WO2005074944A1

WO2005074944A1 - Use of sodium neridronate to promote new bone formation

Info

Publication number: WO2005074944A1
Application number: PCT/EP2005/001293
Authority: WO
Inventors: Silvano Adami; Sergio Rosini
Original assignee: Abiogen Pharma S.P.A.
Priority date: 2004-02-10
Filing date: 2005-02-09
Publication date: 2005-08-18
Also published as: ITMI20040218A1

Abstract

The use of sodium neridronate for the preparation of a medicament useful to promote new bone formation is disclosed.

Description

USE OF SODIUM NERIDRONATE TO PROMOTE NEW BONE FORMATION

This invention relates to the use of sodium neridronate to prepare a medicinal product useful to promote new bone formation, characterised in that the medicament is administered every 30 or 60 days at the dose of 25 mg, preferably every 30 days. Background of the invention The bisphosponates (BPs) are bone resorption inhibitors which have been used for a long time to prevent the bone lysis induced by metastasis in Paget's disease and, more recently, to prevent fractures in menopausal woman. The BPs used to date (alendronate and risedronate) are administered orally in daily doses or, more recently, weekly doses, to prevent fractures in patients with a densitometry T-score < 2 standard deviations. However, the results obtained, though favourable on the whole, are not entirely satisfactory because of their inconsistency. A high proportion of patients lost bone mass despite the treatment, and the fracture risk was only reduced by 30-48%. Scientific research has consequently focused on compounds with a different action mechanism (parathormone or PTH, growth factors, etc.) that stimulate new bone formation. It has been known for some time that BPs can interact with osteoclasts, inhibiting their activity and thus reducing their resorption; however, the discovery that the BPs can also influence osteoblasts, osteocytes and macrophages, in different ways depending on their chemical structures, is more recent. The effect on these cells is very important in defining the degree of activity of the BPs in the catabolic sense and in terms of reconstruction of the bone lost as a result of various pathological events. A number of specific therapeutic indications have been disclosed for bisphosphonates. WO 02/062351 discloses their use for the treatment of osteonecrosis, a pathology wherein the well-known anti-resorption activity of bisphosphonates play a role but no promotion of new bone formation is suggested or disclosed. The same considerations apply to WO 02/098307, US 5,448,041 (see for instance column 2, line 28) and WO 94/23770 as well, always relying on the classic concept of inhibition of bone resorption. WO 94/21266 discloses the use of clodronic acid (a non-aminated bisphosphonate) or salts therefore in enhancing bone tissue after or before surgery. Apart that it is known that non aminated bisphosphonates have different properties from aminated bisphosphonates such as alendronate, pamidronate, neridronate, etc., it is known that the effect on the healing of bone wounds or the higher bone deposition in implant sites is due to an inhibition of bone resorption occurring in the first days after a fracture or surgery, an effect on an higher osteoblastic activity having never being shown. WO 01/13922 discloses the use of different BPs again on bone fractures, i.e in a situation well different from osteoporosis and characterised by the release of a number of "growth factors" not occurring in osteoporosis or in other osteopoenias. This document does not provide any reference to an effect on osteoblasts,inducing a stimulus on the deposition of new bone, a condition which is particularly desired for the treatment of pathologies characterised by a low turn over of bone and where the formation of bone matrix does not compensate the negative effects of the more active osteoclasts. WO 02/080933 discloses the use of BPs in the treatment of patients requiring bone grafting. No information may be found both on the relevant effective doses and on the different properties of different BPs. Reports on the use of sodium neridronate for the treatment of osteogenesis imperfecta have been published in J.of Bone and Mineral Research 18(1), 2003, 126-130; Bone,30 (3), 2002, pages 45S-45s, XP002294155, B34; Bone, 30(3), 2002, 46S-46S, XP002294157, B35. Osteogenesis imperfecta is however quite a peculiar pathology of genetic origin and the doses used are different from that according to the invention. Finally, Braga et al, in Bone,30(3), 2002,46S-46S,XP 002294156, B38, discloses the use of sodium neridronate at a dose of 50 mg every two months in osteoporotic women without mentioning any stimulation property on osteoblasts, which stimulation may treat sever conditions where the stimulation and increase of neodeposition is more important than bone reabsorption. It has now been discovered that the use of sodium neridronate, by injection (i.v. and/or i.m.) at a specific dosage regimen induces far more marked regrowth of lost bone than other drugs in common use, despite the fact that neridronate showed lower anti-resorption efficacy in pre-clinical trials and that the global dose of neridronate in clinical use is less than that used to treat osteoporosis with alendronate (10 mg/os/day) or risedronate (5 mg/os/day) in terms of anti-resorption bioequivalence. It is now known that late treatment, when the patient has already lost a considerable amount of bone mass, with loss of connection between the bone trabeculae, vertebral collapse or extravertebral fractures, has little or no efficacy. This has led to research into products with a different action mechanism, which stimulates new bone formation rather than inhibiting the resorption of seriously impoverished bone. The BPs available for the treatment of osteoporosis have so far been used on a preventive basis or when the osteoporosis was still in the early stages, because these mainly oral treatments produced limited increases in bone mass and required very long treatment times. It has now surprisingly been discovered that sodium neridronate, when administered by the intravenous or intramuscular route once every one or two months preferably at the dose of 25 mg i.m. or i.v.once a month, generates a greater increase in bone mass than other BPs in shorter times, thus producing an earlier therapeutic effect, with the additional advantage that compliance by patients is excellent. Knowledge of the action mechanisms of BPs at cell and molecular level has improved with time, but the best therapeutic regimens, which provide the greatest efficacy with adequate patient compliance, still remain to be established. There has been a changeover from daily oral administration to weekly administration of different doses but with equivalent results; administration spread over a period of up to a year has been proposed, but the results are still doubtful. A rapid increase in bone mass is of crucial importance in the case of high-risk patients with prior fractures. Consequently, recent research has focused on drugs that produce a rapid increase in bone mass, such as PTH and sodium fluoride. However, it is known that the use of NaF does not generate the formation of well-structured bone, and that PTH requires careful use and daily subcutaneous administration for a period that cannot continue for more than 2 years, after which the bone mass may rapidly regress. Surprisingly, sodium neridronate produces very interesting results in clinical practice, with better compliance than is obtained with other products. In particular, the follow-up of patients treated with neridronate shows increases in femoral bone mass which are twice as great as those reported with alendronate and risedronate (see table), and above all a high reduction in the risk of new clinical and morphometric vertebral fractures amounting to 98%. The use of neridronate according to the invention is therefore indicated in the treatment of serious advanced osteoporosis, "advanced osteoporosis" being defined as a reduction in spinal bone density measured as a densitometry T-score equal to or exceeding 3 standard deviations.

