COMPOSITION FOR IMPROVED BONE FRACTURE HEALING

Abstract

The present invention relates to a composition for use as an adjunct in orthopaedic surgery, such as in the treatment of i) delayed fracture healing in bone, manifesting as either a delayed or non-union; ii) in a fusion procedure anywhere in the skeletal system, such as cranial, spinal, foot and ankle, or upper limb; and iii) for use as a bone void filler and to enhance bone in-filling in situations of bone loss such as following combat, e.g. blast injuries, or non-combat related trauma such as road-traffic accidents.

Claims

1. A composition comprising: i) a parathyroid hormone or a derivative thereof in an amount of approximately 0.1 ng/ml to approximately 50 ng/ml; ii) one or more osteoclast inhibitors; and iii) a bone void filler in a solid or liquid phase; wherein the bone void filler is selected from calcium sulphate, or mono-, di-, and tri-calcium phosphates, calcium carbonate, an autograft bone material, an allograft, a synthetic allograft, a ceramic, a bioglass, a collagen sponge, carboxymethylcellulose or a polymethyl methacrylate (PMMA) bone cement, or a or combination of any two or more thereof; and wherein the one or more osteoclast inhibitors are present in an amount of approximately 1 ng/ml to approximately 6000 ng/ml.

2. A composition according to claim 1, wherein the one or more osteoclast inhibitors comprise a bisphosphonate or a derivative thereof; strontium ranelate, denosumab, or romosozumab; or a combination of any two or more thereof.

3. A composition according to claim 2, wherein the bisphosphonate is selected from zoledronic acid, alendronic acid, an etidronate, a pamidronate, ibandronic acid, a risedronate, and/or a clodronate, or a combination of any two or more thereof.

4. A composition according to claim 3, wherein when the bisphosphonate comprises zoledronic acid, alendronic acid or ibandronic acid, they are present in an amount of from approximately 50 ng/ml to approximately 300 ng/ml; when the bisphosphonate comprises an etidronate, it is present in an amount of from approximately 300 ng/ml to approximately 1500 ng/ml; when the bisphosphonate comprises a pamidronate, it is typically present in an amount of from approximately 0.01 nmol/ml to approximately 20 nmol/ml; when the bisphosphonate comprises a risedronate, it is typically present in an amount of from approximately 0.01 ng/ml to approximately 50 ng/ml; and/or when the bisphosphonate comprises a clodronate, it is typically present in an amount of from approximately 500 ng/ml to approximately 3000 ng/ml.

5. A composition according to claim 1, wherein the bisphosphonate comprises, or is, zoledronic acid.

6. A composition according to claim 1, wherein the derivative of the parathyroid hormone is selected from parathyroid hormone-related protein (PTHrP), 1-34 recombinant human parathyroid hormone (1-34 rhPTH), 1-84 recombinant human parathyroid hormone (1-84 rhPTH), H05AA03 parathyroid hormone, preotact parathyroid hormone, teriparatide, abaloparatide, or combinations of any two or more thereof.

7. A composition according to claim 1, further comprising one or more additives selected from vitamin D and its derivatives or isomers thereof, hydroxyapatite and derivatives or isomers thereof, vitamin E and derivatives or isomers thereof, selenium, zinc, magnesium, phosphate, or collagen and derivatives or isomers thereof.

8. A composition according to claim 1, further comprising stem cells.

9. A composition according to claim 8, wherein the stem cells are mesenchymal stem cells.

10. A composition according to claim 1, wherein the composition is in a solid form.

11. A composition according to claim 1, wherein the composition is in a liquid form.

12. A method of manufacturing a composition according to claim 1, the method comprising combining (i) the parathyroid hormone or derivative thereof; (ii) the one or more osteoclast inhibitors; and (iii) the bone void filler.

13. A composition according to claim 1 in the treatment of bone fractures, or in a bone fusion procedure.

14. A method of delivering a composition according to claim 1 into a human or animal body.

15. A method according to claim 14, wherein the composition is delivered via injection or in the form of solid pellets.

16. A kit of parts for the manufacture of a composition according to claim 1, the kit of parts comprising: i) a parathyroid hormone or a derivative thereof; ii) one or more osteoclast inhibitors; and iii) a bone void filler selected from calcium sulphate, or mono-, di-, and tri-calcium phosphates, calcium carbonate, an autograft bone material, an allograft, a synthetic allograft, a ceramic, a bioglass, a collagen sponge, carboxymethylcellulose or a polymethyl methacrylate (PMMA) bone cement, or a or combination of any two or more thereof.

