WO2004004755A1

WO2004004755A1 - Treatment of osteoporosis

Info

Publication number: WO2004004755A1
Application number: PCT/SE2003/001119
Authority: WO
Inventors: Claes Ohlsson
Original assignee: Endocrine Health I Göteborg Ab
Priority date: 2002-07-09
Filing date: 2003-06-27
Publication date: 2004-01-15
Also published as: AU2003245211A1

Abstract

The present invention relates to the use of an agonist of the melanin-concentrating hormone receptor-1, in particular melanin-concentrating hormone, or a derivative thereof, or an analogue thereof at the manufacture of a pharmaceutical preparation for the treatment of osteoporosis in mammalians by providing an agonistic effect on the melanin-concentrating hormone receptor-1, as well as a method for treating or preventing osteoporosis.

Description

TITLE

TREATMENT OF OSTEOPOROSIS

DESCRIPTION

Technical field

The present invention relates to the use of an agonist stimulating the melanin- concentrating hormone receptor-1 in the manufacture of a pharmaceutical composition for the treatment of osteoporosis, as well as a method for treating osteoporosis.

Background of the invention

Osteoporosis is the loss of bone mass or bone density. As bone mass is lost, the structure of the bones becomes weak and they break more easily. Some loss of bone mass is a natural part of the aging process. For the major part of the population, at the age of 70, the bones will have lost 1/3 of their density. Osteoporosis can occur in men as well as women. In women, however, the loss of bone mass is usually greater than in men and it begins at an earlier age (around the time of menopause or sooner if the supply of the hormone estrogen is decreased).

The following factors can increase the chances of developing osteoporosis: family history of osteoporosis general ageing menopause removal of the ovaries without ongoing replacement of estrogen cancer tumour presence inflammations being Caucasian or oriental, as opposed to black immobility or infrequent exercise smoking a diet low in calcium daily alcohol consumption taking corticosteroid medications (steroids) abnormally high levels of natural steriods in the body (Cushing's syndrome)

Many people are unaware of that fact that they have osteoporosis because it causes few symptoms until a broken bone (fracture) occurs. In many cases the amount of force that caused the bone to break would not normally have caused a fracture. Common fracture sites for people with osteoporosis include: the wrist, the top of the thigh bone, and the bones in the spinal column. Gradual crumbling of the bones in the spine can also occur over time and chronic back pain and/or pain in the nerves running down the arms or legs can result.

Osteoporosis is typically diagnosed by doing bone x-rays and a more sophisticated test, called a bone scan or bone density test. In some cases, blood tests can be helpful. On occasion, a bone biopsy may be done to confirm the dignosis.

Osteoporosis is thus caused by a number of factors, such as ageing, as a side-effect of the treament of different conditions using glucocorticoids, or as post-menopausal condition. Osteoporosis is a condition that will affect about 30% of the women after menopause, and about 10 to 15 % of the men at the age above 60 to 70.

Osteoporosis is present in two different forms, either as a reesult of cortical bone mass reduction or as a result of trabecular bone mineral density reduction, whereby the latter often occurs due to influence by medication or reduced hormone levels, such as estrogen, and the former is the type occuring at ageing, i.e., a form which will affect a substantial part of the population.

Any bone can be affected, but of special concern are fractures of the hip and spine. A hip fracture almost always requires hospitalization and major surgery. It can impair a person's ability to walk unassisted and may cause prolonged or permanent disability or even death. Spinal or vertebral fractures also have serious consequences, including loss of height, severe back pain, and deformity.

Summary of the invention

It is well recognized that the hypothalamus is of central importance in the regulation of fat mass and present findings indicate that it also is of importance for the regulation of bone mass.

