US 201701 19801A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2017/0119801 A1 Tabuteau (43) Pub. Date: May 4, 2017

(54) COMPOSITIONS FOR ORAL filed on May 15, 2012, provisional application No. ADMINISTRATION OF 61/654,292, filed on Jun. 1, 2012, provisional appli OR RELATED COMPOUNDS FOR cation No. 61/654,383, filed on Jun. 1, 2012, provi TREATING COMPLEX REGIONAL PAIN sional application No. 61/655,527, filed on Jun. 5, SYNDROME 2012, provisional application No. 61/655,541, filed on Jun. 5, 2012, provisional application No. 61/764, (71) Applicant: ANTECIP BIOVENTURES II LLC, 563, filed on Feb. 14, 2013, provisional application New York, NY (US) No. 61/762,225, filed on Feb. 7, 2013, provisional application No. 61/767,647, filed on Feb. 21, 2013, (72) Inventor: Herriot Tabuteau, New York, NY (US) provisional application No. 61/767,676, filed on Feb. 21, 2013, provisional application No. 61/803,721, (21) Appl. No.: 15/408,783 filed on Mar. 20, 2013. (22) Filed: Jan. 18, 2017 Publication Classification Related U.S. Application Data (51) Int. Cl. (63) Continuation-in-part of application No. 15/055.386, A63/675 (2006.01) filed on Feb. 26, 2016, which is a continuation of A6II 47/12 (2006.01) application No. 14/635,857, filed on Mar. 2, 2015, A6IR 9/00 (2006.01) now Pat. No. 9,283,239, which is a continuation of (52) U.S. Cl. application No. 14/279,232, filed on May 15, 2014, CPC ...... A61 K3I/675 (2013.01); A61K 9/0053 now Pat. No. 9,149,487, which is a continuation of (2013.01); A61K 47/12 (2013.01); A61 K application No. 14/063,979, filed on Oct. 25, 2013, 47/48038 (2013.01) now Pat. No. 8,802,658, which is a continuation-in part of application No. 13/894,274, filed on May 14, 2013, now abandoned, Continuation-in-part of appli (57) ABSTRACT cation No. 15/347,696, filed on Nov. 9, 2016, which Oral dosage forms of osteoclast inhibitors, such as nitrogen is a continuation-in-part of application No. PCT/ containing , such as Zoledronic acid in an US2015/032739, filed on May 27, 2015. acid or a salt form, or in a molecular complex can be used (60) Provisional application No. 61/646.538, filed on May to treat or alleviate pain or related conditions, such as 14, 2012, provisional application No. 61/647,478, complex regional pain syndrome. Patent Application Publication May 4, 2017. Sheet 1 of 17 US 2017/01 19801 A1

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COMPOSITIONS FOR ORAL provides an area under the plasma concentration curve of ADMINISTRATION OF ZOLEDRONIC ACID Zoledronic acid of about 4 ngh/mL to about 2000 ngh/mL OR RELATED COMPOUNDS FOR to a human being to which the dosage form is administered. TREATING COMPLEX REGIONAL PAIN 0008. Some embodiments include a dosage form com SYNDROME prising Zoledronic acid in the disodium salt form, wherein the disodium salt form is present in a lower molar amount CROSS-REFERENCE TO RELATED than would be present if the Zoledronic acid were in the APPLICATIONS diacid form; and wherein the Zoledronic acid in the disodium 0001. This application is a continuation-in-part of U.S. salt form has an improved bioavailability as compared to the patent application Ser. No. 15/055.386, filed Feb. 26, 2016, Zoledronic acid in the diacid form to the extent that the lower which is a continuation of U.S. patent application Ser. No. molar amount of the disodium salt in the dosage form does 14/635,857, filed Mar. 2, 2015, now U.S. Pat. No. 9,283,239, not reduce the amount of Zoledronic acid delivered to the which is a continuation of U.S. patent application Ser. No. plasma of a mammal. 14/279,232, filed May 15, 2014, now U.S. Pat. No. 9,149, 0009. Although an oral dosage form with enhanced bio 487, which is a continuation of U.S. patent application Ser. availability with respect to the compound No. 14/063,979, filed Oct. 25, 2013, now U.S. Pat. No. can be used, the treatment can also be effective using an oral 8,802.658, which is a continuation-in-part of U.S. patent dosage form that includes a bisphosphonate compound, such application Ser. No. 13/894,274, filed May 14, 2013, now as Zoledronic acid, wherein the bioavailability of the bis abandoned, which claims the benefit of U.S. Prov. App. Nos. phosphonate is unenhanced, or is substantially unenhanced. 61/646.538, filed May 14, 2012: 61/647,478, filed May 15, 0010 Some embodiments include a method of relieving 2012: 61/654,292, filed Jun. 1, 2012: 61/654,383, filed Jun. inflammatory pain comprising administering an oral dosage 1, 2012: 61/655,527, filed Jun. 5, 2012: 61/655,541, filed form containing Zoledronic acid to a mammal in need Jun. 5, 2012: 61/764,563, filed Feb. 14, 2013: 61/762,225, thereof, wherein the mammal experiences significant pain filed Feb. 7, 2013: 61/767,647, filed Feb. 21, 2013: 61/767, relief more than 3 hours after administration of the dosage 676, filed Feb. 21, 2013; and 61/803,721, filed Mar. 20, form. 2013; this application is also a continuation-in-part of U.S. 0011. Some embodiments include a method of relieving patent application Ser. No. 15/347,696, filed Nov. 9, 2016, pain associated with an arthritis comprising administering an which is a continuation-in-part of International Pat. App. oral dosage form containing Zoledronic acid to a human No. PCT/US2015/032739, filed May 27, 2015; any of the being in need thereof. applications, U.S. patents issued from, or U.S. publications 0012 Some embodiments include a method of treating of any of the above applications are incorporated by refer complex regional pain syndrome comprising administering ences in their entirety. an oral dosage form containing Zoledronic acid to a mammal in need thereof. SUMMARY 0013 Some embodiments include an oral dosage form comprising Zoledronic acid, wherein the oral bioavailability 0002 Bisphosphonate compounds are potent inhibitors of Zoledronic acid is Substantially unenhanced. For example, of osteoclast activity, and are used clinically to treat bone in some embodiments, the oral bioavailability in the dosage related conditions such as osteoporosis and Paget’s disease form is about 0.01% to about 4%. of bone; and cancer-related conditions including multiple 0014 Some embodiments include a pharmaceutical prod myeloma, and bone metastases from Solid tumors. They uct comprising more than one unit of an oral dosage form generally have low oral bioavailability. described herein. In some embodiments, each unit of the oral 0003 Patchy osteoporosis and bone marrow edema may dosage form contains about 1 mg to about 50 mg of result from osteoclast hyperactivity. Zoledronic acid is a Zoledronic acid. potent inhibitor of bone resorption and osteoclast activity. 0015. Some embodiments include a method of relieving Nitrogen containing bisphosphonates, such as Zoledronic inflammatory pain comprising administering an oral dosage acid, also inhibit the mevalonate pathway in the osteoclast form containing Zoledronic acid to a mammal in need thereby interrupting normal osteoclast function. thereof. 0004. It has been discovered that oral dosage forms of 0016. In some embodiments, the mammal receives a total bisphosphonate compounds. Such as Zoledronic acid, can be monthly dose of Zoledronic acid that is about 800 mg/m or used to treat or alleviate pain or related conditions. less. 0005. Some embodiments include a method of enhancing 0017. In some embodiments, the dosage form contains the oral bioavailability of Zoledronic acid comprising orally about 10 mg/m to about 20 mg/m based upon the body administering a dosage form containing Zoledronic acid in Surface area of the mammal. the disodium salt form. 0018. Some embodiments include a method of relieving 0006. Some embodiments include a dosage form com inflammatory pain comprising orally administering Zole prising Zoledronic acid in the disodium salt form, wherein dronic acid to a mammal in need thereof. the bioavailability, in a mammal, of Zoledronic acid in the (0019. In some embodiments, about 300 mg/m to about disodium salt form is greater than the bioavailability of 600 mg/m of Zoledronic acid is administered per month, Zoledronic acid in the diacid form would be in the same based upon the body Surface area of the mammal. dosage form. I0020. In some embodiments, about 50 mg/m to about 0007 Some embodiments include a dosage form com 600 mg/m of Zoledronic acid is administered per month, prising Zoledronic acid in an acid or a salt form, Such as the based upon the body Surface area of the mammal. disodium salt form, wherein the dosage form contains an 0021. Some embodiments include administering an amount of Zoledronic acid in the disodium salt form that osteoclast inhibitor, such as a bisphosphonate, including US 2017/01 19801 A1 May 4, 2017

Zoledronic acid, , etc. to inhibit the develop treatment in patients with osteoarthritis of the knee, bone ment of pain, unweighting, and edema when administered marrow lesions, and different degrees of joint space narrow early such as when a precipitating event such as fracture ing. occurs, wherein the precipitating event is associated with CRPS. 0037 FIG. 14 depicts hindpaw pain thresholds for 0022. Some embodiments include administering an vehicle and Zoledronic acid treated rats in a rat model of osteoclast inhibitor, such as a bisphosphonate, including complex regional pain syndrome. Zoledronic acid, neridronic acid, etc. to reverse established 0038 FIG. 15 depicts weight bearing for vehicle and allodynia and unweighting when administered at least 4 Zoledronic acid treated rats in a rat model of complex weeks after a precipitating event Such as fracture that is regional pain syndrome. associated with CRPS. 0039 FIG. 16 depicts hindpaw pain thresholds for rats BRIEF DESCRIPTION OF DRAWINGS administered Zoledronic acid at the time of fracture as 0023 FIG. 1 is a plot of pain compression thresholds in compared to rats administered Zoledronic acid four weeks a rat model of inflammatory pain using three different doses after fracture. of Zoledronic acid. Measurements were taken at baseline (BL) and at various time points after dosing on the days DETAILED DESCRIPTION indicated. 0024 FIG. 2A is a graph depicting reversal of arthritis 0040. Inhibitors of osteoclast activity include bisphos pain for two different doses of Zoledronic acid in a rat model phonate compounds such as pamidronate or pamidronic of arthritis pain. acid, neridronate or neridronic acid, olpadronate or olpad 0025 FIG. 2B is a graph depicting pain thresholds for ronic acid, alendronate or , incadronate or two different doses of Zoledronic acid in a rat model of incadronic acid, ibandronate or , risedronate arthritis pain. or , cimadronate or cimadronic acid, Zoledro 0026 FIG. 3 is a graph summarizing the results for nate or Zoledronic acid, etidronate or , clodro vehicle and Zoledronic acid treated rats in a rat model of nate or , tiludronate or , etc. complex regional pain syndrome. 0041 RANK/RANKL antagonists may be inhibitors of 0027 FIG. 4 depicts hindpaw pain thresholds for vehicle osteoclast activity. RANK/RANKL antagonists include but and Zoledronic acid treated rats in a rat model of complex are not limited to OPG (osteoprotegerin) or a variant thereof, regional pain syndrome. an anti-RANKL antibody Such as , a monoclonal 0028 FIG. 5 depicts weight bearing for vehicle and anti-RANKL antibody, a small interfering RNA, a micro Zoledronic acid treated rats in a rat model of complex RNA, a precursor molecule, a ribozyme, an antisense regional pain syndrome. nucleic acid, or an aptamer targeting RANKL. Antibodies 0029 FIG. 6 depicts paw thickness change for vehicle such as AB-25E9, Small molecules, small interfering RNAs, and Zoledronic acid treated rats in a rat model of complex microRNAs, precursor molecules, ribozymes, antisense regional pain syndrome. nucleic acids, or aptamers that target the cell-surface protein 0030 FIG. 7 depicts the aqueous solubility of disodium Siglec-15 may be osteoclast inhibitors. Zoledronate tetrahydrate as compared to the diacid form of Zoledronic acid. 0042 Some Bruton's tyrosine kinase (BTK) inhibitors 0031 FIG. 8 depicts the plasma concentration of Zole may be inhibitors of osteoclast activity. BTK inhibitors can dronic acid in dogs over time after administration of 150 mg include ONO-4059; ibrutinib; Benzobthiophene-2-carbox of the disodium salt form of Zoledronic acid and the diacid amide, N-3-6-4-(2R)-1,4-dimethyl-3-oxo-2-piperazi form of Zoledronic acid. nylphenylamino-4,5-dihydro-4-methyl-5-oxo-2-pyrazi nyl-2-methylphenyl-4,5,6,7-tetrahydro-(GDC-0834); 0032 FIG.9 depicts the compressibility of dosage forms RN-486; Benzamide, 4-(1,1-dimethylethyl)-N-3-8-(phe containing Zoledronic acid in the disodium salt form as nylamino)imidazo[1,2-alpyrazin-6-yl)phenyl-(CGI-560); compared to the diacid form. Benzamide, N-3-4,5-dihydro-4-methyl-6-4-(4-morpholi 0033 FIG. 10 depicts the change in VAS pain score nylcarbonyl)phenyl amino-5-oxo-2-pyrazinyl-2-methyl compared to placebo at three months with Zoledronic acid phenyl)-4-(1,1-dimethylethyl)-(CGI-1746CAS Registry No. treatment in patients with osteoarthritis of the knee, bone 910232-84-7); HM-71224; 2-Propenamide, N-3-5-fluoro marrow lesions, and different degrees of joint space narrow 2-4-(2-methoxyethoxy) phenylamino-4-pyrimidinyl ing. aminolphenyl-(CC-292, CAS Registry No. 1202757-89-8); 0034 FIG. 11 depicts the change in VAS pain score 2-Pyridinecarboxamide, 4-4-5-fluoro-4-3-(1-oxo-2- compared to baseline at three months with Zoledronic acid propen-1-yl)aminophenylamino-2-pyrimidinylamino treatment in patients with osteoarthritis of the knee, bone phenoxy-N-methyl-(CNX-774, CAS Registry No. marrow lesions, and different degrees of joint space narrow 1202759-32-7), AVL-101 (CAS Registry No. 1552307-34 ing. 2), AVL-291 (CAS Registry No. 1552307-35-3), and AVL 0035 FIG. 12 depicts the change in VAS pain score 292 (CAS Registry No. 1552307-36-4), N-(2-chloro-6- compared to placebo at three months with Zoledronic acid methylphenyl)-2-(6-(4-(2-hydroxyethyl) piperazin-1-yl)-2- treatment in different Subgroups of patients with osteoar methylpyrimidin-4-ylamino)thiazole-5-carboxamide thritis of the knee and bone marrow lesions. (dasatinib), alpha-cyano-beta-hydroxy-beta-methyl-N-(2,5- 0036 FIG. 13 depicts the change in BML lesion size bromophenyl) propenamide (LFM-A13), and ONO-WG compared to placebo at six months with Zoledronic acid 307. US 2017/01 19801 A1 May 4, 2017

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0043. Inhibitors of osteoclast activity may be used for a may be provided independent of improvement of the disease number of medical purposes, such as treatment of undesir or condition or the underlying cause of the disease or able conditions or diseases, including pain relief. This may condition. For example, although the underlying disease be accomplished in many instances by administration of oral may not improve, or may continue to progress, an individual dosage forms. Generally, an oral dosage form comprising a Suffering from the disease may experience pain relief. In bisphosphonate such as Zoledronic acid is administered some embodiments, enhanced bioavailability of the Zole orally to a mammal. Such as a human being, at least once, to dronic acid may be achieved in treating one of these con treat a disease or condition, or to relieve pain. ditions by administering a dosage form comprising Zole 0044. The compounds containing Ion 1 or Ion 2 may also dronic acid in the form of a disodium salt. This may allow be osteoclast inhibitors: a reduced molar amount of the disodium salt to be used as compared to what would be used with the diacid form. 0047. In some embodiments, the mammal being treated is Ion 1 not suffering from bone metastasis. In some embodiments, O POH -- the mammal being treated is not suffering from cancer. In Some embodiments, the mammal being treated is not suf -- N N1 N - on fering from osteoporosis. OH 0048 For example, Zoledronic acid or another bisphos Ion 2 phonate may be administered orally to relieve musculoskel -- etal pain including low back pain, and pain associated with PO3H ?—\ PO3H rheumatoid arthritis, juvenile rheumatoid arthritis, osteoar thritis, erosive osteoarthritis, sero-negative (non-rheuma 1- NS1 N POH toid) arthropathies, non-articular rheumatism, peri-articular HO OH disorders, axial spondyloarthritis including ankylosing spondylitis, Paget’s disease, fibrous dysplasia, SAPHO syn drome, transient osteoarthritis of the hip, vertebral crush 0045. The term “treating” or “treatment” broadly fractures, osteoporosis, etc. In some embodiments, enhanced includes any kind of treatment activity, including the diag bioavailability of the Zoledronic acid may be achieved in nosis, cure, mitigation, or prevention of disease in man or treating one of these conditions by administering a dosage other animals, or any activity that otherwise affects the form comprising Zoledronic acid in the form of a disodium structure or any function of the body of man or other salt. This may allow a reduced molar amount of the diso animals. dium salt to be used as compared to what would be used with 0046. An oral dosage form of a bisphosphonate such as the diacid form. Zoledronic acid may be used to treat, or provide relief of any 0049. An osteoclast inhibitor, such as a bisphosphonate, type of pain including, but not limited to, inflammatory pain, e.g. Zoledronic acid, may also be used to treat bone fractures arthritis pain, complex regional pain syndrome, lumbosacral or to enhance the healing of bone fractures. In some embodi pain, musculoskeletal pain, neuropathic pain, chronic pain, ments, a human being that is treated for CRPS, suffered from cancer-related pain, acute pain, postoperative pain, etc. In a precipitating injury Such as a bone fracture associated with Some instances, pain relief may be palliative, or pain relief the CRPS at least 4 weeks, at least 8 weeks, at least 12 US 2017/01 19801 A1 May 4, 2017