Description

[0058] The present invention will also be further explained with reference to the following figures:

[0059] FIGS. 1 and 2 refer to an ovine tibial critical segmental defect model of non-union that was used to demonstrate efficacy of the invention in three doses within the therapeutic range of PTH 0.1 ng/ml to approximately 50 ng/ml, and an amount of osteoclast inhibitor that is within the therapeutic range of 1 ng/ml to approximately 6000 ng/ml. This is an established large-animal model of non-union (Reichert et al, TISSUE ENGINEERING: Part B Volume 00, Number 00, 2009).

[0060] Across Doses 1-3, a range of different concentrations of the components have been used. These doses correspond to each other in the ratio of 1:2:5 and have been used to demonstrate the composition according to the invention, containing an amount of parathyroid hormone that is within the therapeutic range of 0.1 ng/ml to 50 ng/ml, and an amount of osteoclast inhibitor that is within the therapeutic range of 1 ng/ml to approximately 6000 ng/ml. In this study, the bisphosphonate selected in the composition was zoledronic acid combined with 1-34 teriparatide. The control used was plain calcium sulphate pellets.

[0061] FIG. 1 shows the immediate post-operation radiographs and the 6-week radiographs taken of an ovine tibia with treatment using a control and a composition according to the invention with an amount of parathyroid hormone within the therapeutic range of 0.1 ng/ml to approximately 50 ng/ml, and an amount of osteoclast inhibitor that is within the therapeutic range of 1 ng/ml to approximately 6000 ng/ml (Dose 1).

[0062] FIG. 2 shows the immediate post-operation radiographs and the 6-week radiographs taken of an ovine tibia with treatment using two different compositions according to the invention with an amount of parathyroid hormone within the therapeutic range of 0.1 ng/ml to approximately 50 ng/ml, and an amount of osteoclast inhibitor that is within the therapeutic range of 1 ng/ml to approximately 6000 ng/ml (Doses 2 and 3).

[0063] FIG. 3 shows a graph depicting the optimal concentrations of zoledronate required in respect of bone resorption.

[0064] FIG. 4 shows a graph depicting the optimal concentrations of zoledronate required in respect of osteoclast number.

[0065] FIG. 5 shows graphs depicting the elution/release profile of a composition according to the invention in terms of the amount of the zoledronic acid and rhPTH(1-34) polypeptide released over time.

[0066] FIGS. 6-8 show axial CT scans of an ovine tibia using a control and three different compositions according to the invention, taken at 3, 6 and 12 weeks after treatment was commenced.

[0067] In FIG. 1, a control containing only calcium sulphate was used to treat an ovine model of non-union. In the immediate post-operation radiograph, the presence of the pellets of the composition of the invention can be seen in the bone defect.

[0068] However, in the radiograph taken 6 weeks after the operation, the partially resorbed pellets can still be seen and there is little callus present. Callus is the bulge of new immature bone formation seen in X-rays and is a crucial stage in bone healing. The lack of callus formation indicates repair of the bone defect has not occurred and that the subsequent recovery of the patient will be delayed.

[0069] On the right-hand side of FIG. 1 is the same situation, but this time using a composition according to the invention (Dose 1). Dose 1 corresponds to a composition according to the invention, containing an amount of parathyroid hormone that is within the therapeutic range of 0.1 ng/ml to 50 ng/ml, and an amount of osteoclast inhibitor that is within the therapeutic range of 1 ng/ml to approximately 6000 ng/ml. Again, in the immediate post-operation radiograph, the presence of the pellets of the composition of the invention can be seen in the bone defect.

[0070] However, in the radiograph taken 6 weeks after the operation, a bridging callus can clearly be seen across the bone defect. This shows that the bone defect, e.g. the critical segmental defect, is being filled with new bone, and at a significantly faster rate than the calcium sulphate control.

[0071] In FIG. 2, the same is demonstrated. Both of the examples in FIG. 2 employed compositions according to the invention (Doses 2 and 3). Across Doses 1-3, a range of different concentrations of the PTH have been used, and these doses correspond to each other in the ratio of 1:2:5. Doses 2 and 3 corresponded to each other in a ratio of 2:5 in terms of composition according to the invention, containing an amount of parathyroid hormone that is within the therapeutic range of 0.1 ng/ml to 50 ng/ml, and an amount of osteoclast inhibitor that is within the therapeutic range of 1 ng/ml to approximately 6000 ng/ml. Again, in the immediate post-operation radiograph, the presence of the pellets of the composition of the invention can be seen in these bone defects.

