Combination treatment with strontium for the prophylaxis and/or treatment of cartilage and/or bone conditions

Abstract

A combination treatment, wherein a strontium-containing compound together with one or more active substances capable of reducing the incidence of bone fracture and/or increasing bone density and/or improving healing of fractured bone and/or improving bone quality are administered for use in the treatment and/or prophylaxis of cartilage and/or bone conditions.

1 . A method for the treatment and/or prophylaxis of a cartilage and/or bone disease and/or conditions resulting in a dysregulation of cartilage and/or bone metabolism in a mammal the method comprising administering to a subject in need thereof a) a strontium-containing compound and b) one or more further active substances capable of reducing the incidence of bone fracture and/or increasing bone density and/or improving healing of fractured bone.  
     
     
         2 . The method according to  claim 1 , wherein a) and b) are administered in amounts that render the combination of the two effective in treating a cartilage and/or bone disease.  
     
     
         3 . The method according to  claim 1 , wherein the administration of a) and b) leads to at least one of the following: 
 i) improvement of bioavailability of a) and/or b) compared with administration of a) alone or b) alone in the same doses,    ii) improvement of pharmacokinetic parameters of a) and/or b) compared with administration of a) alone or b) alone in the same doses,    iii) reduction of frequency and/or magnitude of side-effects of a) and/or b) compared with administration of a) alone or b) alone in the same doses,    iv) obtaining an additive or synergistic effect of a) and b) compared with administration of a) alone or b) alone in the same doses,    v) reduction of the recommended daily dose (RDD) of a) and/or b) compared with RDD for a) alone or b) alone in the same doses to obtain a prophylactic and/or therapeutic effect.    
     
     
         4 . The method according to  claim 3 , wherein the administration of a) and b) in combination leads to an improvement of bioavailability of a) and/or b) of 10% or more compared with administration of a) alone or b) alone in the same doses.  
     
     
         5 . The method according to  claim 3 , wherein the administration of a) and b) in combination leads to an improvement in at least one parameter selected from the group consisting of absorption rate, time to reach peak concentration (t max ), peak concentration (c max ), concentration vs. time curve, distribution volume or distribution to specific tissues, rate of metabolism, elimination rate and excretion rate.  
     
     
         6 . The method according to  claim 3 , wherein the administration of a) and b) in combination leads to a reduction of the daily dose of a) and/or b) needed to obtain a therapeutic or prophylactic effect as compared with the daily dose of a) or b) alone needed to obtain the same or almost same effect.  
     
     
         7 . The method according to  claim 6 , wherein the amount of a) and/or b) administered in combination is reduced by 10% or more.  
     
     
         8 . The method according to  claim 3 , wherein the administration of a) and b) in combination leads to a reduction in side-effects.  
     
     
         9 . The method according to  claim 1 , wherein a) and b) is administered as a single composition.  
     
     
         10 . The method according to  claim 1 , wherein a) and b) are administered as separate compositions.  
     
     
         11 . The method according to  claim 1 , wherein the administration of a) and b) takes place simultaneously or sequentially.  
     
     
         12 . The method according to  claim 1 , wherein the strontium-containing compound comprises strontium salts of an organic or an inorganic acid.  
     
     
         13 . The method according to  claim 12 , wherein the inorganic acid comprises hydrofluoric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, nitrous acid, phosphoric acid, phosphinic acid, phosphonic acid, sulfonic acid, sulfuric acid, sulfurous acid, disulfuric acid carbonic acid or boric acid.  
     
     
         14 . The method according to  claim 12 , wherein the organic acid comprises acetic acid, C 2 H 5 COOH, C 3 H 7 COOH, C 4 H 9 COOH, (COOH) 2 , CH 2 (COOH) 2 , C 2 H 4 (COOH) 2 , C 3 H 6 (COOH) 2 , C 4 H 8 (COOH) 2 , C 5 H 10 (COOH) 2 , fumaric acid, maleic acid, malonic acid, lactic acid, citric acid, tartaric acid, oxalic acid, ascorbic acid, benzoic acid, salicylic acid, phthalic acid, pyruvic acid, L-aspartic acid, D-aspartic acid, carbonic acid, formic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, glucosamine sulphate, L-threonic acid, camphoric acid, gluconic acid, L-glutamic acid, D-glutamic acid, trifluoroacetic acid or ranelic acid.  
     
     
         15 . The method according to  claim 12 , wherein the salt is in hydrate, anhydrous, solvate, polymorphous, amorphous, crystalline, microcrystalline or polymeric form.  
     
     
         16 . The method according to  claim 12 , wherein the salt is water-soluble.  
     