Thus the present invention is based on the use of an agonist of the melanin- concentrating hormone receptor-1 (MCHrl), in particular the use of melanine- concentrating hormone (MCH) or a derivative thereof or an analogue thereof in the manufacture of pharmaceuticals for the treatment of osteoporosis by being an agonist to MCHrl and stimulating the same. Two G-protein-coupled receptors have recently been identified as MCH receptors in mammals. MCHrl and MCHr2 are expressed in overlapping patterns in many regions of the brain, including the cortex, hippocampus, thalamus and hypothalamus. As MCHr2 has only been identified in humans and non-human primates, MCHrl is considered to be the key mediator of MCH action in mice and rats. This view is supported by studies showing that effects of MCH on food intake in rats could be mimicked by MCHrl- selective agonists.

Melanin-concentrating hormone (MCH) is highly expressed in the hypothalamus and an over expression of MCH results in obesity, while MCHrl^{" "} mice (mice lacking the melanin-concentrating hormone receptor-1) have reduced fat mass. In a study of obesity using MCHr^" mice it was interestingly shown, by dual X-ray absorptiometry (DXA) measurements of femur demonstrated that MCHr^" mice have osteoporosis. The decreased bone mass is caused by a reduction in the cortical bone mass, while the trabecular bone mineral density is mainly unaffected. The reduction in cortical bone mass is due to a decreased cortical thickness while neither the cortical volumetric bone mineral density nor the outer dimensions are changed. Four-month-old female MCHrl^{" "} mice have decreased cortical bone mass without having a decreased fat mass or body weight, indicating that the effect of MCHrl-signalling on bone mass is independent of its effect on fat mass and body weight. In conclusion, the MCHrl^{' "} mice have osteoporosis. This is the first evidence that MCHrl-signalling is involved in a tonic stimulation of bone mass.

It is well known that obesity protects from osteoporosis and it is speculated that bone mass and fat mass are regulated by a common mechanism (1-3). Recent studies indicate that the hypothalamus, besides its well known regulation of fat mass, is involved in the regulation of bone mass (4, 5) via leptin receptor (ob-R) and the Y2 receptor. Thus, these studies imply that osteoporosis, the most frequent bone remodelling disease, is partly at least a hypothalamic disease. The inactivation of central leptin receptor- (ob-R) as well as Y2 receptor- signalling results in increased bone mass and it is proposed that activation of either of these two receptors causes a tonic inhibition of the bone mass (4, 5). One may speculate that these two inhibitory mechanisms are not the only central regulators of bone mass and furthermore the downstream pathways for the ob-R and the Y2 receptor mediated inhibition of bone mass are unknown. Interestingly, leptin decreases MCHrl expression in the hypothalamus and ob/ob mice have a dramatic increase in MCHrl expression in arcuate nucleus (6). Thus, one may speculate that some of the central inhibitory effect of leptin on bone mass may be mediated via a downstream regulation of MCHrl expression and signalling. However, it is unknown if MCHrl signalling is involved in the regulation of bone homeostasis. MCHrl inactivated mice were developed to evaluate the physiological role of this receptor and found that these mice develop osteoporosis and are resistant to diet-induced obesity.

DESCRIPTION OF THE PRESENT INVENTION

It has now thus turned out that osteoporosis can be treated or prevented to occur by administering an agonist of the melanin-concentrating hormone receptor-1.

One first object of the invention is the use of an agonist of the melanin-concentrating hormone receptor-1, in particular melanin-concentrating hormone, or a derivative thereof, or an analogue thereof at the manufacture of a pharmaceutical preparation for the treatment of osteoporosis in mammalians by providing an agonistic effect on the melanin-concentrating hormone receptor-1.

According to one embodiment thereof, the osteoporosis is caused by menopausal reduction of estrogen.

According to a further embodiment thereof, the osteoporosis is caused by ageing.

According to a further embodiment thereof, the osteoporosis is caused by medication using glucocorticoids.

According to a further embodiment thereof, the pharmaceutical preparation comprises 0.5 to 99.5 % of the agonist, in particular melanin-concentrating hormone, or a derivative thereof, or an analogue thereof, besides commonly known inert pharmaceutical agents.

According to a further embodiment thereof, the pharmaceutical preparation is present as an injectable solution, dispersion or suspension.