weeks, at least six months, or at least 1 year before first inflammatory condition for at least 1 month, at least 2 administering an osteclast inhibitor, Such as a bisphospho months, at least 3 months, at least 6 months, or at least 1 nate, including Zoledronic acid, neridronic acid, etc. year. Examples of a precipitating event include a fracture, a 0056. In some embodiments, the arthritis affects a knee, cutting injury, a scratch, a puncture injury, etc. an elbow, a finger, a wrist, a shoulder, an ankle, the spine, or 0050. In some embodiments, Zoledronic acid or another a hip. bisphosphonate may also be administered orally to relieve 0057 For treatment of arthritis or joint pain, such as knee neuropathic pain, including diabetic peripheral neuropathy, pain, in some embodiments the person being treated has post-herpetic neuralgia, trigeminal neuralgia, monoradicu OARSI Grade 0, or Kellgren and Lawrence Grades 0 or 1, lopathies, phantom limb pain, and central pain. Other causes joint space narrowing. of neuropathic pain include cancer-related pain, lumbar 0058. In some embodiments, the person has lesions, such nerve root compression, spinal cord injury, post-stroke pain, as bone marrow lesions. In some embodiments the person central multiple Sclerosis pain, HIV-associated neuropathy, being treated for bone marrow lesions has normal joint space and radio-therapy or chemo-therapy associated neuropathy. knee pain, OARSI Grade 0, or Kellgren and Lawrence In some embodiments, enhanced bioavailability of the Zole Grades 0 or 1, joint space narrowing. dronic acid may be achieved in treating one of these con 0059. In some embodiments, the person has baseline pain ditions by administering a dosage form comprising Zole intensity of 5 or greater measured using the 0-10 numerical dronic acid in the form of a disodium salt. This may allow rating scale (NRS), or 50 mm or greater using the 100 mm a reduced molar amount of the disodium salt to be used as visual analog scale (VAS). In some embodiments the person compared to what would be used with the diacid form. being treated for pain has normal joint space knee pain, OARSI Grade 0, or Kellgren and Lawrence Grades 0 or 1, 0051. In some embodiments, Zoledronic acid or another joint space narrowing. bisphosphonate may be administered orally to relieve 0060 Bone marrow lesions (BMLs) include regional inflammatory pain including musculoskeletal pain, arthritis bone marrow signal intensity alterations on magnetic reso pain, and complex regional pain syndrome. In some embodi nance imaging (MRI). BMLS can be present in the knee and ments, enhanced bioavailability of the Zoledronic acid may can be an important feature of osteoarthritis of the knee. be achieved in treating one of these conditions by adminis BMLS have also been described in other rheumatic condi tering a dosage form comprising Zoledronic acid in the form tions such as rheumatoid arthritis, osteonecrosis, ankylosing of a disodium salt. This may allow a reduced molar amount spondylitis, and transient osteoporosis of the hip and are of the disodium salt to be used as compared to what would often referred to as bone marrow edema (BME). be used with the diacid form. 0061. In some embodiments, a person being treated for 0052 Examples of musculoskeletal pain include low arthritis, such as with Zoledronic acid, has osteoarthritis of back pain; and pain associated with vertebral crush fractures, the knee associated with bone marrow lesions. fibrous dysplasia, osteogenesis imperfecta, Paget’s disease 0062. In some embodiments, an inhibitor of osteoclast of bone, transient osteoporosis, and transient osteoporosis of activity can be used to treat bone marrow lesions. the hip. 0063. In some embodiments, an inhibitor of osteoclast 0053 Arthritis refers to inflammatory joint diseases that activity can be used to treat bone marrow lesions of the knee, can be associated with pain. Examples of arthritis pain shoulder, ankle, wrist, hand, fingers, spine, or hip. include pain associated with osteoarthritis, erosive osteoar 0064 Commonly used measures of pain intensity include thritis, rheumatoid arthritis, juvenile rheumatoid arthritis, the visual analog scale (VAS) and the numerical rating scale sero-negative (non-rheumatoid) arthropathies, non-articular (NRS). With the VAS approach, patients rate the severity of rheumatism, peri-articular disorders, neuropathic arthropa their pain by marking a point on a 10-cm (or 100 mm) VAS thies including Charcot's foot, axial spondyloarthritis (0-no pain and 10-worst possible pain). With the NRS including ankylosing spondylitis, and SAPHO syndrome. approach, patients rate the severity of their pain by verbally responding to a 10-point NRS (0=no pain and 10-worst 0054. In some embodiments, a human being that is possible pain). VAS and NRS scores have been shown to be treated for a disease or condition, such as an inflammatory strongly correlated (slope of regression line, 1.01), indicat condition, e.g. arthritis or CRPS, by an osteoclast inhibitor, ing that a score on the 10-cm VAS is equivalent to the same Such as a bisphosphonate, e.g. an oral dosage form of score on 10-point NRS (Bijur PE et al. Acad Emerg Med Zoledronic acid, has an age of at least 18 years, at least 50 2003: 10:390-392). For example, a VAS score of 5 cm (or 50 years (including a male of at least 50 years), a postmeno mm) is equivalent to an NRS score of 5. Knee pain in a pausal female, about 10 years to about 90 years, about 20 person with a VAS score of 5 cm or 50 mm or higher, or an years to about 80 years, about 30 years to about 75 years, NRS score of 5 or higher, may be referred to herein as about 40 years to about 70 years, about 1 year to about 16 moderate to severe knee pain. years, or about 80 years to about 95 years. In some embodi 0065. In some embodiments, the patient suffering from ments, the human being is a male at least 50 years of age or pain, inflammation, a similar condition, or any of the con a postmenopausal female, with knee osteoarthritis (OA) and ditions described herein, has an NRS of 5 or greater, or a bone marrow lessions (BMLs), having moderate or worse VAS of 5 cm or greater. In some embodiments, the patient knee pain. has an NRS of 4 or greater, or a VAS of 4 cm or greater. In 0055. In some embodiments, a human being that is some embodiments, the patient has an NRS of 6 or greater, treated for a disease or condition, such as an inflammatory or a VAS of 6 cm or greater. In some embodiments, the condition, e.g. arthritis, low back pain, or CRPS, by an patient has an NRS of 7 or greater, or a VAS of 7 cm or osteoclast inhibitor, such as a bisphosphonate, e.g. an oral greater. In some embodiments, the patient has an NRS of dosage form of Zoledronic acid, has suffered from the about 1, about 2, about 3, about 4, about 5, about 6, about US 2017/01 19801 A1 May 4, 2017

7, about 8, about 9, or about 10. In some embodiments, the indicating minimal, moderate, and severe JSN, respectively patient has a VAS of about 1 cm, about 2 cm, about 3 cm, (Kellgren and Lawrence, Ann Rheum Dis 1957:16:494-502). about 4 cm, about 5 cm, about 6 cm, about 7 cm, about 8 cm, Based on these criteria, OARSI Grade 0 (absence of JSN), about 9 cm, or about 10 cm. approximates K/L Grades 0-1 (absence of, or doubtful 0066 For knee pain or pain associated with bone marrow presence of JSN). Knee pain in a person having OARSI lesions, in some embodiments, treatment with a nitrogen Grade 0 or K/L Grade or 1 JSN in the knee where the pain containing bisphosphonate Such as Zoledronic acid may occurs may be referred to herein as a “normal joint space decrease the visual analog (VAS) pain score measured using knee pain.” a 100 mm scale, by at least about 5 mm, at least about 8 mm, 0071. In some embodiments for patients having OARSI at least about 10 mm, at least about 15 mm, up to about 50 Grade 0 or K/L Grades 0-1 JSN, the use of an inhibitor of mm, or up to about 100 mm. In some embodiments, the VAS osteoclast activity achieves a reduction in the total area of score, may be decreased by at least about 5 mm, at least the bone marrow lesions of at least about 240 mm. In some about 8 mm, at least about 10 mm, at least about 15 mm, up embodiments, the reduction in total area is at least about 220 to about 50 mm, or up to about 100 mm, as compared to a mm, at least about 200 mm, at least about 150 mm, at placebo. least about 100 mm, or at least about 50 mm. In some 0067 Treatment with a nitrogen-containing bisphospho embodiments, the reduction in size of bone marrow lesions nate such as Zoledronic acid may decrease the numerical represents a reduction relative to baseline of at least about rating scale (NRS) pain score measured using a 0-10 scale, 10%, at least about 15%, at least about 20%, at least about by at least about 0.1, at least about 0.5, at least about 0.8, at 25%, at least about 30%, at least about 35%, at least about least about 1, at least about 1.5, up to about 5, or up to about 40%, at least about 45%, at least about 50%, at least about 10. In some embodiments, the NRS score may be decreased 60%, at least about 70% at least about 80%, at least about by at least about 0.1, at least about 0.5, at least about 0.8, at 90%, or about 100%. In some embodiments, the reduction in least about 1, at least about 1.5, up to about 5, or up to about area of bone marrow lesions represents an improvement 10, as compared to a placebo. relative to placebo of at least about 10%, at least about 20%, 0068. In some embodiments, an inhibitor of osteoclast at least about 30%, at least about 40%, at least about 50%, activity can be used to reduce the size of bone marrow at least about 60%, at least about 70%, at least about 80%, lesions. The area of the lesions may be measured as the total at least about 90%, at least about 100%, at least about 120%, area of all lesions or as the area of any one lesion. In some at least about 150%, at least about 170%, at least about embodiments, the total area includes the medial tibial area, 200%, at least about 250%, at least about 300%, at least the medial femoral area, the lateral tibial area, and the lateral about 350%, at least about 400%, or at least about 450%. In femoral area. In some embodiments the bone marrow lesion some embodiments, the use of an inhibitor of osteoclast in located in the patella. activity inhibits an increase in the size of bone marrow 0069. In some embodiments, the use of an inhibitor of lesions over time. osteoclast activity achieves a reduction in the total area of the bone marrow lesions of at least about 240 mm. In some 0072. In some embodiments for patients having OARSI embodiments, the reduction in total area is at least about 220 Grades 1-2 or K/L Grades 2-4 JSN, the use of an inhibitor mm, at least about 200 mm, at least about 150 mm, at of osteoclast activity achieves a reduction in the total area of least about 100 mm, or at least about 50 mm. In some the bone marrow lesions of at least about 100 mm. In some embodiments, the reduction in size of bone marrow lesions embodiments, the reduction in total area is at least about 50 represents a reduction relative to baseline of at least about mm, at least about 60 mm, at least about 80 mm, at least 10%, at least about 20%, at least about 30%, at least about about 85 mm, at least about 90 mm, at least about 100 40%, at least about 50%, at least about 60%, at least about mm, at least about 105 mm, at least about 110 mm, or at 70% at least about 80%, at least about 90%, or about 100%. least about 115 mm. In some embodiments, the reduction in In some embodiments, the reduction in area of bone marrow size of bone marrow lesions represents a reduction relative lesions represents an improvement relative to placebo of at to baseline of at least about 10%, at least about 20%, at least least about 10%, at least about 20%, at least about 30%, at about 30%, at least about 40%, at least about 50%, at least least about 40%, at least about 50%, at least about 60%, at about 60%, at least about 70% at least about 80%, at least least about 70%, at least about 80%, at least about 90%, at about 90%, or about 100%. In some embodiments, the least about 100%, at least about 120%, at least about 150%, reduction in area of bone marrow lesions represents an at least about 170%, at least about 200%, at least about improvement relative to placebo of at least about 10%, at 250%, at least about 300%, at least about 350%, at least least about 20%, at least about 30%, at least about 40%, at about 400%, or at least about 450%. In some embodiments, least about 50%, at least about 60%, at least about 70%, at the use of an inhibitor of osteoclast activity inhibits an least about 80%, at least about 90%, at least about 100%, at increase in the size of the bone marrow lesions over time. least about 115%, at least about 125%, at least about 135%, 0070 Joint space narrowing (JSN) is typically graded at least about 150%, at least about 170%, at least about using the Osteoarthritis Research Society International 200%, at least about 250%, at least about 300%, at least (OARSI) atlas criteria, or the Kellgren and Lawrence (K/L) about 350%, at least about 400%, or at least about 450%. In system. The OARSI atlas criteria grades JSN using a 0-3 some embodiments, the use of an inhibitor of osteoclast scale with Grade 0 indicating an absence of JSN, and Grades activity inhibits an increase in the size of bone marrow 1, 2 and 3 indicating mild, moderate, and severe JSN, lesions over time. respectively (Altman and Gold, Osteoarthritis Cartilage 0073. In some embodiments, an inhibitor of osteoclast 2007: 15(Suppl A):A1-A56). The K/L system grades JSN activity, such as a nitrogen-containing bisphosphonate, using a 0-4 scale with Grade 0 indicating an absence of JSN, including e.g. Zoledronic acid, , etc., is used Grade 1 indicating doubtful JSN, and grades 2, 3 and 4 to treat fibromyalgia. US 2017/01 19801 A1 May 4, 2017

0074 According to some embodiments, administration I0081 Complex regional pain syndrome is a debilitating of an inhibitor of osteoclast activity achieves a reduction in pain syndrome. It is characterized by severe pain in a limb pain that lasts at least about one month, two months, three that can be accompanied by edema, and autonomic, motor months, four months, six months, or even at least about and sensory changes. twelve months. According some embodiments, administra 0082 In some embodiments, an osteoclast inhibitor, such tion of an inhibitor of osteoclast activity achieves a reduc as a nitrogen-containing bisphosphonate, e.g. Zoledronic tion in pain that is observed at greater than three hours, at acid or minodronic acid, may be used to reduce the use of about one day, at about two to about five days, at about one non-steroidal anti-inflammatory drug (NSAIDs), opioids, or week, at about two weeks, at about three weeks, at about one other pain medications, for a patient Suffering from pain, month, at about five weeks, at about six weeks, at about inflammation, a similar condition, or any condition seven weeks, at about two months, at about nine weeks, at described herein. For example, use of NSAIDs, opioids, or about ten weeks, at about eleven weeks, at about three other pain medications may be reduced by at least about 5%, months, at about four months, at about six months, or at at least about 10%, at least about 15%, at least about 20%, about twelve months after administration of the inhibitor of at least about 25%, at least about 30%, at least about 35%, osteoclast activity. at least about 40%, at least about 45%, at least about 50%, 0075 According some embodiments, administration of at least about 60%, at least about 70%, at least about 80%, an inhibitor of osteoclast activity achieves a reduction in or at least about 90%, up to about 100%, as compared to the pain that is observed at greater than three hours, but at or use of NSAIDs, opioids or other pain medications without before one week, two weeks, three weeks, four weeks, five administration of the osteoclast inhibitor. Use of the opioids, weeks, six weeks, seven weeks, eight weeks, nine weeks, ten NSAIDs, or other pain medications may be reduced by at weeks, eleven weeks, twelve weeks, four months, five least about 5%, at least about 10%, at least about 15%, at months, or six months. least about 20%, at least about 25%, at least about 30%, at 0076 According some embodiments, administration of least about 35%, at least about 40%, at least about 45%, at an inhibitor of osteoclast activity achieves a reduction in least about 50%, at least about 60%, at least about 70%, at pain that is observed at greater than three hours with a least about 80%, or at least about 90%, up to about 100%, duration of no more than about three months, no more than as compared to the use of NSAIDS, opioids, or other pain about four months, no more than about five months, or no medications at baseline. more than about six months. I0083. The reduction in the use of NSAIDs, opioids, or 0077 According to some embodiments, after the admin other pain medications may be observed at about one week, istration of an inhibitor of osteoclast activity, the area of about two weeks, about three weeks, about one month, about bone marrow lesions relative to the size prior to adminis two months, about three months, about four months, about tration remains reduced for up to three months, four months, five months, about six months, about seven months, about five months, six months, or even up to twelve months or eight months, about nine months, about 10 months, about 11 more. According to Some embodiments, after the adminis months, or about one year or more, after the administration tration of an inhibitor of osteoclast activity, the area of bone of osteoclast inhibitor. marrow lesions relative to the size prior to administration is I0084 With respect to use of oral Zoledronic acid in a reduced at about three months, at about four months, at disodium salt form or in an acid form for relieving pain about five months, at about six months, or at about twelve associated with an inflammatory condition or Paget’s dis months. ease of bone, relief of pain can be short-term, e.g. for a 0078. According to some embodiments, after administra period of hours after administration of the dosage form, tion of an inhibitor of osteoclast activity, the size of Modic and/or relief of pain can be long-term, e.g. lasting for days, changes or VESCs relative to the size prior to administration weeks, or even months after oral administration of Zole remains reduced for up to three months, four months, five dronic acid. In some embodiments, a mammal. Such as a months, six months, or even up to twelve months or more. human being, experiences significant pain relief at least According to some embodiments, after the administration of about 3 hours, at least about 6 hours, at least about 12 hours, an inhibitor of osteoclast activity, the size of Modic changes at least about 24 hours, at least about 48 hours, at least about or VESCs relative to the size prior to administration is one week, at least about 2 weeks, or at least about 3 weeks reduced at about three months, at about four months, at after administration of an oral dosage form comprising about five months, at about six months, or at about twelve Zoledronic acid. In some embodiments, a mammal. Such as months. a human being, experiences significant pain relief during at 0079. In some embodiments, an osteoclast inhibitor, such least part of the time from about 3 hours to about 2 weeks, as a nitrogen-containing bisphosphonate, e.g. Zoledronic about 3 hours to about 3 weeks, about 3 hours to about 24 acid, ibandronic acid or minodronic acid, may be adminis hours, about 6 hours to about 2 weeks, or about 6 hours to tered to relieve complex regional pain syndrome, Such as about 24 hours, about 3 days to about 2 weeks, about 6 days complex regional pain syndrome type I (CRPS-I), complex to about 2 weeks, after administration of an oral dosage form regional pain syndrome type II (CRPS-II), CRPS-NOS, or comprising Zoledronic acid. In some embodiments, a human another type of CRPS. being treated has significant pain relief at one month, three 0080. In some embodiments, Zoledronic acid or another months, six months, nine months, one year, 5 years, or bisphosphonate may be administered orally to relieve com longer, after administration of the most recent dose of an plex regional pain syndrome, Such as complex regional pain osteoclast inhibitor Such as Zoledronic acid. syndrome type I (CRPS-I), complex regional pain syndrome I0085. With respect to the treatment of any condition type II (CRPS-II), CRPS-NOS, or another type of CRPS. recited herein, in some embodiments a first oral dosage form CRPS is a type of inflammatory pain. CRPS can also have comprising Zoledronic acid is administered and a second a neuropathic component. oral dosage form comprising oral Zoledronic acid is admin US 2017/01 19801 A1 May 4, 2017

