglobulin
1. A therapeutic agent for bone metabolic diseases, characterized in that it contains a compound of the same type as an active ingredient. (3) The therapeutic agent for bone metabolic disease according to claim 2, wherein the vitamin D_3 is an active vitamin D_3. (4) The active vitamin D_3 types include 1α-hydroxyvitamin D_3, 1,25-dihydroxyvitamin D_
3,1,24-dihydroxyvitamin D_3, 1α-hydroxy-26,27-hexafluorovitamin D_3
The therapeutic agent for bone metabolic disease according to claim 3, which is at least one selected from 1,25-dihydroxy-26,27-hexafluorovitamin D_3. (5) A therapeutic agent for bone metabolic disease characterized by containing a calcium agent as an active ingredient along with β_2-microglobulin. (6) A method for evaluating bone metabolic status, which comprises evaluating the bone metabolic status of a subject by measuring the concentration of β_2-microglobulin in a body fluid collected from the subject. (7) Claim 6, wherein the evaluation of the bone metabolic state of the subject is performed based on the β_2-microglobulin concentration in a body fluid collected and measured in advance from a healthy person.
A method for evaluating bone metabolic status. (8) The method for evaluating the bone metabolic state of claim 6, wherein the evaluation of the bone metabolic state of the subject is performed based on past measured values of the β_2-microglobulin concentration for the subject. . (9) The method for evaluating a bone metabolic state according to any one of claims 6 to 8, wherein the subject is a patient with a bone metabolic disease.