According to a further embodiment thereof, the pharmaceutical preparation is present as an orally administerable preparation.

According to a further embodiment thereof, the pharmaceutical preparation is present as a preparation to be inhaled. According to a further embodiment thereof, the agonist, in particular the melanin- concentrating hormone, or a derivative thereof, or an analogue thereof, is present in such an amount that it agonizes at least 50 % of the MCHrls present in the body.

According to a further embodiment thereof, the agonist, in particular the melanin- concentrating hormone, or a derivative thereof, or an analogue thereof, is present in such an amount that it agonizes at least 75 % of the MCHrls present in the body.

According to a further embodiment thereof, the agonist is administered at least once daily.

According to a further embodiment thereof, the agonist is administered at least twice daily.

According to a further aspect of the present invention there is provided a method for treating osteoporosis or preventing the occurrence of osteoporosis by administering a therapeutically effective amount of an agonist of the melanin-concentrating hormone receptor-1, in particular melanin-concentrating hormone, or a derivative thereof, or an analogue thereof, as an agonist of the melanin-concentrating hormone receptor-1 to cause agonization (stimulation) of said receptor.

According to a further embodiment thereof, the osteoporosis is caused by menopausal reduction of estrogen.

According to a further embodiment thereof, a pharmaceutical preparation comprising 0.5 to 99.5 % of melanin-concentrating hormone, or a derivative thereof, or an analogue thereof, besides commonly known inert pharmaceutical agents is administered.

According to a further embodiment thereof, the agonistic agent is present as an injectable solution, dispersion or suspension. According to a further embodiment thereof, agonistic agent is present as an orally administerable preparation.

According to a further embodiment thereof, the agonistic agent is present as a preparation to be inhaled.

According to a further embodiment thereof, the agonist, in particular the melanin- concentrating hormone, or a derivative thereof, or an analogue thereof, is present in such an amount that it agonizes at least 50 % of the MCHrls present in the body.

As a concequence of these findings and the invention above, an osteopetrosic condition (over production of bone) can be treated or prevented by administering a therapeutically effective amount of an antagonist to said melanin-concentrating hormone receptor-1, which will be a further aspect of this invention.

Material and Methods:

Dual X-ray absorptiometry (DXA) for the determination of area! bone mineral density and fat mass

Measurements of areal Bone Mineral Density (aBMD) of excised tibia and femur were performed with the Norland pDEXA Sabre (Norland, Fort Atkinson, WI, USA) as previously described (7, 8). We have recently adapted and evaluated this pDEXA for accurate measurements of total body fat in mice (9-11).

Peripheral Quantitative Computerized Tomography (pQCT) Computerized tomography was performed with the Stratec pQCT XCT Research M (Norland; v5.4B) operating at a resolution of 70 μm as previously described (7, 8). Cortical parameters, including cortical bone mineral content (BMC), cortical volumetric BMD (cvBMD), cortical cross-sectional area, cortical thickness and periosteal circumference, were determined with mid-diaphyseal pQCT scans of excised tibiae and femur. Trabecular volumetric BMD (tvBMD) was determined with metaphyseal pQCT scans of the proximal tibiae and the distal femur and defined as the inner 45% of the total area.

Biochemical Serum Bone Markers

Serum osteocalcin levels, as a marker of bone formation, were determined by immunoradiometric assay (IRMA) and degradation products of c-terminal telopeptide of collagen-I, as a marker of bone resorption, were measured by ELISA using commercial reagent kits (Osteocalcin, Immutopics Inc, San Clemente, CA; c-telopeptide, Osteometer Bio-Tech, Herlev, Denmark).

Results

MCHrl^{" "} mice have osteoporosis Detailed skeletal analyses were performed on excised femur and tibia. The length of femur was unchanged in both male and female MCHrl^"7" mice compared with WT mice (data not shown). DXA analyses demonstrated that the total femur areal BMD (aBMD) was clearly reduced in four-month-old male MCHrl^'7' mice compared with WT mice (Fig 1 A-B). A similar effect was also seen in tibia (data not shown). The aBMD in the diaphyseal region of femur, which consists predominantly of cortical bone, was clearly decreased in both male and female mice compared with WT mice (Fig 1 A, C).