istered. The timing of the administration of the two dosage include a pain component. For example, Zoledronic acid or forms may be such that, with respect to the first oral dosage another bisphosphonate may be useful to treat any of the form, the second oral dosage with respect to the first oral pain conditions or types of conditions listed above, includ dosage form, the second oral dosage form is administered at ing treatment that does not simply relieve the pain of those 5XT or greater (e.g., if T is 1 hour, at 5 hours or later), conditions, and treatment that is carried out in Such a way at least 10xT or greater, at least about 15XT or greater, that the condition is treated without pain relief occurring. In at least about 20XT, or greater, at least about 50xT or addition to any pain relief Zoledronic acid or another bis greater, or at least about 200xT or greater, wherein T. phosphonate may or may not provide, Zoledronic acid or is the time of maximum plasma concentration for the first another bisphosphonate may be used to treat a disease or oral dosage form. condition Such as a metabolic disease or condition; an 0.086. Some embodiments include treatment of a condi inflammatory disease or condition, including an inflamma tion recited herein, Such as inflammatory pain, arthritis, or tory disease or condition that is not associated with pain; a complex regional pain syndrome, wherein the treatment cancer disease or condition; a neurological disease or con comprises either: administering only one dosage form to a dition, etc. In some embodiments, enhanced bioavailability mammal to treat the condition, or administering a first of the Zoledronic acid may be achieved in treating one of dosage form to the mammal, followed by administering a these conditions by administering a dosage form comprising second dosage form to the mammal. If two or more dosage Zoledronic acid in the form of a disodium salt. This may forms are administered, the second oral dosage form is allow a reduced molar amount of the disodium salt to be administered before the maximum pain relieving effect of used as compared to what would be used with the diacid the first oral dosage form is achieved, or before a peak in the form. pain relieving effect of the first oral dosage form is experi 0090. In some embodiments, oral administration of Zole enced by a mammal, receiving the dosage form. In some dronic acid or another bisphosphonate may also be useful to embodiments, the second oral dosage form is administered treat complex regional pain syndrome, rheumatoid arthritis, before an observable pain relieving effect is achieved. In osteoarthritis, erosive osteoarthritis, axial spondyloarthritis Some embodiments, the second dosage form is administered including ankylosing spondylitis, acute vertebral crush frac about 12 hours to about 60 days, about 24 hours to about 28 ture, fibrous dysplasia, SAPHO syndrome, osteoporosis, days, about 24 hours to about 7 days, about 24 hours to about transient osteoporosis, or transient osteoporosis of the hip. In 14 days, or about 24 hours to about 21 days, after the first some embodiments, enhanced bioavailability of the Zole dosage form is administered. dronic acid may be achieved in treating one of these con 0087. Some embodiments include treatment of a condi ditions by administering a dosage form comprising Zole tion recited herein, Such as inflammatory pain, arthritis, or complex regional pain syndrome, wherein the treatment dronic acid in the form of a disodium salt. This may allow comprises administering a first dosage form to the mammal, a reduced molar amount of the disodium salt to be used as followed by administering a second dosage form to the compared to what would be used with the diacid form. mammal, wherein the second dosage form is administered 0091. In some embodiments, oral administration of Zole after the maximum pain relieving effect of the first oral dronic acid or another bisphosphonate may also be useful to dosage form is achieved, and the second oral dosage form is treat hypercalcemia of malignancy, multiple myeloma, bone administered while the mammal is still experiencing pain metastases from Solid tumors, Paget’s disease of bone, giant relief from the first oral dosage form, or while the pain cell tumor of bone, blood cancers or leukemias, or solid relieving effect from the first oral dosage form is observable. tumors or cancers. In some embodiments, enhanced bio In some embodiments, the second dosage form is adminis availability of the Zoledronic acid may be achieved in tered about 12 hours to about 60 days, about 24 hours to treating one of these conditions by administering a dosage about 28 days, about 24 hours to about 7 days, about 24 form comprising Zoledronic acid in the form of a disodium hours to about 14 days, or about 24 hours to about 21 days, salt. This may allow a reduced molar amount of the diso after the first dosage form is administered. dium salt to be used as compared to what would be used with 0088 Zoledronic acid or another bisphosphonate may the diacid form. also be administered orally to relieve cancer-related pain, 0092. Some nitrogen-containing bisphosphonates may be including pain associated with multiple myeloma and bone represented by Formula A: metastases from Solid tumors. In some embodiments, Zole dronic acid is used to treat pain that is not cancer-related pain. For example, Zoledronic acid may be used to treat pain Formula A that is not associated with multiple myeloma, bone metas tasis from Solid tumors, hypercalcemia of malignancy, giant cell tumor of bone, blood cancers or leukemias, or solid tumors or cancers. In some embodiments, enhanced bio availability of the Zoledronic acid may be achieved in treating one of these conditions by administering a dosage form comprising Zoledronic acid in the form of a disodium salt. This may allow a reduced molar amount of the diso 0093. With respect to Formula A. R' is F, Cl, Br, H, or dium salt to be used as compared to what would be used with OH. In some embodiments, R' is OH. the diacid form. I0094. With respect to Formula A, R is aminoalkyl, such 0089. In addition to relieving pain, oral administration of as aminoethyl, aminopropyl, aminopentyl, dimethylamino Zoledronic acid or another bisphosphonate may also be ethyl, methylpentylaminoethyl, etc.; or optionally Substituted useful to treat diseases or conditions that may or may not heterocyclyl alkyl, such as optionally Substituted imida US 2017/01 19801 A1 May 4, 2017

Zolylmethyl, optionally substituted pyridinymethyl, etc. In -continued some embodiments R is optionally substituted imidazoly lalkyl. 0095. Unless otherwise indicated, when a compound or chemical structural feature Such as heterocyclyl alkyl is referred to as being “optionally substituted, it includes a feature that has no Substituents (i.e. unsubstituted), or a feature that is Substituted, meaning that the feature has one N or more substituents. The term "substituent has the broadest meaning known to one of ordinary skill in the art, and O includes a moiety that replaces one or more hydrogen atoms in a parent compound or structural feature. The term HQ 2. HO “replaces” is merely used herein for convenience, and does O/ HO-PEOOH O HO OH not require that the compound be formed by replacing one Ho? N HO O atom with another. In some embodiments, a Substituent may be any ordinary organic moiety known in the art, which may ibandronic acid risedronic acid have a molecular weight (e.g. the sum of the atomic masses O O N of the atoms of the substituent) of 15 g/mol to 50 g/mol, 15 1y-N g/mol to 100 g/mol, 15 g/mol to 150 g/mol, 15 g/mol to 200 Ho1 NoH N-N 7 V/OH OH OH PS g/mol, 15 g/mol to 300 g/mol, or 15 g/mol to 500 g/mol. In HN OH Some embodiments, a Substituent comprises, or consists of 0-30,0-20, 0-10, or 0-5 carbon atoms; and 0-30, 0-20, 0-10, HO PEO or 0-5 heteroatoms, wherein each heteroatom may indepen dently be: N, O, P, S, Si, F, Cl, Br, or I; provided that the substituent includes one C, N, O, P, S, Si, F, Cl, Br, or I atom. cimadronic acid minodronic acid In some embodiments, Substituents can independently have a molecular weight of about 15 Da to about 600 Da and can consist of 2 to 5 chemical elements, wherein the chemical 0098 Zoledronic acid has the structure shown below, and elements are independently C, H, O, N, P, S, Si, F, Cl, or Br. is also referred to as Zoledronate. In some embodiments, a Substituent is optionally Substituted alkyl, —O-alkyl (e.g. —OCH —OCH5, —OCH7 OH —OCH, etc.). —S-alkyl (e.g. —SCH. —SCH7. On P / —SCH, etc.), -NRR", -OH, -SH, -CN, -CF, NoH —NO, perfluoroalkyl, optionally Substituted aryl, option HO ally substituted heteroaryl, optionally substituted amine or a (COX)P N o?'V halogen, wherein R' and R" are independently H or option OH ally substituted alkyl. Wherever a substituent is described as Zoledronic acid “optionally substituted,” that substituent can be substituted with the above substituents. 0099. Unless otherwise indicated, any reference to a 0096. For convenience, the term “molecular weight' is compound herein, such as Zoledronic acid, by structure, used with respect to a moiety or part of a molecule to name, or any other means, includes pharmaceutically indicate the Sum of the atomic masses of the atoms in the acceptable salts, such as the disodium salt; alternate solid moiety or part of a molecule, even though it may not be a forms, such as polymorphs, Solvates, hydrates, etc.; tautom complete molecule. ers; or any other chemical species that may rapidly convert 0097 Examples of nitrogen-containing bisphosphonates to a compound described herein under conditions in which the compounds are used as described herein. Unless other include but are not limited to , incadronic wise indicated, a phrase such as 'administering a bisphos acid, ibandronic acid, risedronic acid, minodronic acid, phonate.” “administering an osteoclast inhibitor,” “admin cimadronic acid, neridronic acid, alendronic acid, olpad istering Zoledronic acid.” includes administering any form ronic acid, Zoledronic acid, etc. of the bisphosphonate, osteoclast inhibitor, Zoledronic acid, etc., Such as those recited above. 0100. In some embodiments, Zoledronic acid is adminis tered in a dosage form comprising a salt form, such as a salt of a dianion of Zoledronic acid. In some embodiments, Zoledronic acid is administered in a dosage form comprising a disodium salt form of Zoledronic acid. In some embodi HO On P P OH ments, Zoledronic acid is administered in a sodium salt form, HO1V /YoH Such as a monosodium salt, a disodium salt, a trisodium salt, O HO etc. In some circumstances, use of the disodium salt may be pamidronic acid incadronic acid desirable. For example, the disodium salt is much more soluble in water than the diacid form. As a result, in some US 2017/01 19801 A1 May 4, 2017

processes, the disodium salt can be easier to work with than -continued the diacid form. Additionally, the sodium salt may be more bioavailable and/or more rapidly absorbed when taken orally strong X-ray powder diffraction peaks as compared to the diacid form. Form (20 + 0.2) 0101. In some embodiments, a RANK/RANKL antago Zoledronic acid, DL-lysine, about 8.3, about 11.8, about 12.3, about nists or an osteoclast inhibitor, such as Zoledronic acid or and water complex 15.8, and about 20.8 Zoledronic acid, L-lysine, about 9.6, about 10.7, about 14.3, about neridronic acid may be in the form of a molecular complex. and water complex 21.4, and about 23.5 For example, molecular complexes of Zoledronic acid Zoledronic acid, DL-lysine, about 9.7, about 10.8, about 14.4, about include cocrystals, salts, Solvates Such as hydrates and and water complex 18.9, and about 21.4 mixed solvates of an acid or a salt form, and mixtures Zoledronic acid, DL-lysine 7.2, about 14.0, about 18.3, about 19.1, complex about 20.7, about 24.6, and about 34.4 containing Such materials. Molecular complexes of Zole Zoledronic acid, DL-lysine 6.6, about 11.0, about 14.2, about 18.3, dronic acid may be in amorphous forms or polymorphs. complex about 19.7, about 22.7, and about 27.6 0102) Of particular interest are compositions, or com plexes comprising Zoledronic acid or neridronic acid and the standard amino acids or natural existing amino acids, Such 0105 Solid forms of Zoledronic acid such as complexes as alanine, arginine, asparagine, aspartic acid, cysteine, of Zoledronic acid with sodium, ammonium, ammonia, glutamic acid, glutamine, glycine, histidine, isoleucine, leu L-lysine, DL-lysine, nicotinamide, adenine and glycine may cine, lysine, methionine, phenylalanine, proline, serine, be prepared by methods such as dry or solvent-drop grinding threonine, tryptophan, tyrosine, Valine, etc. Some examples (liquid assisted grinding), heating or solvent evaporation of of useful molecular complexes include, but are not limited their solution in single or mixed solvent systems, slurry to, complexes of Zoledronic acid or neridronic acid with Sodium cation, ammonium, ammonia, L-lysine, DL-lysine, Suspension, Supercritical fluids or other techniques known to nicotinamide, adenine, glycine, and Selenocysteine. a person skilled in the art. 0103 Zoledronic acid may also be in a form represented 0106 For example, Zoledronic acid and nicotinamide by one of the structural depictions below. may be complexed by dissolving both compounds in water: ethyl acetate (1:1 V/v) and allowing the solvents in the mixture to evaporate to form crystalline material. 0107. In some embodiments, a Zoledronic acid complex may have an excess at least one coformer (e.g. the compo nent other than Zoledronic acid) to the Zoledronic acid complexes, which may be the same as the coformer in the NH' complex, a different coformer, or a mixture thereof. In some embodiments, the excess coformer may be a standard or natural amino acid. Examples of compounds in salt forms containing Ion 1 are shown below:

O ?—\ POH HO N.N2 . .N - on X 0104 Zoledronic acid in a salt or an acid form may be OH present in a molecular complex having strong X-ray powder diffraction peaks in one of the following positions: O ?—\ POH HO N.N2 . .N - so strong X-ray powder diffraction peaks OH Form (20 + 0.2) Zoledronic acid, Sodium about 8.1, about 13.3, about 21.5, about NS-2N M Zoledronate and water 24.6, and about 25.6 HO N2 POH complex OH ammonium Zoledronate Salt about 11.0, about 14.6, about 15.4, and water complex about 19.9, and about 29.4 O f POH Zoledronic acid, L-lysine, about 9.0, about 14.4, about 18.1, about and water complex 26.0, and about 29.6 Ns. 2 N POH M Zoledronic acid, DL-lysine, about 9.1, about 14.7, about 18.0, about O N2 3 and water complex 21.2, and about 26.0 OH Zoledronic acid, DL-lysine, about 8.8, about 9.7, about 17.6, about O PO2 ethanol, and water complex 23.1, and about 26.5 Zoledronic acid, nicotinamide, 13.1, about 15.2, about 21.0, about 23.9, N. . .N 4M and water complex and about 26.5 O N2 PO2 Zoledronic acid, adenine, bout 13.6, about 15.9, about 19.7, OH and water complex bout 27.9, and about 29.5 Zoledronic acid and bout 10.2, about 17.8, about 19.9, glycine complex bout 22.9, and about 28.1 Zoledronic acid diammonia, bout 12.2, about 13.0, about 14.1, wherein X is any suitable anion, e.g. F. Br, Cl, I, OH, and water complex bout 17.1, and about 19.3 acetate, etc.; and M is any Suitable cation, e.g. Na', K", NH, etc. Many other salt forms are also possible. US 2017/01 19801 A1 May 4, 2017 11

0108. In some embodiments, a compound containing Ion 0113. In some embodiments, a salt of a compound con 1 may be further represented by a formula, taining Ion 2 may be further represented by a formula,

O ?—\ PONa) POHNa ?—\ POHNa O 's--tos -- N.N2 . .N POHNa OH PO3HNa e OH OH

0109. In some embodiments, a compound containing Ion 0114. In some embodiments, a compound containing Ion 1 may be in a hydrate form. 2 may be in a hydrate form. 0.115. In some embodiments, a compound containing Ion 0110. In some embodiments, a compound containing Ion 2 is administered in a dosage form comprising a salt form, 1 is administered in a dosage form comprising a salt form, Such as a Zwitterionic form, or a salt of a cation, a mono Such as a Zwitterionic form, or a salt of a cation, a mono anion, a dianion, a trianion, etc. . . . . anion, a dianion, a trianion, etc. 0116. A compound containing Ion 2 can be present in any 0111. A compound containing Ion 1 can be present in any amount, such as less than about 100% w/w, less than about amount, such as less than about 100% w/w, less than about 50% w/w, less than about 20% w/w, less than about 10% 50% w/w, less than about 20% w/w, less than about 10% wfw, less than about 1% w/w, less than about 0.3%, less than wfw, less than about 1% w/w, less than 0.1% w/w, less than about 0.2%, less than 0.1% w/w, less than about 0.08% w/w, about 0.07% w/w, less than about 0.05% w/w, less than less than about 0.07% w/w, less than about 0.05% w/w, less about 0.04% w/w, less than about 0.03% w/w, less than than about 0.04% w/w, less than about 0.03% w/w, less than about 0.02% w/w; and/or greater than 0% w/w, at least about about 0.02% w/w; and/or greater than 0% w/w, at least about 0.00000001% w/w, at least about 0.000001% w/w, or at least 0.00000001% w/w, at least about 0.000001% w/w, or at least about 0.00001% w/w, based upon the total amount of about 0.00001% w/w, based upon the total amount of Zoledronic acid, a compound containing Ion 1, and a com Zoledronic acid, a compound containing Ion 1, and a com pound containing Ion 2 present in the composition. pound containing Ion 2 present in the composition. 0117. In some embodiments, a compound containing Ion 0112 Examples of salts of compounds containing Ion 2 1 and a compound containing Ion 2 are present in an amount are shown below: that is less than 0.1% w/w. 0118. In some embodiments, the administration of an osteoclast inhibitor, such as a nitrogen-containing bisphos PO3H ?—\ PO3H phonate, including, e.g. Zoledronic acid, minodronic acid, N. , N etc., to a patient or mammal in need thereof affects Modic -- N2 POH, X changes (MCs). For example, any of the above compounds POH OH could be used to treat Modic changes, or vertebral endplate signal changes (VESC) and bone marrow changes visible PO3H ?—\ POH using magnetic resonance imaging (MRI), or neck pain or -- NsN2 2N POH back pain associated with Modic changes. POH OH 0119 Modic changes, as used herein, includes its ordi nary meaning in the art and refers to pathological vertebral POH ?—\ POH endplate and bone marrow changes visible using magnetic Nsit N M resonance imaging (MRI). Modic changes may also be -- Na POH referred to as vertebral endplate signal changes (VESC). POH OH Modic changes, can be classified into various types includ POH ?—\ POH ing type 1 (M1), type 2 (M2), and type 3 (M3) lesions or changes, any of which may be treated using an osteoclast -- NsitNa N POH 2M inhibitor, Such as a nitrogen-bisphosphonate, including, e.g. POH OH Zoledronic acid, minodronic acid, etc. Different types of Modic changes may occur in the same patient, for example PO3H = POH type 1 and type 2 Modic changes (M1/2). In some cases, M1 N N 4M changes are related to lower back pain than other types of HO N2 POH X Modic change. POH OH I0120 VESCs may be found in patients with different PO3H = POH types of low back pain including but not limited to spon N N 4Na" dylitis, trauma, spondyloarthropathies including ankylosing HO N2 PO3H -OH spondylitis, Schmorl’s nodes, fracture, tumor, and spinal POH OH cord infarction. Lesions in ankylosing spondylitis include osteitis and spondylodiscitis, which can be detected using MRI or another medical imaging instrument. wherein X is any suitable anion, e.g. F. Br, Cl, I, OH, I0121 Modic changes may be found in the cervical, acetate, etc.; and M is any suitable cation, e.g. Na', K", thoracic, lumbar, and Sacral spine. Modic changes may be NH, etc. Many other salt forms are also possible. found at various spinal levels such as at C1/2, C2/3, C3/4, US 2017/01 19801 A1 May 4, 2017