* and ** from published meta-analysis data These results can be considered wholly unforeseeable in view of the lower level of activity exhibited by neridronate in inhibiting osteoclastic resorption, thus demonstrating that other mechanisms are important causes of the therapeutic activity. Expansion of the cross-section area of the radius has been found in these cases, which is attributable to stimulation of new periosteal bone formation (these findings have never been observed with other bisphosphonates). It is therefore considered that the clinical results obtained with sodium neridronate at the specific proposed dosage, may be due to strong stimulation of new bone forming activity, whereas the activity of other BPs appears to be due to their known effect on bone resorption, stimulation of new bone formation being limited to the uncoupling generated by inhibition of resorption alone. Neridronate therefore possesses some distinctive, special pharmacological properties. Despite its structural similarity to other BPs, especially alendronate and risedronate, many recent studies have confirmed differences in the action mechanisms of the various BPs and in their pharmacodynamic characteristics, which have been proved to vary widely, even as a result of small structural modifications. Administration of neridronate by the parenteral route (at doses of 10 to 50 mg, preferably 25 mg, approx. every 30-60 days) also produces drug concentrations in the extracellular fluids which are much higher than those obtained with orally administered bisphosphonates. Stimulation of osteoblast activity is probably achieved solely by exposing these target cells to high concentrations of active constituent. It is particularly surprising the administration of 25 mg im or iv once a month induces increases of bone mass higher than that obtainable by administering a double dose (50 mg) as disclosed in the above mentioned study. The dosage appears therefore a critical feature, allowing to differentiate between the known inhibition of bone reabsorption (occurring at high dosage) and the contemporaneous effects on osteoclasts and osteoblasts resulting in an increased bone formation. Actually, a further study carried out on postmenopausal women treated for 6 months with 12.5, 25 and 50 mg i.m. once a month (20 women per group), confirmed the unexpected activity of the administration of 25 mg every 30 days, as reported in the following Table. TABLE

The above data show once again that the dose of 25 mg induces a more marked effect which may be explained only by the combination of anti- reabsorption effects with the peculiar effect of the stimulation of new bone formation. In vitro studies have also clearly provided evidence that only in a restricted concentration ranges, neridronate induces an increase of osteoblasts proliferation and an increase of alkaline phosphatase, both indexes of an higher osteogenic activity, whereas a negative effect on the osteoblasts themselves is observed at lower or higher concentrations. Other salts compatible with parenteral administration, in any form (anhydrous, hydrate, polymorphic, etc.), can be used as an alternative to sodium neridronate. The drug may be administered once every one or two months. The formulations which can be used are conventional ones and they may be prepared also in the form of slow-release solutions or suspensions, containing 25 mg of unit base of sodium neridronate and a sterile solvent suitable for parenteral administration, together with conventional excipients such as buffering agents, pH control agents, local anaesthetics and the like. In view of its special bone formation stimulating characteristics, neridronate can also be used for local or systemic administration in the dental field, to remedy bone-mass deficiencies or to facilitate the healing of fractures or surgical wounds. In these cases, it can be used with suitable substances which allow better application.

Claims

1. Use of neridronate sodium for the preparation of a medicament useful to promote new bone formation, wherein sodium neridronate is administered every 30 or 60 days at the dose of 25 mg.

2. Use according to claim 1 wherein sodium neridronate is administered every 30 days.

3. Use as claimed in claim 1 or 2 to prepare a medicinal product useful to increase bone mass in patients with a densitometry T-score less than or equal to three standard deviations.

4. Use as claimed in claim 1-3 to prevent fractures in patients with a history of fractures, vertebral collapse or extravertebral fractures.

5. Use as claimed in any of claims 1 to 4, wherein sodium neridronate is administered by the intramuscular or intravenous route.

6. Use as claimed in claim 1-5 for the preparation of a medicament useful in the dental field.