     
         17 . The method according to  claim 16 , wherein the salt has a water solubility of at least 1 g/l measured at a temperature of 25° C.  
     
     
         18 . The method according to  claim 12 , wherein the salt comprises strontium chloride, strontium chloride hexahydrate, strontium citrate, strontium malonate, strontium succinate, strontium fumarate, strontium ascorbate, strontium pyruvate, strontium L-glutamate, strontium D-glutamate, strontium L-aspartate, strontium D-aspartate, strontium tartrate, strontium glutarate, strontium maleate, strontium methanesulfonate, strontium benzenesulfonate, or mixtures thereof.  
     
     
         19 . The method according to  claim 12 , wherein the acid is a monoprotic or a diprotic acid.  
     
     
         20 . The method according to  claim 12 , wherein the salt comprises strontium bromide, strontium bromide hexahydrate, strontium acetate, strontium carbonate, strontium gluconate, strontium lactate, strontium ranelate, or mixtures thereof.  
     
     
         21 . The method according to  claim 1 , the method comprising administering an amount of a) strontium and an amount of b) calcium, to a subject in need thereof, wherein the weight ratio between the amount of strontium and the amount of calcium is from about 0.05 to about 4.  
     
     
         22 . The method according to  claim 21 , wherein the daily dose of strontium is at least about 0.01 g.  
     
     
         23 . The method according to  claim 21  wherein the daily dose of calcium is at least about 0.01 g.  
     
     
         24 . The method according to  claim 21 , wherein calcium is administered at least 0.5 h after the administration of the strontium component.  
     
     
         25 . The method according to  claim 21 , wherein calcium is administered at least 0.5 h before the administration of the strontium component.  
     
     
         26 . The method according to  claim 1 , wherein the method comprises administering an amount of a) strontium and an amount of b) vitamin D to a subject in need thereof.  
     
     
         27 . The method according to  claim 26 , wherein the daily dose of strontium is at least about 0.01 g.  
     
     
         28 . The method according to  claim 26 , wherein the vitamin D is vitamin D 3  and the weight ratio between the amount of strontium and the amount of vitamin D is from about 200 to about 2,000,000.  
     
     
         29 . The method according to  claim 26 , wherein the daily dose of vitamin D 3  is at least about 1 μg.  
     
     
         30 . The method according to  claim 29 , wherein the daily dose of vitamin D 3  is from about 5 μg to about 30 μg.  
     
     
         31 . The method according to  claim 26 , wherein vitamin D is vitamin D 2 , and the daily dose of vitamin D 2  is at least 1 μg.  
     
     
         32 . The method according to  claim 31 , wherein the daily dose of vitamin D 2  is from about 5 μg to about 125 μg.  
     
     
         33 . The method according to  claim 26 , wherein strontium and the vitamin D component are administered simultaneously.  
     
     
         34 . The method according to  claim 1 , the method comprising administering an amount of a) strontium and an amount of b) a parathyroid hormone or a fragment thereof or a parathyroid hormone related peptide or a fragment thereof to a subject in need thereof.  
     
     
         35 . The method according to  claim 34 , wherein the weight ratio between the amount of strontium and the amount of PTH, when calculated as recombinant human parathyroid hormone (1-34), is from about 165 to about 2,000,000.  
     
     
         36 . The method according to  claim 34 , wherein the daily dose of strontium is at least about 0.01 g.  
     
     
         37 . The method according to  claim 34 , wherein the daily dose of PTH, when calculated as recombinant human parathyroid hormone (1-35), is at least 1 μg.  
     
     
         38 . The method according to  claim 37 , wherein the daily dose of PTH, when calculated as recombinant human parathyroid hormone (1-35), is from about 10 μg to about 40 μg.  
     
     
         39 . The method according to  claim 1 , the method comprising administering an amount of a) strontium and an amount of b) bisphosphonate to a subject in need thereof.  
     
     
         40 . The method according to  claim 39 , wherein the bisphosphonate is selected from the group comprising ibandronate, zoledronate, alendronate, risedronate, ethidronate chlodronate, tiludronate and pamidronate  
     
     
         41 . The method according to  claim 39 , wherein the amount of bisphosphonate administered corresponds to 100% or less of RDD.  
     
     
         42 . The method according to  claim 1 , the method comprising administering an amount of a) strontium and an amount of b) calcitonin to a subject in need thereof.  
     
     
         43 . The method according to  claim 42 , wherein the amount of calcitonin administered corresponds to 100% or less of RDD.  
     
     
         44 . The method according to  claim 1 , the method comprising administering an amount of a) strontium and an amount of b) a selective estrogen receptor modulator to a subject in need thereof.  
     