C4/5, C5/6, C6/7, C7/T1, T1/2, T2/3, T3/4, T4/5, T5/6, T6/7, ments, greater pain relief may be obtained in patients who T7/8, T8/9, T9/10, T10/11, T11/12, T12/L1, L1/2, L2/3, experience a reduction or a greater reduction in the levels of L3/4, L4/5, L5/S1, etc., any of which may be treated using pro-inflammatory cytokines when treated with an inhibitor an osteoclast inhibitor, such as a nitrogen-bisphosphonate, of osteoclast activity, Such as a nitrogen-containing bispho including, e.g. Zoledronic acid, minodronic acid, etc. sphonate, including e.g. Zoledronic acid, minodronic acid, 0122. In some embodiments, the Modic change being etc. Pro-inflammatory cytokines include but are not limited treated is located at L2/3. In some embodiments, the Modic to IL-1, IL-2, IL-3, IL-6, IL-8, IL-10, IL-12, tumor necrosis change being treated is located at L3/4. In some embodi alpha (TNF-alpha), interferon gamma, etc. ments, the Modic change being treated is located at L4/5. In (0132. In some embodiments, the use of an inhibitor of Some embodiments, the Modic change being treated is osteoclast activity. Such as a nitrogen-containing bisphos located at L5/S1. phonate, including e.g. Zoledronic acid, minodronic acid, 0123. In some embodiments, the Modic change being etc., to a patient or mammal in need thereof, achieves a treated is located at C3/4. In some embodiments, the Modic reduction relative to baseline in the size of Modic changes change being treated is located in at C4/5. In some embodi or VESCs of at least about 5%, at least about 10%, at least ments, the Modic change being treated is located in at C5/6. about 15%, at least about 20%, at least about 25%, at least In some embodiments, the Modic change being treated is about 30%, at least about 40%, at least about 50%, at least located in at C6/7. about 60%, at least about 70% at least about 80%, at least 0.124. In some embodiments, the Modic change being about 90%, or about 100%. In some embodiments, the treated is located at T5/6. In some embodiments, the Modic reduction the size of Modic changes or VESCs represents an change being treated is located in at T6/7. In some embodi improvement relative to placebo of at least about 10%, at ments, the Modic change being treated is located in at T7/8. least about 15%, at least about 20%, at least about 25%, at In some embodiments, the Modic change being treated is least about 30%, at least about 40%, at least about 50%, at located in at T8/9. In some embodiments, the Modic change least about 60%, at least about 70%, at least about 80%, at being treated is located at T9/10. least about 90%, at least about 100%, at least about 120%, 0.125. In some embodiments, the patient being treated has at least about 150%, at least about 170%, at least about predominantly M1. In some embodiments, the patient being 200%, at least about 250%, at least about 300%, at least treated has predominantly M1/M2. In some embodiments, about 350%, at least about 400%, or at least about 450%. In the patient being treated has predominantly M2. In some some embodiments, the use of an inhibitor of osteoclast embodiments, the patient being treated has predominantly activity inhibits an increase in the size of Modic changes or M3. VESCs over time. 0126. In some embodiments, the worst type of lesion that I0133. The oral bioavailability of Zoledronic acid may be the patient being treated has is M1. In some embodiments, enhanced by orally administering the Zoledronic acid in the the worst type of lesion that the patient being treated has is disodium salt form. For example, the bioavailability of M1/2. In some embodiments, the worst type of lesion that Zoledronic acid may be improved by at least about 10%, at the patient being treated has is M2. least about 20%, at least about 30%, at least about 50%, 0127. In some embodiments, the patient being treated has and/or up to about 100%, or up to about 200%, as compared Modic changes at more two or more levels. In some embodi to administration of Zoledronic acid in the diacid form. ments the patient being treated has Modic changes at three I0134. Because of the improved bioavailability of the or more levels. In some embodiments greater pain relief is disodium salt a dosage form may contain, or a mammal, obtained when treating a patient with Modic changes at two Such as a human being, may receive, on a molar basis, less levels, or three or more levels, than is obtained when treating of the disodium salt form of Zoledronic acid than would a patient with Modic changes at a single level or at two otherwise be administered of the diacid form of Zoledronic levels. acid. For example, a dosage form may contain, or a mammal 0128. In some embodiments greater pain relief is may receive, at least about 10 mole % less, at least about 20 obtained when treating a patient with Modic changes at two mole 96 less, at least about 40 mole % less, at least about 50 levels than is obtained when treating a patient with Modic mole % less, and/or up to about 90 mole % less or 95 mole changes at a single level. % less, of the disodium salt form as compared the amount 0129. In some embodiments greater pain relief is of the diacid form of Zoledronic acid that would otherwise obtained when treating a patient with Modic changes at three be administered, such as a molar amount that would be or more levels than is obtained when treating a patient with administered of Zoledronic acid in the diacid form in order Modic changes at a single level. to achieve the same plasma levels of Zoledronic acid. 0130. In some embodiments greater pain relief is I0135) In some embodiments, a dosage form contains, or obtained when treating a patient with Modic changes three a mammal (Such as a human being) is administered, an or more levels than is obtained when treating a patient with amount of the disodium salt form, on a molar basis, that has Modic changes at two levels. a value of about 0.8 n to about 1.2 n or about 0.9 n to about 0131. In some embodiments, the inhibitor of osteoclast 1.1 n, wherein: activity may be used to effect a reduction in the levels of pro-inflammatory cytokines in the patient with low back ni (b/b)(n) pain or any other type of pain or condition recited herein. In wherein b is the bioavailability of the diacid form, b is the Some embodiments greater pain relief may be obtained in bioavailability of the disodium salt form, and n is the patients with greater baseline levels of pro-inflammatory number of moles of the diacid that would be administered in cytokines when treated with an inhibitor of osteoclast activ a dosage form containing the diacid form of Zoledronic acid. ity, Such as a nitrogen-containing bisphosphonate, including For example, if the diacid form has a bioavailability (b) of e.g. Zoledronic acid, minodronic acid, etc. In some embodi 0.01 and the disodium salt form has a bioavailability (b) of US 2017/01 19801 A1 May 4, 2017

0.015, and a dosage form would normally contain 0.001 about 40 ng/mL, about 95 ng/mL, about 97 ng/mL, or any moles of the diacid, n would be (0.01/0.015)(0.001 moles), C in a range bounded by, or between, any of these values, or about 0.00067 moles. In some embodiments, the diso upon administration of the oral dosage form to a mammal. dium salt is administered in an amount that has a value of 0141 An oral dosage form comprising Zoledronic acid about n. having a dose of Zoledronic acid and a configuration Suitable 0136. With respect to oral dosage forms comprising a for a particular species of mammal may be configured so that reduced molar amount of the disodium salt of Zoledronic administration of the oral dosage form to the particular acid as compared to the diacid form of Zoledronic acid, in species of mammal results in a T of Zoledronic acid of some embodiments, the bioavailability of the Zoledronic about 0.4 hr to about 1 hr., about 0.5 hr, or about 0.75 hr, or acid in the disodium salt form is sufficiently high that, if the any T in a range bounded by, or between, any of these drug is administered to a mammal, at least as much Zole values. dronic acid is present in the blood of the mammal as would 0142. In some embodiments, the Zoledronic acid in the be present if Zoledronic acid were administered in the diacid disodium salt form is present in an amount Such that the oral form. dosage form provides an area under the plasma concentra 0.137 With respect to oral dosage forms comprising the tion curve of Zoledronic acid of about 4 ngh/mL to about disodium salt form of Zoledronic acid, in some embodi 2000 ngh/mL to the mammal each time the Zoledronic acid ments, the disodium salt form is present in a lower molar in the disodium salt is administered. amount than would be present if the Zoledronic acid were in 0143. In some embodiments, the Zoledronic acid, includ the diacid form; and the Zoledronic acid in the disodium salt ing Zoledronic acid in an acid or a salt form, e.g. the disodium form has an improved bioavailability as compared to the salt form, is present in an amount Such that the oral dosage Zoledronic acid in the diacid form to the extent that the lower form provides an area under the plasma concentration curve molar amount of the disodium salt in the dosage form does of Zoledronic acid of about 100 ngh/mL to about 2000 not reduce the amount of Zoledronic acid delivered to the ngth/mL, about 100 ngh/mL to about 1000 ngh/mL, about plasma of a mammal. 500 ngh/mL to about 1000 ngh/mL, or about 500 ngh/mL 0.138. Some oral dosage forms comprising Zoledronic to about 700 ngh/mL in the mammal to which the dosage acid have a dose of Zoledronic acid and a configuration form is administered. This amount may be suitable for Suitable for a particular species of mammal, e.g. dog, rat, administration of the oral dosage form about every 3 to 4 human, etc. Such a dosage form may have Zoledronic acid weeks. present in an amount that results in a desired range for an 0144. In some embodiments, the Zoledronic acid, such as area under the plasma concentration curve (AUC) of Zole Zoledronic acid in an acid form or a salt form, such as the dronic acid in that particular species of mammal. For disodium salt form, is present in an amount Such that the oral example the dose of Zoledronic acid and a configuration of dosage form provides an area under the plasma concentra the oral dosage form may result in an AUC of Zoledronic tion curve (AUC) of Zoledronic acid of about 20 ngh/mL to acid of about 1 ngh/mL to about 700 ngh/mL, about 3 about 700 ngh/mL, about 50 ngh/mL to about 500 ngh/mL, ngh/mL to about 30 ngh/mL, about 3 ngh/mL to about 10 about 50 ngh/mL to about 400 ngh/mL, about 50 ngh/mL ngh/mL, about 50 ngh/mL to about 700 ngh/mL, about 130 to about 300 ngh/mL, about 50 ngh/mL to about 200 ngh/mL to about 180 ngh/mL, about 300 ngh/mL to about ngth/mL, about 50 ngh/mL to about 100 ngh/mL, about 130 450 ngh/mL, about 300 ngh/mL to about 350 ngh/mL, ngth/mL to about 150 ngh/mL, about 130 ngh/mL to about about 300 ngh/mL to about 310 ngh/mL, about 340 ngh/ 140 ngh/mL, about 150 ngh/mL to about 200 ngh/mL, mL to about 350 ngh/mL, about 370 ngh/mL to about 420 about 200 ngh/mL to about 300 ngh/mL, about 250 ngh/ ngh/mL, about 380 ngh/mL to about 390 ngh/mL, about mL to about 300 ngh/mL, about 300 ngh/mL to about 400 405 ngh/mL to about 415 ngh/mL, about 140 ngh/mL to ngth/mL, about 400 ngh/mL to about 500 ngh/mL, about about 160 ngh/mL, about 140 ngh/mL to about 150 ngh/ 350 ngh/mL to about 400 ngh/mL, about 450 ngh/mL to mL, about 150 ngh/mL to about 160 ngh/mL, about 140 about 500 ngh/mL, about 130 ngh/mL to about 160 ngh/ ngh/mL, 142 ngh/mL, about 155 ngh/mL, about 305 mL, about 405 ngh/mL to about 450 ngh/mL, about 100 ngh/mL, 304 ngh/mL, about 345 ngh/mL, 343 ngh/mL, ngth/mL to about 500 ngh/mL, about 100 ngh/mL to about about 385 ngh/mL, 384 ngh/mL, about 410 ngh/mL, or 400 ngh/mL, about 100 ngh/mL to about 300 ngh/mL, any AUC in a range bounded by, or between, any of these about 100 ngh/mL to about 200 ngh/mL, about 125 ngh/ values, upon administration of the oral dosage form to a mL to about 500 ngh/mL, about 125 ngh/mL to about 400 mammal. ngth/mL, about 125 ngh/mL to about 300 ngh/mL, about 0.139. Unless otherwise indicated, the AUC refers to the 125 ngh/mL to about 200 ngh/mL, or about 200 ngh/mL AUC calculated to the last measured concentration (AUC to about 300 ngh/mL, in the mammal to which the dosage co) and extrapolated to infinity (AUCo.). form is administered. This amount may be suitable for 0140. An oral dosage form comprising Zoledronic acid weekly administration of the oral dosage, or for administra having a dose of Zoledronic acid and a configuration Suitable tion of 3 to 5 individual dosages during a month. The for a particular species of mammal may have Zoledronic acid individual dosages could be given at regular intervals, given present in an amount that results in a C of Zoledronic acid during the first week, or at any other schedule that provides of about 0.2 ng/mL to about 300 ng/mL, about 0.5 ng/mL to 3 to 5 dosages during the month. about 5 ng/mL, about 5 ng/mL to about 300 ng/mL, about 5 0145. In some embodiments, the Zoledronic acid is pres ng/mL to about 50 ng/mL, about 20 ng/mL to about 50 ent in an amount Such that the oral dosage form provides an ng/mL, about 30 ng/mL to about 50 ng/mL, about 50 ng/mL area under the plasma concentration curve of Zoledronic acid to about 200 ng/mL, about 50 ng/mL to about 150 ng/mL, of about 4 ngh/mL to about 100 ngh/mL, about 10 ngh/mL about 80 ng/mL to about 120 ng/mL, about 90 ng/mL to to about 50 ngh/mL, about 10 ngh/mL to about 30 ngh/mL, about 100 ng/mL, about 50 ng/mL to about 200 ng/mL, 20 ngh/mL to about 700 ngh/mL, about 50 ngh/mL to US 2017/01 19801 A1 May 4, 2017

about 500 ngh/mL, about 50 ngh/mL to about 400 ngh/mL, intravenous or Subcutaneous. For example, the amount of about 50 ngh/mL to about 300 ngh/mL, about 50 ngh/mL Zoledronic acid in the plasma can be significantly higher for to about 200 ngh/mL, about 100 ngh/mL to about 500 oral administration of the disodium salt about 24 hours or 48 ngh/mL, about 100 ngh/mL to about 400 ngh/mL, about hours, or longer, after administration. In some embodiments, 100 ngh/mL to about 300 ngh/mL, about 100 ngh/mL to oral Zoledronic acid has a 24 hour Sustained plasma level about 200 ngh/mL, about 125 ngh/mL to about 500 ngh/ factor of about 1 or higher, such as about 1 to about 10, about mL, about 125 ngh/mL to about 400 ngh/mL, about 125 1 to about 5, about 3 to about 5, or about 3 to about 4. In ngh/mL to about 300 ngh/mL, about 125 ngh/mL to about Some embodiments, an orally administered dosage form of 200 ngh/mL, or about 200 ngh/mL to about 300 ngh/mL Zoledronic acid has a 24 hour Sustained plasma level factor in the mammal to which the dosage form is administered. or a 48 hour Sustained plasma level factor that is higher. Such This amount may be suitable for daily administration of the as at least 1.2 times, at least about 2 times, at least about 5 oral dosage form. In some embodiments, the dosage form times, about 1.2 times to about 20 times, about 2 times to may be administered for 2, 3, 4, 5, 6, 7, 8, 9, or 10, 5 to 10, about 15 times, about 5 times to about 10 times, or about 8 or 6 to 10 consecutive days. to about 15 times that of intravenously administered Zole 0146 In some embodiments, the Zoledronic acid, such as dronic acid. A “sustained plasma level factor.” pa is deter Zoledronic acid in an acid form or a salt form, Such as the mined by the equation: disodium salt form, is present in an amount Such that the oral p-1000(C/C)ex administration of the dosage form in a fasted State results in an area under the plasma concentration curve (AUC) of wherein C is the maximum plasma concentration of Zoledronic acid of about 50 ngh/mL to about 500 ngh/mL, Zoledronic acid after it is administered and C, is the plasma about 50 ngh/mL to about 100 ngh/mL, about 100 ngh/mL concentration of Zoledronic acid at the time of interest. Such to about 200 ngh/mL, about 130 ngh/mL to about 180 as 24 hours. For parenteral administration, the C can be ngh/mL, about 130 ngh/mL to about 150 ngh/mL, about about the Co, or the concentration right after injection of the 130 ngh/mL to about 140 ngh/mL, about 140 ngh/mL to entire amount of the drug into the body. Sustained plasma about 150 ngh/mL, about 150 ngh/mL to about 200 ngh/ level factors can also be obtained for other times, such as 48 mL, about 200 ngh/mL to about 300 ngh/mL, about 250 hours, by using the plasma concentration of Zoledronic acid ngh/mL to about 300 ngh/mL, about 300 ngh/mL to about for C, in the equation above. For example, if the maximum 400 ngh/mL, about 300 ngh/mL to about 350 ngh/mL, plasma level of Zoledronic acid after administration is 1000 about 400 ngh/mL to about 500 ngh/mL, about 350 ngh/ ng/mL and the plasma level of Zoledronic acid at 24 hours mL to about 400 ngh/mL, about 450 ngh/mL to about 500 is 1 ng/mL, the 24 hour Sustained plasma level factor is 1. ngh/mL, about 130 ngh/mL to about 160 ngh/mL, about 0150. An oral dosage form comprising Zoledronic acid 405 ngh/mL to about 450 ngh/mL, measured over a 24 hour having a dose of Zoledronic acid and a configuration Suitable period. for a particular species of mammal may be configured so that 0147 In some embodiments, molecular complex com the Zoledronic acid has a 12 hour Sustained plasma level prising neridronic acid is administered in an amount that factor of about 12 to about 50, about 20 to about 40, about results in an AUC of neridronic acid, measured over the 25 to about 30, about 30 to about 35, about 35 to about 40, entire course of treatment, of about 10,000-30,000 ngh/mL about 33, about 30, about 35, or any 12 hour sustained about 30,000-100,000 ngh/mL about 30,000-50,000 ngh/ plasma level factor in a range bounded by, or between, any mL, about 30,000-40,000 ngh/mL, about 40,000-50,000 of these values, for the particular species of mammal. ngh/mL, about 50,000-60,000 ngh/mL, about 60,000-70, 0151. An oral dosage form comprising Zoledronic acid 000 ngh/mL, about 50,000-70,000 ngh/mL, about 70,000 having a dose of Zoledronic acid and a configuration Suitable 80,000 ngh/mL, about 80,000-90,000 ngh/mL, about for a particular species of mammal may be configured so that 90,000-100,000 ngh/mL, about 70,000-100,000 ngh/mL, the Zoledronic acid has a 24 hour Sustained plasma level about 100,000-200,0000ngh/mL, about 200,000-300,0000 factor of about 10 to about 30, about 10 to about 20, about ngh/mL, about 300,000-400,0000ngh/mL, about 400,000 10 to about 15, about 12 to about 15 or 16, about 15 to about 500,0000ngh/mL, or any AUC in a range bounded by any 20, about 14, about 12, about 15, or any 24 hour sustained of these values. plasma level factor in a range bounded by, or between, any 0148. In some embodiments, an osteoclast inhibitor, a of these values, for the particular species of mammal. bisphosphonate, or a RANK/RANKL antagonist, such as 0152 An oral dosage form comprising Zoledronic acid Zoledronic acid, etc., is administered at an interval of about having a dose of Zoledronic acid and a configuration Suitable once, twice, or thrice daily, or every 1, 2, 3, 4, 5, 6, 7, 8, 9. for a particular species of mammal may be configured so that 10, 11, 12, 13, or 14 days; or 15, 16, 17, 18, 19, 20, or 21 the Zoledronic acid has a 36 hour sustained plasma level days; or 22, 23, 24, 25, 26, 27, 28, 29, 30, or 31 days; or 32, factor of about 6 to about 20, about 8 to about 15, about 9 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, or 45; or 46, to about 12 or 13, about 8 to about 10, about 11 to about 13, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, or 60 days: about 9, about 13, or any 24 hour sustained plasma level or 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, factor in a range bounded by, or between, any of these 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, or 90 values, for the particular species of mammal. days; or 91, 92,93, 94, 95, 96, 97,98,99, 100, 101, 102, 103, 0153. An oral dosage form comprising Zoledronic acid 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, having a dose of Zoledronic acid and a configuration Suitable 116, 117, 118, 119, or 120 days. for a particular species of mammal may be configured so that 0149 Oral administration of Zoledronic acid, particularly the Zoledronic acid has a 48 hour Sustained plasma level oral administration of the disodium salt form of Zoledronic factor of about 5 to about 20, about 6 to about 15, about 7 acid, can result in more Sustained plasma levels of the drug or 8 to about 12 or 13, about 8 to about 10, about 11 to about as compared to parenteral modes of administration, Such 13, about 8, about 12, or any 48 hour sustained plasma level US 2017/01 19801 A1 May 4, 2017