The results obtained from DXA measurements are a combination of effects on trabecular bone and cortical bone parameters. To be able to distinguish between effects on trabecular and cortical bone, the mice were analysed by pQCT. The trabecular volumetric bone mineral density (tvBMD) was measured in the metaphyseal regions of the distal femur and the proximal tibiae, using pQCT. The tvBMD in the distal metaphyseal part of femur was unchanged in both male and female MCHrl^"7" mice compared with respectively WT mice (male WT 265±12 mg/cm³, male MCHrl^"7" 242±18 mg/cm³; female WT 297+28 mg/cm³, female MCHrl^"7" 295±27 mg/cm³). Similarly, no significant effect on tvBMD was found in tibia (data not shown).

Cortical bone parameters (BMC, cortical volumetric density, cortical cross-sectional area, cortical thickness and periosteal circumference) were measured by a mid- diaphyseal pQCT scan of femur. Interestingly, the cortical BMC was clearly decreased in four-month-old MCHrl^'7' mice (Fig ID). This reduction in cortical BMC was due to a decreased cortical cross-sectional area while the cortical volumetric BMD was unchanged (Fig ID). The decreased cortical cross-sectional area was a result of a clearly reduced cortical thickness while the periosteal appositional growth was unaffected as demonstrated by unchanged periosteal circumference (Fig ID). Similar results regarding the cortical bone were also found in femur (data not shown).

Biochemical Bone Markers

Serum levels of c-telopeptide were measured as a marker of bone resorption and serum levels of osteocalcin were measured as a marker of bone formation. Serum levels of c- telopeptide were increased in MCHrl^"7' mice compared with WT mice (Fig IE). A non significant tendency of increased serum levels of osteocalcin were found in MCHrl^{" '} mice compared with WT mice (Fig IF; P=0,15).

Discussion

Here we provide the first evidence that MCHrl-signalling is involved in a tonic stimulation of the bone mass as MCHrl inactivated mice develop a low bone mass phenotype. Two important recent publications demonstrate that the hypothalamus, besides its well-known regulation of fat mass, is involved in the regulation of bone mass (4, 5). Central activation of either the ob-R or the Y2 receptor in hypothalamus results in a decreased bone mass (4, 5). Leptin is a central negative regulator of both fat mass and bone mass (3, 4). In contrast, our present data indicate that MCH via a stimulation of the MCHrl is a positive regulator of both fat mass and bone mass. Therefore, one may speculate that there are both positive (MCHrl activation) and negative (ob-R activation) hypothalamic regulators of bone mass.

Leptin decreases MCHrl expression in the hypothalamus and together with the low bone mass phenotype in MCHrl inactivated mice one may speculate that reduction of MCHrl expression in the hypothalamus is downstream of the ob-R in the inhibitory effect of leptin on bone mass (6). Thus, MCHrl regulation could be a part of the downstream pathway for the effect of leptin on bone mass. However, inactivation of central ob-R- signalling results in increased trabecular bone mass (4) while MCHrl inactivated mice, with a clear cortical bone loss, have no major effect on trabecular BMD, indicating that the mechanism of action on bone mass, at least partly, differs for these two receptors. Further studies are required to determine the downstream pathway for the effect of MCHrl-signalling on bone mass.

The low bone mass phenotype in MCHR1^"7" mice might either be due to a lack of a direct peripheral stimulatory effect on bone or to a central influence of MCHR1, similarly as described for the ob-R and the Y2 receptor, on a hypothalamic relay of importance for bone homeostasis. The MCHrl is predominantly expressed in the brain, including the hypothalamus, areas of the olfactory pathway and the nucleus of the solitary tract (6, 13-16), supporting the notion that the low bone mass phenotype in MCHrl^'7" mice is primarily caused by a central mechanism in a similar manner as described for the effect of MCH on body weight regulation (12). However, low levels of the MCHrl are detected in several peripheral tissues, including kidney, testis, white adipose tissue, skeletal muscle and tongue (6, 17). Therefore, one cannot exclude the possibility of a peripheral function of MCHrl in the regulation of bone mass. Further studies are required to determine if it is activation of central or peripheral MCHrl that are responsible for the stimulatory effect of this receptor on bone mass.