     
         45 . The method according to  claim 44 , wherein the selective estrogen receptor modulator comprises raloxifene, arzoxifene, droloxifene, tamoxifen, 4-hydroxy-tamoxifen, 4′-iodotamoxifen, toremifene, (deaminohydroxy)-toremifene, chlomiphene, levormeloxifene, ormeloxifene, chroman derivatives, coumarin derivatives, idoxifene, nafoxidine, TAT-59, LY-353381, CP-336156, MDL-103323, EM-800, ICI-182, ICI 183,780, ICI 164,384, ICI 183,780, ICI 164,384, diethylstilbesterol, genistein, nafoxidine, nitromifene citrate, moxesterol, diphenol hydrochrysene, erythro-MEA, allenolic acid, equilin-3-sulphate, cyclophenyl, chlorotrianisene, ethamoxytriphetol, lasofoxifene, bazedoxifene, genistein, tibolone, ospemifene, tesmilifene, droloxifene, panomifene, zindoxifene, meproxifene or faslodex.  
     
     
         46 . The method according to  claim 44 , wherein the amount of the selective estrogen receptor modulator administered corresponds to 100% or less of RDD.  
     
     
         47 . A method for the prophylaxis and/or treatment of a disease or condition involving alteration in the turnover of cartilage and/or bone turnover, the method comprising administering to a subject in need thereof a strontium-containing compound together with one or more further active substances capable of reducing the incidence of bone fracture and/or increasing bone density and/or improving healing of fractured bone and/or improving bone quality.  
     
     
         48 . A method for the prophylaxis and/or treatment of a disease or condition involving alteration in the turnover of cartilage and/or bone turnover, as quantified with biochemical markers of either cartilage turnover or bone turnover, the method comprising administering to a subject in need thereof a strontium-containing compound together with one or more further active substances capable of reducing the incidence of bone fracture and/or increasing bone density and/or improving healing of fractured bone and/or improving bone quality to a subject in need thereof.  
     
     
         49 . A method for reducing the incidence of bone fracture and/or increasing bone density and/or improving healing of fractured bone and/or improving bone quality in a subject in need thereof, the method comprising 
 detecting the presence of elevated bone turnover by use of specific biochemical markers of bone turnover and/or decreased bone mineral density identified by X-ray measurement of a skeletal site in the subject; and    administering to the subject a strontium-containing compound together with one or more further active substances capable of reducing the incidence of bone fracture and/or increasing bone density and/or improving healing of fractured bone and/or improving bone quality.    
     
     
         50 - 51 . (canceled)  
     
     
         52 . A pharmaceutical composition comprising a) a strontium-containing compound and b) one or more further active substances capable of reducing the incidence of bone fracture and/or increasing bone density and/or improving healing of fractured bone and/or improving bone quality, together with one or more physiologically acceptable excipients.  
     
     
         53 . The pharmaceutical composition according to  claim 52  in the form of a tablet.  
     
     
         54 . The pharmaceutical composition according to  claim 53 , wherein the tablet is coated with a coating that enables release of at least part of the salt in the proximal part of the small intestine.  
     
     
         55 . The pharmaceutical composition according to  claim 53 , wherein the tablet has a shape that makes it easy and convenient for a patient to swallow.  
     
     
         56 . The pharmaceutical composition according to  claim 55 , wherein the tablet has a rounded or a rod-like shape without any sharp edges.  
     
     
         57 . The pharmaceutical composition according to  claim 52 , wherein the tablet is designed to be divided into two or more parts.  
     
     
         58 . The method according to  claim 1 , wherein the bone disease and/or condition comprises osteoporosis, osteoarthritis, osteopetrosis, osteopenia and Paget's disease, hypercalcemia of malignancy, periodontal disease, hyperparathyroidism, periarticular erosions in rheumatoid arthritis, osteodystrophy, myositis ossificans, Bechterew's disease, malignant hypercalcemia, osteolytic lesions produced by bone metastasis, bone pain due to bone metastasis, bone loss due to sex steroid hormone deficiency, bone abnormalities due to steroid hormone treatment, bone abnormalities caused by cancer therapeutics, osteomalacia, Bechet's disease, hyperostosis, metastatic bone disease, immobilization-induced osteopenia or osteoporosis, or glucocorticoid-induced osteopenia or osteoporosis, osteoporosis pseudoglioma syndrome, idiopathic juvenile osteoporosis, for the improvement of fracture healing after traumatic or atraumatic fracture, and for the maintenance or increase of energy level, for building up or strengthening muscle tissues or for weight gain.