factor in a range bounded by, or between, any of these 0160 An oral dosage form comprising Zoledronic acid values, for the particular species of mammal. having a dose of Zoledronic acid and a configuration Suitable 0154 An oral dosage form comprising Zoledronic acid for a particular species of mammal may be configured so that having a dose of Zoledronic acid and a configuration Suitable the elimination half-life of Zoledronic acid in the particular for a particular species of mammal may be configured so that species of mammal is about 30 hours to about 100 hours, the Zoledronic acid has a 72 hour sustained plasma level about 40 hours to about 60 hours, about 40 hours to about factor of about 4 to about 20, about 5 to about 10, about 5 50 hours, about 50 hours to about 60 hours, about 42 hours, or 6 to about 10 or 11, about 5 to about 6, about 9 to about about 51 hours, about 59 hours, or any half-life in a range 10, about 6, about 10, or any 72 hour sustained plasma level bounded by, or between, any of these values. factor in a range bounded by, or between, any of these 0.161. As used herein, the "elimination half-life” refers to values, for the particular species of mammal. the apparent first-order terminal plasma elimination half 0155. An oral dosage form comprising Zoledronic acid life, obtained by non-compartmental analysis using Win having a dose of Zoledronic acid and a configuration Suitable Nonlin. A terminal plasma elimination half-life is the time for a particular species of mammal may be configured so that required to reduce the plasma concentration to half after the particular species of mammal has a plasma concentration reaching pseudo-equilibrium, and not the time required to of Zoledronic acid at 12 hours that is about 0.5 ng/mL to eliminate half the administered dose. For orally adminis about 5 ng/mL, about 1 ng/mL to about 3 ng/mL, about 1 tered drugs, terminal plasma elimination half-life can be ng/mL to about 2 ng/mL, about 2 ng/mL to about 3 ng/mL, affected by absorption of the drug, as well as plasma about 3 ng/mL to about 4 ng/mL, about 1.2 ng/mL, about 2.6 clearance and extent of distribution. ng/mL, about 3.2 ng/mL, or any plasma concentration in a (0162. In some embodiments, the disodium salt form of range bounded by, or between, any of these values. Zoledronic acid provides an enhancement to bioavailability, 0156 An oral dosage form comprising Zoledronic acid as compared to the diacid form of Zoledronic acid, which having a dose of Zoledronic acid and a configuration Suitable adds to any enhancement to bioavailability provided by any for a particular species of mammal may be configured so that bioavailability-enhancing agents in the dosage form. In the particular species of mammal has a plasma concentration some embodiments, the disodium salt form of Zoledronic of Zoledronic acid at 24 hours that is about 0.2 ng/mL to acid provides an enhancement to bioavailability, as com about 2 ng/mL, about 0.5 ng/mL to about 1.5 ng/mL, about pared to the diacid form of Zoledronic acid, which is greater 0.5 ng/mL to about 1 ng/mL, about 1 ng/mL to about 1.5 than any enhancement to bioavailability provided by any ng/mL, about 0.5 ng/mL, about 1.0 ng/mL, about 1.4 ng/mL, bioavailability-enhancing agents in the dosage form. In or any plasma concentration in a range bounded by, or some embodiments, the disodium salt form of Zoledronic between, any of these values. acid may be administered in a dosage form that is substan 0157 An oral dosage form comprising Zoledronic acid tially free of bioavailability-enhancing agents. having a dose of Zoledronic acid and a configuration Suitable (0163 The C-terminal telopeptide (CTX) is one of the for a particular species of mammal may be configured so that products from type I collagen degradation by osteoclasts the particular species of mammal has a plasma concentration during bone resorption. Thus, CTX serum levels may be of Zoledronic acid at 36 hours that is about 0.1 ng/mL to used as a biomarker to indicate and monitor bone break about 2 ng/mL, about 0.2 ng/mL to about 1.5 ng/mL, about down, resorption, and loss. In some embodiments, Zole 0.2 ng/mL to about 0.5 ng/mL, about 0.5 ng/mL to about 1 dronic acid and other bisphosphonates may be used to ng/mL, about 1 ng/mL to about 1.3 ng/mL, about 0.3 ng/mL, inhibit osteoclast activity and/or lower CTX serum levels, about 0.8 ng/mL, about 1.1 ng/mL, or any plasma concen for example, by at least about 5%, at least about 10%, at least tration in a range bounded by, or between, any of these about 15%, at least about 20%, at least about 25%, at least values. about 30%, at least about 35%, at least about 40%, at least 0158 An oral dosage form comprising Zoledronic acid about 45%, at least about 50%, at least about 55%, at least having a dose of Zoledronic acid and a configuration Suitable about 60%, at least about 70%, at least about 75%, at least for a particular species of mammal may be configured so that about 80%, at least about 85%, at least about 90%, at least the particular species of mammal has a plasma concentration about 95%, at least about 99%, at least about 100%, about of Zoledronic acid at 48 hours that is about 0.1 ng/mL to 60%–70%, about 70%–80%, about 80%-90%, about about 2 ng/mL, about 0.2 ng/mL to about 1.5 ng/mL, about 85-95%, about 80%-85%, about 85%-90%, about 90%- 0.2 ng/mL to about 0.5 ng/mL, about 0.5 ng/mL to about 0.9 95%, or any other reduction in osteoclast activity or CTX ng/mL, about 0.9 ng/mL to about 1.3 ng/mL, about 0.3 serum levels in a range bounded by, or between, any of these ng/mL, about 0.7 ng/mL, about 1.1 ng/mL, or any plasma values. concentration in a range bounded by, or between, any of (0164. In some embodiments, Zoledronic acid in a diso these values. dium salt or an acid form and other bisphosphonates includ 0159. An oral dosage form comprising Zoledronic acid ing salt or acid form may be used to treat Paget’s disease of having a dose of Zoledronic acid and a configuration Suitable Bone or treat pain associated with Paget’s disease of bone for a particular species of mammal may be configured so that and/or lower serum alkaline phosphatase (ALP) levels. For the particular species of mammal has a plasma concentration example, the reduction of ALP levels by at least about 20%, of Zoledronic acid at 72 hours that is about 0.2 ng/mL to at least about 40%, at least about 50%, at least about 60%, about 1 ng/mL, about 0.2 ng/mL to about 1.5 ng/mL, about at least about 80%, about 50-60%, about 60-80%, about 0.1 ng/mL to about 0.3 ng/mL, about 0.3 ng/mL to about 0.6 80-90%, about 90-95%, or any other reduction in ALP levels ng/mL, about 0.6 ng/mL to about 1 ng/mL, about 0.2 ng/mL, in a range bounded by, or between, any of these values from about 0.5 ng/mL, about 0.9 ng/mL, or any plasma concen baseline, within 12 months, 18 months, or up to at least 5 tration in a range bounded by, or between, any of these years from the time of the last oral administration of values. Zoledronic acid or other bisphosphonates. In some embodi US 2017/01 19801 A1 May 4, 2017

ments, when Zoledronic acid in a disodium salt or an acid Sone Valerate, betamethasone dippropionate, prednicarbate, form, or other bisphosphonate is administered to treat the clobetasone-17-butyrate, clobetasol-17-propionate, fluo Paget’s disease of bone or pain associated with the Paget’s cortilone caproate, fluocortolone pivalate, and fluprednidene disease of bone, the Paget’s disease or the pain associated acetate, hydrocortisone-17-butyrate, 17-aceponate, 17-bute with the Paget’s disease has recurrence rate of less than prate, and prednicarbate. 20%, less than 10%, less than 5%, less than 1%, or does not 0.174 Any effective dose of steroid can be administered return within 12 months, 18 months, or 5 years, or more, to a person. In some embodiment, the dose of a steroid may from the time of the last oral administration of Zoledronic be about 1-500 mg, 5-25 mg, about 1-3 mg, about 2-4 mg. acid, or other bisphosphonates. about 3-5 mg, about 4-6 mg, about 5-7 mg, about 6-8 mg, 0165. In some embodiments, a dosage form comprising a about 7-9 mg, about 8-10 mg, about 10-15 mg, about 10-20 disodium salt of Zoledronic acid is a Solid. mg, about 20-50 mg, about 50-100 mg, about 100-200 mg. 0166 In some embodiments, a dosage form comprising a about 200-300 mg, about 300-400 mg. 400-500 mg 1-20 mg. disodium salt of Zoledronic acid is used to treat an inflam about 10-30 mg, about 20-40 mg, about 30-50 mg, about matory condition. 40-60 mg, about 50-70 mg, about 60-80 mg, about 70-90 0167. In some embodiments, a dosage form comprising a mg, about 80-100 mg, about 90-110 mg, about 100-120 mg. disodium salt of Zoledronic acid is used to treat arthritis. about 110-130 mg, about 120-140 mg, about 130-150 mg. 0168 In some embodiments, a dosage form comprising a about 140-160 mg, about 150-170 mg, about 160-180 mg. disodium salt of Zoledronic acid is used to treat complex about 170-190 mg, about 180-200 mg, about 190-210 mg. regional pain syndrome. about 200-220 mg, about 210-230 mg, about 220-240 mg. 0169. In some embodiments, Zoledronic acid is in a form about 230-250 mg, about 240-260 mg, about 250-270 mg. that has an aqueous solubility, meaning the solubility in about 260-280 mg, about 270-290 mg, about 280-300 mg. water, greater than 1% (w/v), about 5% (w/v) to about 50% about 290-310 mg, about 300-320 mg, about 310-330 mg. (w/v), about 5% (w/v) to about 20% (w/v), about 10% (w/v) about 320-340 mg, about 330-350 mg, about 340-360 mg. to about 15% (w/v), or about 12% (w/v) to about 13% (w/v). about 350-370 mg, about 360-380 mg, about 370-390 mg, 0170 The disodium salt form of Zoledronic acid can be about 380-300 mg, about 390-410 mg, about 400-420 mg. more compressible than the diacid form of Zoledronic acid. about 410-430 mg, about 420-440 mg, about 430-450 mg. This can make it easier for a dosage form to have a desired about 440-460 mg, about 450-470 mg, about 460-480 mg. hardness. It can also make it easier to increase the drug load, about 470-490 mg, about 480-300 mg, about 490-510 mg of so that a smaller tablet can be given for a given dosage the steroid, or any amount in a range bounded by any of strength. In some embodiments, a solid dosage form of these values. Zoledronic acid, Such as the diacid form of Zoledronic acid 0.175. The steroid can be given orally (for example, 7.5 or the disodium salt form of Zoledronic acid, can have a mg of prednisone), by a separate infusion (for example, 7.5 hardness of about 5 kPa to about 20 kPa or about 5 kPa to mg of methyl prednisolone), mixed in with Zoledronic acid about 14 kPa. in the same infusion, or be administered intramuscularly, 0171 Zoledronic acid or another bisphosphonate may be Subcutaneously, by rectal Suppository, by inhalation, or combined with a pharmaceutical carrier selected on the basis injected directly into a joint. of the chosen route of administration and standard pharma 0176 Zoledronic acid or another bisphosphonate may be ceutical practice as described, for example, in Remington's administered to a human patient in a variety of forms Pharmaceutical Sciences, 2005, the disclosure of which is adapted to the chosen route of administration, e.g., orally, hereby incorporated herein by reference, in its entirety. The rectally, or parenterally. Parenteral administration in this relative proportions of active ingredient and carrier may be respect includes, but is not limited to, administration by the determined, for example, by the solubility and chemical following routes: pulmonary, intrathecal, intravenous, intra nature of the compounds, chosen route of administration and muscular, Subcutaneous, intraocular, intrasynovial, transepi standard pharmaceutical practice. thelial including transdermal, Sublingual and buccal; topi 0172 Zoledronic acid or another bisphosphonate may be cally; nasal inhalation via insufflation; and rectal systemic. administered by any means that may result in the contact of the active agent(s) with the desired site or site(s) of action in 0177. The effective amount of Zoledronic acid or another the body of a patient. The compounds may be administered bisphosphonate will vary depending on various factors by any conventional means available for use in conjunction known to the treating physicians, such as the severity of the with pharmaceuticals, either as individual therapeutic agents condition to be treated, route of administration, formulation or in a combination of therapeutic agents. For example, they and dosage forms, physical characteristics of the bisphos may be administered as the sole active agents in a pharma phonate compound used, and age, weight and response of ceutical composition, or they can be used in combination the individual patients. with other therapeutically active ingredients. 0178. In some embodiments, the daily oral dose of 0173. In some embodiments, an osteoclast inhibitor is pamidronate is about 10 mg to about 1,000 mg, about 50 mg co-administered with a steroid. Suitable steroids include, for to about 500 mg, about 100 mg to about 500 mg. or about example, hydrocortisone, hydrocortisone acetate, cortisone 150 mg to about 300 mg. In some embodiments, the par acetate, tiXocortol pivalate, prednisolone, methylpredniso enteral dose of pamidronate is about 5 mg to about 500 mg. lone, prednisone, triamcinolone acetonide, triamcinolone about 5 mg to about 200 mg. or about 10 mg to about 150 alcohol, mometasone, amcinonide, budesonide, desonide, ng. fluocinonide, fluocinolone acetonide, halcinonide, betame 0179. In some embodiments, the daily oral dose of thasone, betamethasone sodium phosphate, dexamethasone, neridronate is about 10 mg to about 1,000 mg, about 50 mg dexamethasone sodium phosphate, fluocortolone, hydrocor to about 500 mg, about 100 mg to about 500 mg. or about tisone-17-Valerate, acleometasone dipropionate, betametha 150 mg to about 300 mg. In some embodiments, the par US 2017/01 19801 A1 May 4, 2017

enteral dose of neridronate is about 5 mg to about 500 mg. bisphosphonate, e.g. Zoledronic acid, minodronic acid, or about 5 mg to about 200 mg. or about 10 mg to about 150 ibandronic acid, may be used. Some solid or liquid oral ng. dosage forms, or units of oral dosage forms (referred to 0180. In some embodiments, the daily oral dose of allen collectively herein as "oral dosage form(s)) may contain dronate is about 0.5 mg to about 200 mg, about 1 mg to about 0.005 mg to about 20 mg, about 0.1 mg to about 10 about 100 mg, about 5 mg to about 100 mg, or about 2 mg mg, about 0.5 mg to about 10 mg, about 0.2 mg to about 5 to about 50 mg. In some embodiments, the parenteral dose mg, about 1 mg to about 500 mg, about 1 mg to about 50 mg. of alendronate is about 1 mg to about 100 mg, about 1 mg about 10 mg to about 250 mg, about 100 mg to about 300 to about 40 mg, or about 2 mg to about 30 mg. mg, about 20 mg to about 200 mg, about 20 mg to about 150 0181. In some embodiments, the daily oral dose of olpad mg, about 30 mg to about 100 mg, about 50 mg to about 200 ronate is about 0.5 mg to about 200 mg, about 1 mg to about mg, about 1 mg to about 1,000 mg, about 10 mg to about 50 100 mg, about 5 mg to about 100 mg. or about 2 mg to about mg, about 40 mg to about 60 mg, about 50 mg to about 60 50 mg. In some embodiments, the parenteral dose of olpad mg, about 55 mg, about 10 mg to about 300 mg, about 10 ronate is about 1 mg to about 100 mg, about 1 mg to about mg to about 150 mg, about 10 mg to about 100 mg, about 40 mg. or about 2 mg to about 30 mg. 40 mg to about 150 mg, about 10 mg to about 600 mg, about 0182. In some embodiments, the daily oral dose of iban 40 mg to about 600 mg, about 40 mg to about 2000 mg. dronate is about 0.25 mg to about 100 mg, about 0.5 mg to about 40 mg to about 800 mg, about 25 mg to about 800 mg. about 50 mg, about 2.5 mg to about 50 mg. or about 1 mg about 30 mg to about 800 mg, about 10 mg to about 500 mg. to about 25 mg. In some embodiments, the parenteral dose about 50 mg to about 150 mg, about 50 mg, about 100 mg. of ibandronate is about 0.5 mg to about 50 mg, about 0.5 mg about 50 mg to about 500 mg, about 150 mg to about 200 to about 20 mg, or about 1 mg to about 15 mg. mg, about 100 mg to about 2000 mg, about 300 mg to about 0183 In some embodiments, the daily oral dose of rise 1500 mg, about 200 mg to about 1000 mg, about 100 mg to dronate is about 0.25 mg to about 100 mg, about 0.5 mg to about 500 mg, about 160 mg, or about 150 mg of Zoledronic about 50 mg, about 2.5 mg to about 50 mg. or about 1 mg acid in an acid form or in a salt form Such as disodium salt to about 25 mg. In some embodiments, the parenteral dose form, or any amount of osteoclast inhibitor in a range of risedronate is about 0.25 mg to about 25 mg, about 0.25 bounded by, or between, any of these values. In some mg to about 10 mg, or about 0.5 mg to about 7.5 mg. embodiments, the oral osteoclast inhibitor is administered 0184. In some embodiments, the daily oral dose of Zole daily, weekly, biweekly, monthly, every two or three months, dronate is about 0.005 mg to about 20 mg, about 0.1 mg to once a year, or twice a year. about 10 mg, about 0.5 mg to about 10 mg. or about 0.2 mg 0189 Some oral dosage forms may contain about 0.005 to about 5 mg. In some embodiments, the parenteral dose of mg to about 20 mg, about 0.1 mg to about 10 mg, about 0.5 Zoledronate is about 0.25 mg to about 25 mg, about 0.25 mg mg to about 10 mg, about 0.2 mg to about 5 mg, about 1 mg to about 10 mg. or about 0.5 mg to about 7.5 mg. to about 500 mg, about 1 mg to about 50 mg, about 10 mg 0185. The dose of pamidronate, neridronate, olpadronate, to about 250 mg, about 100 mg to about 300 mg, about 20 alendronate, ibandronate, risedronate, Zoledronate or mg to about 200 mg, about 20 mg to about 150 mg, about another bisphosphonate compound may be administered in 30 mg to about 100 mg, about 1 mg to about 1,000 mg, about a single or divided dose. 10 mg to about 50 mg, about 40 mg to about 60 mg, about 0186 The amount of Zoledronic acid or another bispho 50 mg to about 60 mg, about 55 mg, about 10 mg to about sphonate in a therapeutic composition may vary. For 300 mg, about 10 mg to about 150 mg, about 10 mg to about example, Some liquid compositions may comprise about 100 mg, about 40 mg to about 150 mg, about 10 mg to about 0.0001% (w/v) to about 50% (w/v), about 0.01% (w/v) to 600 mg, about 40 mg to about 600 mg, about 40 mg to about about 20% (w/v), about 0.01% to about 10% (w/v), about 2000 mg, about 40 mg to about 800 mg, about 25 mg to 0.001% (w/v) to about 1% (w/v), about 0.1% (w/v) to about about 800 mg, about 30 mg to about 800 mg, about 10 mg 0.5% (w/v), about 1% (w/v) to about 3% (w/v), about 3% to about 500 mg, about 50 mg to about 150 mg, about 50 mg. (w/v) to about 5% (w/v), about 5% (w/v) to about 7% (w/v), about 100 mg, about 50 mg to about 200 mg, about 50 mg about 7% (w/v) to about 10% (w/v), about 10% (w/v) to to about 500 mg, about 150 mg to about 200 mg, about 100 about 15% (w/v), about 15% (w/v) to about 20% (w/v), mg to about 2000 mg, about 300 mg to about 1500 mg, about about 20% (w/v) to about 30% (w/v), about 30% (w/v) to 200 mg to about 1000 mg, about 100 mg to about 500 mg. about 40% (w/v), or about 40% (w/v) to about 50% (w/v) of about 160 mg. or about 150 mg of osteoclast inhibitor, or any Zoledronic acid. amount of osteoclast inhibitor in a range bounded by, or 0187. Some solid compositions may comprise at least between, any of these values. In some embodiments, the oral about 5% (w/w), at least about 10% (w/w), at least about osteoclast inhibitor is administered daily, weekly, bi-weekly, 20% (w/w), at least about 50% (w/w), at least about 70% monthly, every two or three months, once a year, or twice a (w/w), at least about 80%, about 10% (w/w) to about 30% year. (w/w), about 10% (w/w) to about 20% (w/w), about 20% 0190. Any suitable amount of an osteoclast inhibitor, (w/w) to about 30% (w/w), about 30% (w/w) to about 50% including a bisphosphonate, such as a nitrogen-containing (w/w), about 30% (w/w) to about 40% (w/w), about 40% bisphosphonate, e.g. Zoledronic acid, neridronate (w/w) to about 50% (w/w), about 50% (w/w) to about 80% (neridronic acid), pamidronate, olpadronate, alendronate, (w/w), about 50% (w/w) to about 60% (w/w), about 70% risedronate, minodronic acid, or ibandronic acid, may be (w/w) to about 75% (w/w), about 70% (w/w) to about 80% used. Some solid or liquid dosage forms, or units of dosage (w/w), or about 80% (w/w) to about 90% (w/w) of Zole forms may contain about 0.005 mg to about 20 mg, about 0.1 dronic acid. mg to about 10 mg, about 0.5 mg to about 10 mg, about 0.2 0188 Any suitable amount of an osteoclast inhibitor, mg to about 5 mg, about 1 mg to about 500 mg, about 1 mg including a bisphosphonate, such as a nitrogen-containing to about 50 mg, about 10 mg to about 250 mg, about 100 mg US 2017/01 19801 A1 May 4, 2017