Serum levels of c-telopeptide, a marker of bone resorption, were increased in MCHrl^{" "} mice. Thus, the bone resorption was increased in the MCHrl^"7" mice compared with WT mice. These data indicate that MCHrl^"7" mice have a high bone turnover osteoporosis. Neither the length nor the periosteal circumference of femur was affected in the MCHrl^" ^7" mice, demonstrating that the effect on aBMD in femur not was caused by regulation of the outer dimensions of the bone but rather by a specific effect on the thickness of the cortical bone.

Interestingly, four-month-old female MCHrl^'7" mice have a low bone mass phenotype without having a decreased fat mass or body weight, indicating that the effect of MCHrl-signalling on bone mass is independent of its effect on fat mass and body weight. Thus, the low bone mass phenotype precedes the appearance of a lean phenotype. In terms of therapeautic implications, it will be interesting to study if it is possible to differentiate the downstream signalling in the effects of MCHrl activation on bone mass and fat mass regulation. Our data indicate that effect of MCHrl-signaling on bone homeostasis is not less important physiologically than its role in body weight control. Therefore, one may speculate that manipulation of the MCHrl pathway may be a novel therapeutic approach to prevent and/or treat osteoporosis. In conclusion, the MCHrl^"7" mice are lean and osteoporotic. This is the first evidence that MCHrl-signalling is involved in a tonic stimulation of bone mass.

The agonist stimulating the melanin-concentrating hormone receptor-1 can be admministered in any suitable form for oral, injection, or inhalation regimens. When present in injectable form it can be present as a solution, dispersion or suspension in a suitable inert liquid carrier, commonly as an aqueous carrier, with or without adjuvants. The active compound can be present in an amount of 0.5 to 99.5 % by weight, normally 2 to 50 % by weight. If present for oral administration it is commonly manufactured using different expanders, filling agents, dissolution rate increasing compounds, or sustained releasing providing substances and compositions, tabletting aiding compounds such magnesium stearate. The active compound can be present in an amount of 0.5 to 99.5 % by weight, normally 2 to 50 % by weight.

The active compound may also be present in a form suitable for inhalation, which has turned out to be an administration route which uses the active compound to a higher degree avoiding the gastro-intestinal tract, compared to oral admninistration. The active compound can be present in an amount of 0.5 to 99.5 % by weight, normally 2 to 50 % by weight.

The daily dose of active compound is 0.1 to 10 mg per kg body-weight, i.e., an intake of 7.5 to 750 mg per day for an average man. The intake can be made once, twice or more times a day depending on the condition of the patient and administration route.

LEGENDS TO FIGURE

Figure 1. Osteoporosis in MCHR1^~'^~ mice. DXA measurements of excised femur (A-

C). (A) Image of a representative DXA scan of femur from wild type (WT) and MCHrl^'7" mice. The relative areal BMD is indicated: High = high areal BMD, Low = low areal BMD. The average areal BMD of total femur (B) and the diaphyseal part of femur (C) are presented. (D) pQCT measurements of cortical bone in the diaphyseal region of femur, cvBMD=cortical volumetric BMD, Area= cross-sectional area, CT= cortical thickness,

PC= periosteal circumference. Biochemical serum bone markers (E-F). Serum levels of c-telopeptide (E) and osteocalcin (F). n=7-9, Values are given as means±SEM; * p< 0,05, ** p<0.01 MCHrl^"7" vs WT mice, Student ^'s t-test.