[0072] However, in the radiographs taken 6 weeks after the operation, large bridging calluses can clearly be seen across the bone defect. As with Dose 1 In FIG. 1, this shows that the critical segmental defect is being filled with new bone, and at a significantly faster rate than the calcium sulphate control.

[0073] These X-rays therefore demonstrate a significantly superior bone callus formation at 6 weeks with the compositions according to the invention, compared with a control containing only calcium sulphate. The presence of the callus in the doses employing compositions according to the invention is critical in the recovery of a patient to a non-union bone fracture.

[0074] The graphs in FIGS. 3 and 4 depict the optimal concentrations of zoledronate (derived from zoledronic acid as the bisphosphonate) required to suppress bone resorption by means of a proportionate decrease in osteoclast number.

[0075] FIGS. 3 and 4 demonstrate optimal efficacy of zoledronic acid at a concentration of approximately 10.sup.−6M of zoledronic acid, at which concentration it can be seen that the amount of osteoclast activity (as measured by bone resorption) decreases significantly in correlation with decreasing osteoclast number, when compared to lower concentrations of zoledronic acid.

[0076] The elution profiles illustrated in FIG. 5 demonstrate the composition according to the invention is able to achieve a controlled release over a period of time, to facilitate the bone repair process. 20000 minutes equates to 47.6 days, or just under 7 weeks.

[0077] In FIGS. 6-8, the respective CT scans of an ovine tibia using a control and three different compositions according to the invention, taken at 3, 6 and 12 weeks after treatment was commenced, are shown. Again, the compositions according to the invention contain a range of different concentrations of the PTH, corresponding to each other in the ratio of 1:2:5, while the control contains calcium sulphate only.

[0078] In FIG. 6, the axial CT scan demonstrates pellets in situ with early callus formation at 3 weeks, versus the control. The amount of callus formed is incremental with increasing dose, from Dose 1 to Dose 3.

[0079] In FIG. 7, the axial CT scan demonstrates abundant callus formation at 6 weeks of treatment, versus the control. The amount of callus formed is incremental with increasing dose, from Dose 1 to Dose 3.

[0080] In FIG. 8, the axial CT scan demonstrates greater bone volume at 12 weeks of treatment, versus the control. The amount of new bone formation is incremental with increasing dose, from Dose 1 to Dose 3.

[0081] This study indicates that PTH has a positive effect on fracture healing, and qualitative assessment indicated that bone formation was greater in the animals treated with PTH compared with the control. This was particularly true at the early time points. Longitudinal assessment using CTs and radiographs is important because 12-week evaluation disguises the positive effects that PTH may have on early fracture healing. In all the three animals treated with PTH there is evidence of bone bridging the osteotomy gap earlier than with the controls. This is important because early fracture healing may lead to reduced non-unions or reduced delayed fracture union. A comprehensive study of the use of calcium sulphate-based bone substitutes in revision lower limb arthroplasty reported an average reabsorption period of 6 to 8 weeks (Kallala et al; Bone Joint Res, 2018; 7:570-579; McPherson et al; Dissolvable Antibiotic Beads in Treatment of Periprosthetic Joint Infection and Revision Arthroplasty—The Use of Synthetic Pure Calcium Sulfate (Stimulan®) Impregnated with Vancomycin & Tobramycin. Reconstr Rev 2013; 3:32-43).

[0082] The present invention has therefore demonstrated that the composition according to the invention, containing an amount of parathyroid hormone that is within the therapeutic range of 0.1 ng/ml to 50 ng/ml, and an amount of osteoclast inhibitor that is within the therapeutic range of 1 ng/ml to approximately 6000 ng/ml, is also able to achieve this, while simultaneously also demonstrating superior bone callus formation at 6 weeks, to facilitate bone healing. Alternative materials, such as calcium phosphate or hydroxyapatites, result in prolonged reabsorption over months, not weeks.

[0083] Therefore, it can clearly be seen that for the present invention, the PMOA of the bone void filler is enhanced by the addition of the PTH or a derivative thereof in an amount of approximately 0.1 ng/ml to approximately 50 ng/ml, and one or more osteoclast inhibitors. The PMOA is changed from solely osteoconduction with the bone void filler alone, also to include osteoinduction and osteogenesis with the addition of the other components.

[0084] There is a synergistic effect between the bone void filler and the PTH and one or more osteoclast inhibitors, which enhances the PMOA for the bone void filler.

[0085] It is of course to be understood that the present invention is not intended to be restricted to the foregoing examples which are described by way of example only.