to about 300 mg, about 20 mg to about 200 mg, about 20 mg a range bounded by, or between, any of these values. In some to about 150 mg, about 30 mg to about 100 mg, about 50 mg embodiments, the daily oral dose of osteoclast inhibitor is to about 200 mg, about 1 mg to about 1,000 mg, about 10 less than about 35 mg/m, less than about 30 mg/m, less mg to about 50 mg, about 40 mg to about 60 mg, about 50 than about 25 mg/m, about 1 mg/m to about 35 mg/m. mg to about 60 mg, about 55 mg, about 10 mg to about 300 about 1 mg/m to about 30 mg/m, about 1.5 mg/m to about mg, about 10 mg to about 150 mg, about 10 mg to about 100 25 mg/m, about 1.8 mg/m to about 20 mg/m, about 10 mg, about 40 mg to about 150 mg, about 10 mg to about 600 mg/m to about 20 mg/m, about 10 mg/m to about 30 mg, about 40 mg to about 600 mg, about 40 mg to about mg/m, about 15 mg/m to about 20 mg/m, about 18 2000 mg, about 40 mg to about 800 mg, about 25 mg to mg/m, or any amount of Zoledronic acid in a rangebounded about 800 mg, about 30 mg to about 800 mg, about 10 mg by, or between, any of these values. to about 500 mg, about 50 mg to about 150 mg, about 50 mg. 0194 In some embodiments, the daily oral dose of an about 100 mg, about 50 mg to about 500 mg, about 150 mg osteoclast inhibitor, including a bisphosphonate. Such as a to about 200 mg, about 100 mg to about 2000 mg, about 300 nitrogen-containing bisphosphonate, e.g. Zoledronic acid, mg to about 1500 mg, about 200 mg to about 1000 mg, about minodronic acid, or ibandronic acid, is about 0.005 mg to 100 mg to about 500 mg, about 160 mg, or about 150 mg of about 20 mg, about 0.1 mg to about 10 mg, about 0.5 mg to Zoledronic acid in an acid form or in a salt form Such as about 10 mg, about 0.2 mg to about 5 mg. or any amount of disodium salt form, or any amount of osteoclast inhibitor in osteoclast inhibitor in a range bounded by, or between, any a range bounded by, or between, any of these values. In some of these values. In some embodiments, the daily oral dose of embodiments, the oral or IV osteoclast inhibitor is admin osteoclast inhibitor is less than about 35 mg/m, less than istered daily, every other day, every third day, weekly, about 30 mg/m, less than about 25 mg/m, about 1 mg/m biweekly, monthly, every two or three months, every six to about 35 mg/m, about 1 mg/m to about 30 mg/m, about months, once a year, or twice a year from day 1. 1.5 mg/m to about 25 mg/m, about 1.8 mg/m to about 20 0191 Some dosage forms may contain about 0.005 mg to mg/m, about 10 mg/m to about 20 mg/m, about 10 mg/m about 20 mg, about 0.1 mg to about 10 mg, about 0.5 mg to to about 30 mg/m, about 15 mg/m to about 20 mg/m. about 10 mg, about 0.2 mg to about 5 mg, about 1 mg to about 18 mg/m, or any amount of osteoclast inhibitor in a about 500 mg, about 1 mg to about 50 mg, about 10 mg to range bounded by, or between, any of these values. about 250 mg, about 100 mg to about 300 mg, about 20 mg 0.195. In some embodiments the daily oral dose of Zole to about 200 mg, about 20 mg to about 150 mg, about 30 mg dronic acid is about 0.005 mg to about 20 mg, about 0.1 mg to about 100 mg, about 1 mg to about 1,000 mg, about 10 to about 10 mg, about 0.5 mg to about 10 mg, about 0.2 mg mg to about 50 mg, about 40 mg to about 60 mg, about 50 to about 5 mg, or any amount of Zoledronic acid in a range mg to about 65 mg, about 65 mg to about 70 mg, about 50 bounded by, or between, any of these values. In some mg to about 60 mg, about 55 mg, about 10 mg to about 300 embodiments, the daily oral dose of Zoledronic acid is less mg, about 10 mg to about 150 mg, about 10 mg to about 100 than about 35 mg/m, less than about 30 mg/m, less than mg, about 40 mg to about 150 mg, about 10 mg to about 600 about 25 mg/m, about 1 mg/m to about 35 mg/m, about mg, about 40 mg to about 600 mg, about 100 mg to about 1 mg/m to about 30 mg/m, about 1.5 mg/m to about 25 600 mg, about 40 mg to about 2000 mg, about 40 mg to mg/m, about 1.8 mg/m to about 20 mg/m, about 10 about 800 mg, about 25 mg to about 800 mg, about 30 mg mg/m to about 20 mg/m, about 10 mg/m to about 30 to about 800 mg, about 10 mg to about 500 mg, about 50 mg mg/m, about 15 mg/m to about 20 mg/m, about 18 to about 150 mg, about 50 mg, about 100 mg, about 50 mg mg/m, or any amount of Zoledronic acid in a range bounded to about 200 mg, about 50 mg to about 500 mg, about 150 by, or between, any of these values. mg to about 200 mg, about 100 mg to about 2000 mg, about 0196. In some embodiments, the weekly oral dose of the 300 mg to about 1500 mg, about 200 mg to about 1000 mg. osteoclast inhibitor, including a bisphosphonate. Such as a about 100 mg to about 500 mg, about 160 mg. or about 150 nitrogen-containing bisphosphonate, e.g. Zoledronic acid, mg of osteoclast inhibitor, or any amount of osteoclast minodronic acid, ibandronic acid, is about 1 mg to about inhibitor in a range bounded by, or between, any of these 1000 mg, about 1 mg to about 500 mg, about 10 mg to about values. In some embodiments, the oral or IV osteoclast 250 mg, about 100 mg to about 300 mg, about 10 mg to inhibitor is administered daily, every other day, every third about 100 mg, about 10 mg to about 150 mg, about 10 mg day, weekly, bi-weekly, monthly, every two or three months, to about 100 mg, about 10 mg to about 300 mg, about 20 mg every 6 months, once a year, or twice a year from day 1. to about 150 mg, about 20 mg to about 60 mg, about 30 mg 0.192 In some embodiments, an oral dosage form may to about 70 mg, about 40 mg to about 60 mg, about 50 mg contain about 10 mg/m to about 20 mg/m, about 15 mg/m to about 70 mg, about 50 mg, about 55 mg, about 100 mg to about 20 mg/m, about 18 mg/m, about 80 mg/m to to about 150 mg. or about 30 mg to about 100 mg. In some about 150 mg/m, about 90 mg/m to about 150 mg/m. embodiments, the weekly oral dose of the osteoclast inhibi about 100 mg/m to about 150 mg/m of zoledronic acid, or tor is less than about 250 mg/m, less than about 200 mg/m. any amount of Zoledronic in a range bounded by, or between, less than about 175 mg/m, about 6 mg/m to about 250 any of these values. All dosage ranges or amounts expressed mg/m, about 10 mg/m to about 210 mg/m, about 10 in mg/m are based upon the body surface area of the mg/m to about 170 mg/m, about 4 mg/m to about 140 mammal. mg/m, about 100 mg/m to about 140 mg/m, about 126 0193 In some embodiments, the daily oral dose of an mg/m, or any amount in a range bounded by, or between, osteoclast inhibitor, including a bisphosphonate, such as a any of these values. The weekly oral dose may be given as nitrogen-containing bisphosphonate, e.g. Zoledronic acid, a single dose, given once during the week, or may be given minodronic acid, or ibandronic acid, is about 0.005 mg to in 2, 3, 4, 5, 6, or 7 individual doses during the week. about 20 mg, about 0.1 mg to about 10 mg, about 0.5 mg to 0.197 In some embodiments the weekly oral dose of about 10 mg, about 0.2 mg to about 5 mg, or any amount in Zoledronic acid is about 1 mg to about 1000 mg, about 1 mg US 2017/01 19801 A1 May 4, 2017

to about 500 mg, about 10 mg to about 250 mg, about 100 mg or less, about 1000 mg or less, about 700 mg or less, mg to about 300 mg, about 10 mg to about 100 mg, about about 600 mg or less, about 1 mg to about 4,000 mg, about 10 mg to about 150 mg, about 10 mg to about 100 mg, about 1 mg to about 1,000 mg, about 10 mg to about 1000 mg. 10 mg to about 300 mg, about 20 mg to about 150 mg, about about 50 mg to about 1000 mg, about 10 mg to about 600 20 mg to about 60 mg, about 30 mg to about 70 mg, about mg, about 40 mg to about 600 mg, about 50 mg to about 600 40 mg to about 60 mg, about 50 mg to about 70 mg, about mg, about 40 mg to about 400 mg, about 50 mg to about 200 50 mg, about 55 mg, about 100 mg to about 150 mg. or about mg, about 200 mg to about 300 mg, about 250 mg to about 30 mg to about 100 mg. In some embodiments, the weekly 350 mg, or about 100 mg to about 600 mg, about 40 mg to oral dose of Zoledronic acid is less than about 250 mg/m. about 2000 mg, about 40 mg to about 800 mg, about 50 mg less than about 200 mg/m, less than about 175 mg/m. to about 800 mg. or about 100 mg to about 800 mg, about about 6 mg/m to about 250 mg/m, about 10 mg/m to about 40 mg to about 1000 mg, about 50 mg to about 1000 mg. or 210 mg/m, about 10 mg/m to about 170 mg/m, about 4 about 100 mg to about 1000 mg. or any monthly dose in a mg/m to about 140 mg/m, about 100 mg/m to about 140 range bounded by, or between, any of these values. In some mg/m, about 126 mg/m, or any amount of Zoledronic acid embodiments, the monthly oral dose of Zoledronic acid is in a range bounded by, or between, any of these values. The less than about 1000 mg/m, less than about 800 mg/m, less weekly oral dose may be given as a single dose, given once than about 600 mg/m, about 10 mg/m to about 1000 during the week, or may be given in 2, 3, 4, 5, 6, or 7 mg/m, about 50 mg/m to about 800 mg/m, about 70 individual doses during the week. mg/m to about 700 mg/m, about 100 mg/m to about 700 0198 In some embodiments, the monthly dose of the mg/m, about 100 mg/m to about 600 mg/m, about 50 osteoclast inhibitor, including a bisphosphonate, such as a mg/m to about 200 mg/m, about 300 mg/m to about 600 nitrogen-containing bisphosphonate, e.g. Zoledronic acid, mg/m, about 450 mg/m to about 600 mg/m, about 300 minodronic acid, or ibandronic acid, or the amount of the mg/m to about 1000 mg/m, about 400 mg/m to about osteoclast inhibitor that is administered over a period of a 1000 mg/m, about 500 mg/m to about 1000 mg/m, about month, is about 5000 mg or less, about 4000 mg or less, 400 mg/m to about 700 mg/m, about 500 mg/m to about about 3000 mg or less, about 2000 mg or less, about 1000 600 mg/m, about 540 mg/m, or any amount of Zoledronic mg or less, about 700 mg or less, about 600 mg or less, about acid in a range bounded by, or between, any of these values. 1 mg to about 4,000 mg, about 1 mg to about 1,000 mg. A monthly dose may be given as a single dose, or as two or about 10 mg to about 1000 mg, about 50 mg to about 1000 more individual doses administered during the month. In mg, about 10 mg to about 600 mg, about 40 mg to about 600 some embodiments, the monthly dose is administered in 2 or mg, about 50 mg to about 600 mg, about 40 mg to about 400 3 weekly doses. In some embodiments, the monthly dose is mg, about 50 mg to about 200 mg, about 200 mg to about administered in 4 or 5 weekly doses. In some embodiments, 300 mg, about 250 mg to about 350 mg. or about 100 mg to the monthly dose is administered in 28 to 31 daily doses. In about 600 mg, about 40 mg to about 2000 mg, about 40 mg Some embodiments, the monthly dose is administered in 5 to to about 800 mg, about 50 mg to about 800 mg. or about 100 10 individual doses during the month. The monthly dose mg to about 800 mg, about 40 mg to about 1000 mg, about may be administered for only 1 month, or may be repeatedly 50 mg to about 1000 mg. or about 100 mg to about 1000 mg. administered for 2 or more months. or any monthly dose in a range bounded by, or between, any 0200. With respect to orally administering Zoledronic of these values. In some embodiments, the monthly oral acid to a mammal. Such as a dog, a rat, a rabbit, a monkey, dose of the osteoclast inhibitor is less than about 1000 an ape, or a human being, doses of about 0.03 mg/kg to mg/m, less than about 800 mg/m, less than about 600 about 10 mg/kg, or any Smaller range within this range. Such mg/m, about 10 mg/m to about 1000 mg/m, about 50 as about 0.4 mg/kg to about 3 mg/kg, about 0.4 mg/kg to mg/m to about 800 mg/m, about 70 mg/m to about 700 about 1.5 mg/kg, mg/kg, about 0.4 mg/kg to about 0.5 mg/m, about 100 mg/m to about 700 mg/m, about 100 mg/kg, about 0.5 mg/kg to about 0.6 mg/kg, about 0.6 mg/kg mg/m to about 600 mg/m, about 50 mg/m to about 200 to about 0.7 mg/kg, about 0.7 mg/kg to about 0.8 mg/kg, mg/m, about 300 mg/m to about 600 mg/m, about 450 about 0.8 mg/kg to about 0.9 mg/kg, about 0.9 mg/kg to mg/m to about 600 mg/m, about 300 mg/m to about 1000 about 1 mg/kg, about 1 mg/kg to about 1.1 mg/kg, about 1.1 mg/m, about 400 mg/m to about 1000 mg/m, about 500 mg/kg to about 1.2 mg/kg, about 1.2 mg/kg to about 1.3 mg/m to about 1000 mg/m, about 400 mg/m to about 700 mg/kg, about 1.3 mg/kg to about 1.4 mg/kg, about 1.4 mg/kg mg/m, about 500 mg/m to about 600 mg/m, about 540 to about 1.5 mg/kg, about 1.5 mg/kg to about 1.6 mg/kg, mg/m, or any amount in a range bounded by, or between, about 1.6 mg/kg to about 1.7 mg/kg, about 1.7 mg/kg to any of these values. A monthly dose may be given as a single about 1.8 mg/kg, about 1.8 mg/kg to about 1.9 mg/kg, about dose, or as two or more individual doses administered during 1.9 mg/kg to about 2 mg/kg, about 2 mg/kg to about 2.1 the month. In some embodiments, the monthly dose is mg/kg, about 2.1 mg/kg to about 2.2 mg/kg, about 2.2 mg/kg administered in 2 or 3 weekly doses. In some embodiments, to about 2.3 mg/kg, about 2.3 mg/kg to about 2.4 mg/kg, the monthly dose is administered in 4 or 5 weekly doses. In about 2.4 mg/kg to about 2.5 mg/kg, about 2.5 mg/kg to some embodiments, the monthly dose is administered in 28 about 2.6 mg/kg, about 2.6 mg/kg to about 2.7 mg/kg, about to 31 daily doses. In some embodiments, the monthly dose 2.7 mg/kg to about 2.8 mg/kg, about 2.8 mg/kg to about 2.9 is administered in 5 to 10 individual doses during the month. mg/kg, about 2.9 mg/kg to about 3 mg/kg, about 3 mg/kg to The monthly dose may be administered for only 1 month, or about 3.1 mg/kg, about 3.1 mg/kg to about 3.2 mg/kg, about may be repeatedly administered for 2 or more months. 3.2 mg/kg to about 3.3 mg/kg, about 3.3 mg/kg to about 3.4 0199. In some embodiments, the monthly dose of Zole mg/kg, about 3.4 mg/kg to about 3.5 mg/kg, about 3.5 mg/kg dronic acid, or the amount of Zoledronic acid that is admin to about 3.6 mg/kg, about 3.6 mg/kg to about 3.7 mg/kg, istered over a period of a month, is about 5000 mg or less, about 3.7 mg/kg to about 3.8 mg/kg, about 3.8 mg/kg to about 4000 mg or less, about 3000 mg or less, about 2000 about 3.9 mg/kg, about 3.9 mg/kg to about 4 mg/kg, about US 2017/01 19801 A1 May 4, 2017 20