REFERENCES

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Claims

1. Use of an agonist of the melanin-concentrating hormone receptor-1 at the manufacture of a pharmaceutical preparation for the treatment of osteoporosis in mammalians by providing an agonistic effect on the melanin-concentrating hormone receptor-1.

2. Use according to claim 1, wherein melanin-concentrating hormone, or a derivative thereof, or an analogue thereof is used in said manufacture.

3. Use according to claim 1, wherein the osteoporosis is caused by menopausal reduction of estrogen.

4. Use according to claim 1, wherein the osteoporosis is caused by ageing.

5. Use according to claim 1, wherein the osteoporosis is caused by medication using glucocorticoids.

6. Use according to claims 1-5, wherein the pharmaceutical preparation comprises 0.5 to 99.5 % of an agonist of the melanin-concentrating hormone receptor-1, in particular melanin-concentrating hormone, or a derivative thereof, or an analogue thereof, besides commonly known inert pharmaceutical agents.

7. Use according to claims 1-6, wherein the pharmaceutical preparation is present as an injectable solution, dispersion or suspension.

8. Use according to claims 1-6, wherein the pharmaceutical preparation is present as an orally administerable preparation.

9. Use according to claims 1-6, wherein the pharmaceutical preparation is present as a preparation to be inhaled.

10. Use according to claims 1-9, wherein the agonist of the melanin-concentrating hormone receptor-1, in particular the melanin-concentrating hormone, or a derivative thereof, or an analogue thereof, is present in such an amount that it agonizes at least 50 % of the MCHrls present in the body.

11. Use according to claims 1-8, wherein the agonist of the melanin-concentrating hormone receptor-1, in particular the melanin-concentrating hormone, or a derivative thereof, or an analogue thereof, is present in such an amount that it agonizes at least 75 % of the MCHrls present in the body.

12. Use according to claims 1-10, wherein the agonist is administered at least once daily.

13. Use according to claims 1-10, wherein the agonist is administered at least twice daily.

14. Method for treating osteoporosis or preventing the occurrence of osteoporosis by administering a therapeutically effective amount of an agonist of the melanin- concentrating hormone receptor-1, as an agonist of the melanin-concentrating hormone receptor-1 to cause agonization of said receptor.

15. Method according to claim 14, wherein the agonist is melanin-concentrating hormone, or a derivative thereof, or an analogue thereof

16. Method according to claims 14-15, wherein the osteoporosis is caused by menopausal reduction of estrogen.

17. Method according to claims 14-15, wherein the osteoporosis is caused by ageing.

18. Method according to claims 14-15, wherein the osteoporosis is caused by medication using glucocorticoids.

19. Method according to claims 14-18, wherein a pharmaceutical preparation comprising 0.5 to 99.5 % of the agonist of the melanin-concentrating hormone receptor-1, in particular melanin-concentrating hormone, or a derivative thereof, or an analogue thereof, besides commonly known inert pharmaceutical agents is administered.

20. Method according to claims 14-19, wherein the agonistic agent is present as an injectable solution, dispersion or suspension.

21. Method according to claims 14-19, wherein the agonistic agent is present as an orally administerable preparation.

22. Method according to claims 14-19, wherein the agonistic agent is present as a preparation to be inhaled.

23. Method according to claims 14-22, wherein the agonist of the melanin- concentrating hormone receptor-1, in particular the melanin-concentrating hormone, or a derivative thereof, or an analogue thereof, is present in such an amount that it agonizes at least 50 % of the MCHrls present in the body.

24. Method according to claims 14-23, wherein the agonist of the melanin- concentrating hormone receptor-1, in particular the melanin-concentrating hormone, or a derivative thereof, or an analogue thereof, is present in such an amount that it agonizes at least 75 % of the MCHrls present in the body.

25. Method according to claims 14-24, wherein the agonist is administered at least once daily.

26. Method according to claims 14-24, wherein the agonist is administered at least twice daily.

27. Method for treating an osteopetrosic condition (over production of bone) by administering a therapeutically effective amount of an antagonist to the melanin- concentrating hormone receptor-1, to block said receptor.