0.4 mg/kg to about 0.6 mg/kg, about 0.6 mg/kg to about 0.8 mg/kg to about 0.2 mg/kg, about 0.05 mg/kg to about 0.15 mg/kg, about 0.8 mg/kg to about 1 mg/kg, about 1 mg/kg to mg/kg, about 0.06 mg/kg to about 0.15 mg/kg, about 0.07 about 1.2 mg/kg, about 1.2 mg/kg to about 1.4 mg/kg, about mg/kg to about 0.15 mg/kg, about 0.08 mg/kg to about 0.15 1.4 mg/kg to about 1.6 mg/kg, about 1.6 mg/kg to about 1.8 mg/kg, about 0.09 mg/kg to about 0.15 mg/kg, about 0.1 mg/kg, about 1.8 mg/kg to about 2 mg/kg, about 2 mg/kg to mg/kg to about 0.15 mg/kg, about 0.03 mg/kg to about 0.5 about 2.2 mg/kg, about 2.2 mg/kg to about 2.4 mg/kg, about mg/kg, about 0.06 mg/kg to about 0.2 mg/kg, about 0.07 2.4 mg/kg to about 2.6 mg/kg, about 2.6 mg/kg to about 2.8 mg/kg to about 0.2 mg/kg, about 0.08 mg/kg to about 0.2 mg/kg, about 2.8 mg/kg to about 3 mg/kg, about 3 mg/kg to mg/kg, about 0.09 mg/kg to about 0.2 mg/kg, about 0.1 about 3.2 mg/kg, about 3.2 mg/kg to about 3.4 mg/kg, about mg/kg to about 0.2 mg/kg, about 0.4 mg to about 4 mg. 3.4 mg/kg to about 3.6 mg/kg, about 3.6 mg/kg to about 3.8 about 0.4 mg/kg to about 0.6 mg/kg, about 0.6 mg/kg to mg/kg, about 3.8 mg/kg to about 4 mg/kg, about 0.4 mg/kg about 0.8 mg/kg, about 0.8 mg/kg to about 1 mg/kg, about to about 0.7 mg/kg, about 0.7 mg/kg to about 1 mg/kg, about 1 mg/kg to about 1.2 mg/kg, about 1.2 mg/kg to about 1.4 1 mg/kg to about 1.3 mg/kg, about 1.3 mg/kg to about 1.6 mg/kg, about 1.4 mg/kg to about 1.6 mg/kg, about 1.6 mg/kg mg/kg, about 1.6 mg/kg to about 1.9 mg/kg, about 1.9 mg/kg to about 1.8 mg/kg, about 1.8 mg/kg to about 2 mg/kg, about to about 2.2 mg/kg, about 2.2 mg/kg to about 2.5 mg/kg, 2 mg/kg to about 2.2 mg/kg, about 2.2 mg/kg to about 2.4 about 2.5 mg/kg to about 2.8 mg/kg, about 2.8 mg/kg to mg/kg, about 2.4 mg/kg to about 2.6 mg/kg, about 2.6 mg/kg about 3 mg/kg, about 3.3 mg/kg to about 3.6 mg/kg, about to about 2.8 mg/kg, about 2.8 mg/kg to about 3 mg/kg, about 3.6 mg/kg to about 4 mg/kg, about 0.4 mg/kg to about 1 3 mg/kg to about 3.2 mg/kg, about 3.2 mg/kg to about 3.4 mg/kg, or about 0.5 mg/kg to about 1 mg/kg, may be a safe mg/kg, about 3.4 mg/kg to about 3.6 mg/kg, about 3.6 mg/kg dose for repeated oral administration, such as once daily to about 3.8 mg/kg, about 3.8 mg/kg to about 4 mg/kg, about dosing to once yearly dosing, once daily dosing to twice 0.5 mg/kg to about 2 mg/kg, about 0.6 mg/kg to about 2 yearly dosing, once daily dosing to thrice yearly dosing, mg/kg, about 0.7 mg/kg to about 2 mg/kg, about 0.8 mg/kg once daily dosing to dosing every three months, once daily to about 2 mg/kg, about 0.5 mg/kg to about 1.5 mg/kg, about dosing to dosing every two months, once daily dosing to 0.6 mg/kg to about 1.5 mg/kg, about 0.7 mg/kg to about 1.5 dosing every two months, once daily dosing to dosing every mg/kg, about 0.8 mg/kg to about 1.5 mg/kg, about 0.5 mg/kg month, once daily dosing to dosing every 2-4 weeks, once to about 0.9 mg/kg, about 0.6 mg/kg to about 0.9 mg/kg, daily dosing to once weekly dosing, etc. about 0.7 mg/kg to about 0.9 mg/kg, about 0.5 mg/kg to 0201 The doses referred to in the paragraph above for about 1 mg/kg, about 0.6 mg/kg to about 1 mg/kg, about 0.7 administration of Zoledronic acid to a mammal may be mg/kg to about 1 mg/kg, about 0.8 mg/kg to about 1 mg/kg, safely administered 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or about 0.8 mg/kg to about 0.9 mg/kg. or 15 times, or about 3 to about 10 times, once a day, or less 0203 For once weekly or less frequent oral administra frequently, such as once week, once every two weeks, once tion of Zoledronic acid to a mammal such as a mouse, rat, a month, etc. dog, primate, or a human being, in some embodiments, a 0202 For once daily to once weekly oral administration safely repeated dose may be about 0.4 mg to about 10 mg. of Zoledronic acid to a mammal such as a mouse, rat, dog, or any Smaller range within this range, such as about 0.4 primate, or a human being, in Some embodiments, a safely mg/kg to about 0.6 mg/kg, about 0.6 mg/kg to about 0.8 repeated dose may be about 0.03 mg/kg to about 4 mg/kg, mg/kg, about 0.8 mg/kg to about 1 mg/kg, about 1 mg/kg to or any Smaller range within this range, such as about 0.01 about 1.2 mg/kg, about 1.2 mg/kg to about 1.4 mg/kg, about mg/kg to about 0.02 mg/kg, about 0.02 mg/kg to about 0.03 1.4 mg/kg to about 1.6 mg/kg, about 1.6 mg/kg to about 1.8 mg/kg, about 0.03 mg/kg to about 0.04 mg/kg, about 0.04 mg/kg, about 1.8 mg/kg to about 2 mg/kg, about 2 mg/kg to mg/kg to about 0.05 mg/kg, about 0.05 mg/kg to about 0.06 about 2.2 mg/kg, about 2.2 mg/kg to about 2.4 mg/kg, about mg/kg, about 0.06 mg/kg to about 0.07 mg/kg, about 0.07 2.4 mg/kg to about 2.6 mg/kg, about 2.6 mg/kg to about 2.8 mg/kg to about 0.08 mg/kg, about 0.08 mg/kg to about 0.09 mg/kg, about 2.8 mg/kg to about 3 mg/kg, about 3 mg/kg to mg/kg, about 0.09 mg/kg to about 0.1 mg/kg, about 0.1 about 3.2 mg/kg, about 3.2 mg/kg to about 3.4 mg/kg, about mg/kg to about 0.11 mg/kg, about 0.11 mg/kg to about 0.12 3.4 mg/kg to about 3.6 mg/kg, about 3.6 mg/kg to about 3.8 mg/kg, about 0.12 mg/kg to about 0.13 mg/kg, about 0.13 mg/kg, about 3.8 mg/kg to about 4 mg/kg, about 4 mg/kg to mg/kg to about 0.14 mg/kg, about 0.14 mg/kg to about 0.15 about 4.2 mg/kg, about 4.2 mg/kg to about 4.4 mg/kg, about mg/kg, about 0.15 mg/kg to about 0.16 mg/kg, about 0.16 4.4 mg/kg to about 4.6 mg/kg, about 4.6 mg/kg to about 4.8 mg/kg to about 0.17 mg/kg, about 0.17 mg/kg to about 0.18 mg/kg, about 4.8 mg/kg to about 5 mg/kg, about 5 mg/kg to mg/kg, about 0.18 mg/kg to about 0.19 mg/kg, about 0.19 about 5.2 mg/kg, about 5.2 mg/kg to about 5.4 mg/kg, about mg/kg to about 0.2 mg/kg, about 0.2 mg/kg to about 0.21 5.4 mg/kg to about 5.6 mg/kg, about 5.6 mg/kg to about 5.8 mg/kg, about 0.21 mg/kg to about 0.22 mg/kg, about 0.22 mg/kg, about 5.8 mg/kg to about 6 mg/kg, about 6 mg/kg to mg/kg to about 0.23 mg/kg, about 0.23 mg/kg to about 0.24 about 6.2 mg/kg, about 6.2 mg/kg to about 6.4 mg/kg, about mg/kg, about 0.24 mg/kg to about 0.25 mg/kg, about 0.25 6.4 mg/kg to about 6.6 mg/kg, about 6.6 mg/kg to about 6.8 mg/kg to about 0.26 mg/kg, about 0.26 mg/kg to about 0.27 mg/kg, about 6.8 mg/kg to about 7 mg/kg, about 7 mg/kg to mg/kg, about 0.27 mg/kg to about 0.28 mg/kg, about 0.28 about 7.2 mg/kg, about 7.2 mg/kg to about 7.4 mg/kg, about mg/kg to about 0.29 mg/kg, about 0.29 mg/kg to about 0.3 7.4 mg/kg to about 7.6 mg/kg, about 7.6 mg/kg to about 7.8 mg/kg, about 0.3 mg/kg to about 0.31 mg/kg, about 0.31 mg/kg, about 7.8 mg/kg to about 8 mg/kg, about 8 mg/kg to mg/kg to about 0.32 mg/kg, about 0.32 mg/kg to about 0.33 about 8.2 mg/kg, about 8.2 mg/kg to about 8.4 mg/kg, about mg/kg, about 0.33 mg/kg to about 0.34 mg/kg, about 0.34 8.4 mg/kg to about 8.6 mg/kg, about 8.6 mg/kg to about 8.8 mg/kg to about 0.35 mg/kg, about 0.35 mg/kg to about 0.36 mg/kg, about 8.8 mg/kg to about 9 mg/kg, about 9 mg/kg to mg/kg, about 0.36 mg/kg to about 0.37 mg/kg, about 0.37 about 9.2 mg/kg, about 9.2 mg/kg to about 9.4 mg/kg, about mg/kg to about 0.38 mg/kg, about 0.38 mg/kg to about 0.39 9.4 mg/kg to about 9.6 mg/kg, about 9.6 mg/kg to about 9.8 mg/kg, about 0.39 mg/kg to about 0.4 mg/kg, about 0.05 mg/kg, about 9.8 mg/kg to about 10 mg/kg, about 0.5 mg/kg US 2017/01 19801 A1 May 4, 2017

to about 2 mg/kg, about 0.6 mg/kg to about 2 mg/kg, about 0.2% to about 2%, about 0.2% to about 1.5%, about 0.3% to 0.7 mg/kg to about 2 mg/kg, about 0.8 mg/kg to about 2 about 1.5%, about 0.3% to about 1%, about 1% to about 3%, mg/kg, about 0.5 mg/kg to about 1.5 mg/kg, about 0.6 mg/kg about 1.2% to about 3.5%, about 1.2% to about 3%, about to about 1.5 mg/kg, about 0.7 mg/kg to about 1.5 mg/kg, 1% to about 4%, about 1.5% to about 4.5%, about 0.1% to about 0.8 mg/kg to about 1.5 mg/kg, about 0.5 mg/kg to about 0.5%, about 0.3% to about 0.5%, about 0.5% to about about 1 mg/kg, about 0.6 mg/kg to about 1 mg/kg, about 0.7 1%, about 0.6% to about 0.7%, about 0.7% to about 0.8%, mg/kg to about 1 mg/kg, about 0.8 mg/kg to about 1 mg/kg, about 0.8% to about 0.9%, about 0.9%, about 1% to about or about 0.8 mg/kg to about 0.9 mg/kg, 1.1%, about 1.1% to about 1.2%, about 1.2% to about 1.3%, 0204. In some embodiments, the osteoclast inhibitor about 1.3% to about 1.4%, about 1.4% to about 1.5%, about comprises Zoledronic acid, and the oral Zoledronic acid, or 1.5% to about 1.6%, about 1.6% to about 1.8%, about 1.8% disodium salt thereof, may be administered in combination to about 2%, about 2% to about 2.2%, about 2.2% to about with about 0.1 mg to about 10 mg of Zoledronic acid, or a 2.4%, about 2.4% to about 2.6%, about 2.6% to about 2.8%, salt thereof, administered parenterally, Such as intrave about 2.8% to about 3.0%, about 3% to about 3.2%, about nously. In some embodiments, about 50 mg, about 100 mg. 3.2% to about 3.4%, about 3.4% to about 3.6%, about 3.6% or about 150 mg of the disodium salt of Zoledronic acid is to about 3.8%, about 3.8% to about 4%, about 2% to about administered orally in combination with 1 mg parenteral, 2.5%, or any bioavailability of Zoledronic acid in a range Such as intravenous, Zoledronic acid. In some embodiments bounded by, or between, any of these values. the parenteral dose of Zoledronic acid is about 0.25 mg to 0207. One embodiment is a pharmaceutical composition about 25 mg, about 0.25 mg to about 10 mg. or about 0.5 mg comprising an osteoclast inhibitor Such as Zoledronic acid, to about 7.5 mg. minodronic acid, or ibandronic acid wherein the oral bio 0205 With respect to oral administration of an osteoclast availability of Zoledronic acid in the dosage form is from inhibitor, Such as Zoledronic acid, minodronic acid, iban about 0.01% to about 10%. dronic acid, or another bisphosphonate, for the treatment of 0208. In some embodiments, the oral bioavailability of pain associated with inflammation, arthritis, CRPS, or any the osteoclast inhibitor in the dosage form is about 0.01% to other condition recited herein, it may helpful if the mammal about 5%, about 0.1% to about 7%, about 0.1% to about 5%, or human being to which the osteoclast inhibitor is admin about 0.1% to about 3%, about 0.1% to about 2%, about istered does not eat food or drink beverage, (other than any 0.2% to about 2%, about 0.2% to about 1.5%, about 0.3% to water required to swallow the oral dosage form) for at least about 1.5%, or about 0.3% to about 1.0%. about 1 hour, at least about 2 hours, at least about 4 hours, 0209. In some embodiments, the oral bioavailability of at least about 6 hours, at least about 8 hours, at least about Zoledronic acid in the dosage form is about 0.01% to about 10 hours, or at least about 12 hours before the osteoclast 5%. inhibitor is administered. It may also be helpful if the 0210. In some embodiments, the oral bioavailability of mammal or human being to which the osteoclast inhibitor is Zoledronic acid in the dosage form is about 0.1% to about administered does not eat food or drink beverage for at least 7%. about 30 minutes, at least about 1 hour, at least about 2 0211. In some embodiments, the oral bioavailability of hours, at least about 3 hours, or at least about 4 hours after Zoledronic acid in the dosage form is about 0.1% to about the osteoclast inhibitor is administered. In some embodi 5%. ments, a human being to which the Zoledronic acid is 0212. In some embodiments, the oral bioavailability of administered avoids lying down, or remains upright or sits Zoledronic acid in the dosage form is about 0.1% to about upright, for at least about 30 minutes or about 1 hour after 3%. receiving a dosage form containing the osteoclast inhibitor. 0213. In some embodiments, the oral bioavailability of Avoiding food or beverage before or after oral administra Zoledronic acid in the dosage form is about 0.1% to about tion of the osteoclast inhibitor can improve the bioavailabil 2%. ity of the osteoclast inhibitor. 0214. In some embodiments, the oral bioavailability of 0206. The oral bioavailability of osteoclast inhibitor in a Zoledronic acid in the dosage form is about 0.2% to about dosage form can vary. Some dosage forms may have ingre 2%. dients added to enhance the bioavailability. However, bio availability enhancement is not necessary for an oral dosage 0215. In some embodiments, the oral bioavailability of form to be effective. In some embodiments, the dosage form Zoledronic acid in the dosage form is about 0.2% to about is Substantially free of bioavailability-enhancing agents, 1.5%. Such as amino acids or large quantities (e.g. at least about 0216. In some embodiments, the oral bioavailability of 5%, 10%, 20%, 50%, 70%, or more) of carboxylic acid salts. Zoledronic acid in the dosage form is about 0.3% to about In some embodiments, an oral dosage form may have an oral 1.5%. bioavailability of the osteoclast inhibitor—such as Zole 0217. In some embodiments, the oral bioavailability of dronic acid, minodronic acid, ibandronic acid—of about Zoledronic acid in the dosage form is about 0.3% to about 0.01% to about 10%, about 0.1% to about 7%, about 0.1% 1.0%. to about 5%, etc. Without ingredients or other methods to 0218. In some embodiments, an oral dosage form com enhance bioavailability, bisphosphonates Such as Zoledronic prises about 10 mg to about 300 mg of Zoledronic acid, acid typically have a low bioavailability in an oral dosage minodronic acid, or ibandronic acid and is administered form. In some embodiments, the oral bioavailability of daily for about 2 to about 15 consecutive days. This regimen Zoledronic acid is unenhanced or Substantially unenhanced. may be repeated once monthly, once every two months, once For example, the oral bioavailability of Zoledronic acid can every three months, once every four months, once every five be about 0.01% to about 5%, about 0.01% to about 4%, months, once every six months, once yearly, or once every about 0.1% to about 3%, about 0.1% to about 2%, about two years. US 2017/01 19801 A1 May 4, 2017 22

0219. In some embodiments, an oral dosage form com 0225. In some embodiments, an osteoclast inhibitor, prises about 10 mg to about 150 mg or about 10 mg to about including a bisphosphonate, such as Zoledronic acid, 100 mg of Zoledronic acid, minodronic acid, or ibandronic neridronic acid, etc., is in a dosage form containing one of acid and is administered daily for about 2 to about 15 or a combination of the ingredients in the Table E below. consecutive days. This regimen may be repeated once monthly, once every two months, once every three months, TABLE E once every four months, once every five months, once every Iron six months, once yearly, or once every two years. Methyl Paraben 0220. In some embodiments, an oral dosage form com Propyl Paraben prises about 10 mg to about 150 mg or about 10 mg to about Sorbitol Carob Bean Gum 100 mg of Zoledronic acid, minodronic acid, or ibandronic Mannitol acid and is administered daily for about 5 to about 10 Gum Tragacanth consecutive days. This regimen may be repeated once Guar Gum monthly, once every two months, once every three months, Benzoic Acid Sodium Benzoate once every four months, once every five months, once every Garlic and Oil of Garlic six months, once yearly, or once every two years. Oil of Rue 0221. In some embodiments, an oral dosage form com Propyl Gallate Gum Ghatti prises about 40 mg to about 150 mg of Zoledronic acid, Gum Arabic minodronic acid, or ibandronic acid and is administered Sterculia Gum (karaya gum) daily for about 5 to about 10 consecutive days. This regimen Indian Dill Seed may be repeated once monthly, once every two months, once Pulps Clove Bud Extract every three months, once every four months, once every five Clove Bud Oil months, once every six months, once yearly, or once every Clove Bud Oleoresin two years. Clove Leaf Oil 0222. In some embodiments, the oral Zoledronic acid, Clove Stem Oil Cholic acid minodronic acid, or ibandronic acid may be administered as Desoxycholic acid one dose of about 100 mg to about 2000 mg. In some Glycocholic acid embodiments, the oral Zoledronic acid, minodronic acid, or Ox bile extract ibandronic acid may be administered as one dose of about Taurocholic acid Sorbose 300 mg to about 1500 mg. In some embodiments, the oral Sodium thiosulfate Zoledronic acid, minodronic acid, or ibandronic acid may be Gelatin administered as one dose of about 200 mg to about 1000 mg. Mustard or Oil of Mustard (Brown and Yellow) The dose of Zoledronic acid, minodronic acid, or ibandronic Glycyrrhiza Ammoniated Glycyrrhizin acid may be administered in a single or divided dose. Licorice 0223. An osteoclast inhibitor, such as Zoledronic acid, Caprylic Acid minodronic acid, or ibandronic acid, may be formulated for Stannous Chloride Ammonium bicarbonate oral administration, for example, with an inert diluent or Ammonium carbonate with an edible carrier, or it may be enclosed in hard or soft Ammonium chloride shell gelatin capsules, compressed into tablets, or incorpo Ammonium hydroxide rated directly with the food of the diet. For oral therapeutic Ammonium phosphate, such as ammonium phosphate dibasic or Ammonium phosphate monobasic administration, the active compound may be incorporated Ammonium sulfate with an excipient and used in the form of ingestible tablets, Calcium iodate buccal tablets, coated tablets, troches, capsules, elixirs, Potassium iodate dispersions, Suspensions, Solutions, syrups, wafers, patches, Potassium iodide and the like. Aconitic Acid Calcium carbonate 0224 Tablets, troches, pills, capsules and the like may Potassium bicarbonate also contain one or more of the following: a binder Such as Sodium bicarbonate Sodium carbonate gum tragacanth, acacia, corn starch or gelatin; an excipient, Sodium sesquicarbonate Such as dicalcium phosphate; a disintegrating agent Such as Glycerin and Glycerides corn Starch, potato starch, alginic acid and the like; a Dextran lubricant Such as magnesium Stearate; a Sweetening agent Dextrins Corn dextrins Such as Sucrose, lactose or Saccharin; or a flavoring agent Calcium acetate Such as peppermint, oil of wintergreen or cherry flavoring. Calcium chloride When the unit dosage form is a capsule, it may contain, in Calcium gluconate addition to materials of the above type, a liquid carrier. Calcium phytate Various other materials may be present as coating, for Calcium hydroxide Calcium oxide instance, tablets, pills, or capsules may be coated with Succinic acid shellac, Sugar or both. A syrup or elixir may contain the Butylated Hydroxytoluene (BHT) active compound. Sucrose as a Sweetening agent, methyl and Calcium hexametaphosphate propylparabens as preservatives, a dye and flavoring, Such as Calcium phosphate dibasic Calcium phosphate monobasic cherry or orange flavor. It may be desirable for material in Calcium phosphate tribasic a dosage form or pharmaceutical composition to be phar Calcium pyrophosphate maceutically pure and Substantially non toxic in the amounts Phosphoric acid employed. US 2017/01 19801 A1 May 4, 2017 23

TABLE E-continued TABLE E-continued Potassium phosphate dibasic Magnesium phosphate, dibasic Potassium phosphate monobasic Magnesium carbonate Potassium phosphate tribasic Magnesium chloride Potassium polymetaphosphate Magnesium hydroxide Potassium pyrophosphate Magnesium oxide Potassium tripolyphosphate Magnesium Stearate Sodium acid pyrophosphate Magnesium sulfate Sodium hexametaphosphate Magnesium phosphate, tribasic Sodium metaphosphate Adipic acid Sodium phosphate dibasic Hydrogenated Soybean oil Sodium phosphate monobasic Ethyl formate Sodium phosphate tribasic Formic acid Sodium pyrophosphate, tetrabasic Sodium formate Sodium tetrametaphosphate Carrageenan Sodium tetraphosphate Nutmeg and Mace Sodium trimetaphosphate Zinc acetate Sodium tripolyphosphate Zinc carbonate Sulfuric Acid Zinc chloride alpha-Tocopherol acetate Zinc oxide Tocopherols Zinc sulfate Choline Bitaritrate Caramel Choline Chloride Lard Aluminum ammonium sulfate Lard oil Aluminum hydroxide Papain Aluminum oleate Gum guaiac Aluminum palmitate Coconut oil Aluminum potassium sulfate Linoleic acid Aluminum sodium sulfate Oleic acid Aluminum Sulfate Peanut oil Sodium aluminate Calcium hypophosphite Sodium aluminum phosphate, acidic Manganous hypophosphite Sodium aluminum phosphate, basic Potassium hypophosphite Sodium phosphoaluminate Sodium hypophosphite Beeswax (yellow or white) Pectin, amidated Japan wax Pectin, high ester Carnauba wax Pectin, low acid Corn Sugar (Dextrose) Pectinates Corn Syrup Pectinic acid Invert Sugar Carboxymethyl cellulose Inositol Cellulose acetate Calcium stearate Ethyl cellulose Hydrogenated tallow Hydroxypropylmethyl cellulose Stearic acid Methylcellulose Tallow Sodium Carboxymethyl cellulose Malic acid Rennet L-Malic acid Tannic acid (hydrolyzable gallotannins) Calcium sorbate Acetic acid Potassium Sorbate Sodium acetate Sodium sorbate Sodium diacetate Sorbic acid Pyridoxine Sulfamic acid Pyridoxine hydrochloride Sodium hydrosulfite Sodium oleate Zinc hydrosulfite Sodium palmitate Tall oil Ethyl acrylate, monomeric Fish oil, hydrogenated Methyl acrylate, monomeric Sucrose Ethyl acrylate, polymeric Agar-agar Methyl acrylate, polymeric Ammonium alginate Bentonite Calcium alginate Clay (kaolin) Potassium alginate Corn silk Propylene glycol alginate Ammonium citrate Sodium alginate Calcium citrate Propylene Glycol Citric acid Propylene glycol monostearate Isopropyl citrate Brown algae Potassium citrate Red algae Sodium citrate Calcium glycerophosphate Stearyl citrate Manganese glycerophosphate Triethyl citrate Magnesium glycerophosphate Biotin Potassium glycerophosphate Enzymatically hydrolyzed casein Potassium hydroxide Acid hydrolyzed proteins Sodium hydroxide Enzymatically hydrolyzed protein Potassium metabisulfite Soy sauces Sodium bisulfite Yeast autolyzates Sodium metabisulfite Caffeine Sodium sulfite L-Glutamic acid Sulfur dioxide L-Glutamic acid hydrochloride US 2017/01 19801 A1 May 4, 2017 24

TABLE E-continued TABLE E-continued Monoammonium L-glutamate Acetylated Distarch Oxypropanol Monopotassium L-glutamate Acid Modified Starch Monosodium L-glutamate Arrowroot Starch Calcium Lactate Bleached Starch L(+)-calcium lactate Cornstarch D(-)-Lactic acid Distarch Glycerol Lactic acid Distarch Oxypropanol L(+)-lactic acid Distarch Phosphate Butylated Hydroxyanisole (BHA) High Amylose Cornstarch D- or DL-Calcium pantothenate Hydroxypropyl Distarch Glycerol D-Pantothenyl alcohol Hydroxypropyl Distarch Phosphate D- or DL-Sodium pantothenate Hydroxypropyl Starch Urea Hydroxypropyl Starch, oxidized Thiamine hydrochloride Milo Starch Thiamine mononitrate Monostarch Phosphate Magnesium gluconate Potato starch Potassium gluconate Pregelatinized starch Sodium gluconate Rice Starch Zinc gluconate Sodium Hydroxide Gelatinized Starch Vitamin B12 (cyanocobalamin) Starch Acetate Vitamin D2 (ergocalciferol) Starch Aluminum Octenyl Succinate Vitamin D3 (cholecalciferol) Starch Sodium Succinate Potassium chloride Starch Sodium Octenyl Succinate Sodium chloride Succinyl Distarch Glycerol Soy protein isolate Tapioca Starch Hydrochloric acid Waxy Maize Starch Copper (cupric) gluconate Wheat Starch Copper (cupric) sulfate Phosphated Distarch Phosphate Cuprous iodide Starch, Sodium Hypochlorite oxidized Calcium caseinate Vitamin A Casein Vitamin Aacetate Sodium caseinate Vitamin A palmitate Aluminum calcium silicate Diacetyl Calcium silicate Starter distillate Diatomaceous earth (filter aid) Carbonyl Iron Magnesium silicate Carbonyl Iron Perlite (filter aid) Electrolytic Iron Potassium silicate Electrolytic Iron Silica aerogel Ferric ammonium citrate Silicon dioxides Ferric chloride Sodium aluminosilicate Ferric citrate Sodium calcium aluminosilicate Ferric oxide Sodium silicate Ferric phosphate Talc (basic magnesium silicate) Ferric pyrophosphate Tricalcium silicate Ferric sodium pyrophosphate L(+)-potassium acid tartrate Ferric sulfate L(+)-Sodium tartrate Ferrous ascorbate L(+)-tartaric acid Ferrous carbonate Manganous chloride Ferrous citrate Manganous citrate Ferrous fumarate Manganous gluconate Ferrous gluconate Manganous oxide Ferrous lactate Manganous Sulfate Ferrous sulfate Lecithin Ferrous sulfate Lecithin, hydrogen peroxide bleached ron caprylate Riboflavin ron linoleate Riboflavin-5'-phosphate ron naphthenate Calcium propionate ron oxides Dilauryl thiodipropionate ron peptonate Propionic acid ron polyvinylpyrrollidone Sodium propionate ron tallate Thiodipropionic acid Sodium ferric EDTA Hydrogen peroxide Sodium ferricitropyrophosphate Carbon dioxide Dietary Iron Nickel (elemental) Ferric oxide Niacin (nicotinic acid) Potassium carbonate Niacinamide (nicotinamide) Calcium glycerophosphate Carotene (beta-carotene) Cellulose, Such as microcrystalline cellulose L-AScorbic acid Titanium dioxide Ascorbyl palmitate (palmitoyl L-ascorbic) Calcium L-ascorbate Erythorbic acid (D-isoascorbic acid) 0226. Some compositions or dosage forms may be a Sodium erythorbate (sodium D-isoascorbate) liquid, or may comprise a solid phase dispersed in a liquid. Sodium L-ascorbate Acetylated Distarch Adipate 0227. An osteoclast inhibitor, such as Zoledronic acid, Acetylated Distarch Glycerol minodronic acid, or ibandronic acid may be formulated for Acetylated Distarch Phosphate parental or intraperitoneal administration. Solutions of the active compounds as free acids or pharmacologically accept US 2017/01 19801 A1 May 4, 2017

able salts can be prepared in water suitably mixed with a acid. Some pharmaceutical products may comprise 1 to 10 Surfactant, such as hydroxypropylcellulose. A dispersion can units of the oral dosage form, wherein the product contains also have an oil dispersed within, or dispersed in, glycerol, about 200 mg to about 2000 mg of Zoledronic acid, mino liquid polyethylene glycols, and mixtures thereof. Under dronic acid, oribandronic acid. For Such a product, each unit ordinary conditions of storage and use, these preparations of the oral dosage form may be taken daily for 1 to 10 days may contain a preservative to prevent the growth of micro or 5 to 10 days during a month, Such as at the beginning of organisms. a month. 0228. In some embodiments, an oral dosage form may 0236 Some oral dosage forms comprising an osteoclast comprise a silicified microcrystalline cellulose such as inhibitor—such as suitable bisphosphonates like Zoledronic PROSLOV(R). For example, about 20% (wit/wt) to about acid, minodronic acid, or ibandronic acid or salts thereof 70% (wit/wt), about 10% (wit/wt) to about 20% (wt?wt), may have enteric coatings or film coatings. In some embodi about 20% (wit/wt) to about 40% (wt?wt), about 25% (wit/wt) ments, an oral dosage form of an osteoclast inhibitor com to about 30% (wt?wt), about 40% (wit/wt) to about 50% prises a tablet having an enteric coating. In some (wt?wt), or about 45% (wit/wt) to about 50% (wit/wt) silici embodiments, an oral dosage form of an osteoclast inhibitor fied microcrystalline cellulose may be present in an oral comprises a capsule having an enteric coating. In some dosage form or a unit of an oral dosage form. embodiments, an oral dosage form of an osteoclast inhibitor 0229. In some embodiments, an oral dosage form may comprises a tablet having a film coating. In some embodi comprise a crosslinked polyvinylpyrrolidone such as ments, an oral dosage form of an osteoclast inhibitor com crospovidone. For example, about 1% (wit/wt) to about 10% prises a capsule having a film coating. (wt/wt), about 1% (wit/wt) to about 5% (wit/wt), or about 1% 0237 Useful doses for an antibody against RANK or (wt/wt) to about 3% (wit/wt) crosslinked polyvinylpyrroli RANKL, such as denosumab, may range from about 0.1 done may be present in an oral dosage form or a unit of an mg/kg to about 20 mg/kg, about 0.75 mg/kg to about 7.5 oral dosage form. mg/kg, about 0.1 mg/kg to about 5 mg/kg, about 1 mg/kg to 0230. In some embodiments, an oral dosage form may about 2 mg/kg, about 10 mg/kg to about 20 mg/kg, about 12 comprise a fumed silica such as AEROSILR). For example, to about 17 mg/kg, about 15 mg/kg to about 20 mg/kg, about about 0.1% (wit/wt) to about 10% (wit/wt), about 0.1% 1 mg/kg, about 1 mg/kg to about 10 mg/kg, or any value (wt/wt) to about 1% (wit/wt), or about 0.4% (wit/wt) to about bounded by or in between these ranges based on the body 0.6% (wit/wt) fumed silica may be present in an oral dosage weight of the mammal. The chosen dose may be adminis form or a unit of an oral dosage form. tered repeatedly, particularly for chronic conditions, or the 0231. In some embodiments, an oral dosage form may amount per dose may be increased or decreased as treatment comprise magnesium Stearate. For example, about 0.1% progresses. The chosen dose may be administered one or (wt?wt) to about 10% (wit/wt), about 0.1% (wit/wt) to about more times per week, monthly, every two months, every 1% (wit/wt), or about 0.4% (wit/wt) to about 0.6% (wt?wt) three months, every six months, or every year. magnesium Stearate may be present in an oral dosage form 0238. In some embodiments, 60 mg of denosumab is or a unit of an oral dosage form. administered subcutaneously to patient in need of treatment. 0232 An oral dosage form comprising Zoledronic acid or In some embodiments, the administration is repeated every another bisphosphonate or osteoclast inhibitor may be six months. included in a pharmaceutical product comprising more than 0239. There are a number of ways that some part of one unit of the oral dosage form. Compound 1 and/or Compound 2 may be removed from a 0233. A pharmaceutical product containing oral dosage Zoledronic acid product. For example, HPLC, preparative forms for daily use can contain 28, 29, 30, or 31 units of the TLC, crystallization, Sublimation, or Zone purification may oral dosage form for a monthly supply. An approximately 6 be employed. Solvents that may be useful in HPLC, TLC, or week daily supply can contain 40 to 45 units of the oral crystallization, may include, but are not limited to, water or dosage form. An approximately 3 month daily Supply can organic solvents, such as hexanes, diethyl ether, ethyl contain 85 to 95 units of the oral dosage form. An approxi acetate, methyl acetate, acetone, acetic acid, acetonitrile, mately six month daily supply can contain 170 to 200 units tetrahydrofuran, ethanol, methanol, isopropyl alcohol, chlo of the oral dosage form. An approximately one year daily roform, diethyl ether, toluene, dimethylformamide, benzene, supply can contain 350 to 380 units of the oral dosage form. etc. Gradients, or two solvent systems may be employed as 0234. A pharmaceutical product containing oral dosage well. For example, an HPLC separation may begin by forms for weekly use can contain 4 or 5 units of the oral elution with water, after Some time eluting with water, an dosage form for a monthly Supply. An approximately two organic solvent, such as acetonitrile, methanol, ethanol, month weekly supply can contain 8 or 9 units of the oral ethyl acetate, acetone, acetic acid, methyl acetate, or another dosage form. An approximately six week weekly Supply can Solvent could gradually be added to the water, or may contain about 6 units of the oral dosage form. An approxi replace the water entirely. Similarly, crystallization or mately three month weekly Supply can contain 12, 13 or 14 recrystallization may employ a single solvent, or a combi units of the oral dosage form. An approximately six month nation of solvents. For example, Zoledronic acid or a salt weekly Supply can contain 22 to 30 units of the oral dosage thereof. Such as a disodium salt, might be recrystallized from form. An approximately one year weekly Supply can contain water, ethanol, methanol, diethyl ether, methyl acetate, ace 45 to 60 units of the oral dosage form. tic acid, etc., or a combination of these solvents or others. In 0235 A pharmaceutical product may accommodate other Some embodiments, Zoledronic acid or a salt thereof. Such as dosing regimes. For example, a pharmaceutical product may a disodium salt, may be dissolved in one solvent, such as comprise 5 to 10 units of the oral dosage form, wherein each water or acetic acid, and crystallized by a second solvent or unit of the oral dosage form contains about 40 mg to about Solvent system, such as hexane, diethyl ether, chloroform, 150 mg of Zoledronic acid, minodronic acid, or ibandronic dichloromethane, ethyl acetate, methyl acetate, acetic acid, US 2017/01 19801 A1 May 4, 2017 26 ethanol, methanol, or a combination thereof. In some mg/m in a human being, while 3 mg/kg in a rat may not be embodiments, a disodium salt of Zoledronic acid is dissolved equivalent to 3 mg/kg in a human being. in water, and then crystallized by adding hexane. In some 0244 Values for inflammatory pain (mechanical hyper embodiments, a disodium salt of Zoledronic acid is dissolved algesia) in the vehicle and drug-treated animals were in water, and then crystallized by adding diethyl ether. In obtained on day 0 prior to CFA injection, and at baseline and Some embodiments, a disodium salt of Zoledronic acid is post-treatment on days 1-3. Pain was assessed using a digital dissolved in water, and then crystallized by adding chloro Randall-Selitto device (dRS: IITC Life Sciences, Woodland form. In some embodiments, a disodium salt of Zoledronic Hills, Calif.). Animals were placed in a restraint sling that acid is dissolved in water, and then crystallized by adding suspended the animal, leaving the hind limbs available for dichloromethane. In some embodiments, a disodium salt of testing. Paw compression threshold was measured by apply Zoledronic acid is dissolved in water, and then crystallized ing increasing pressure to the plantar Surface of the hind paw by adding ethyl acetate. In some embodiments, a disodium with a dome-shaped tip placed between the 3rd and 4th salt of Zoledronic acid is dissolved in water, and then metatarsus. Pressure was applied gradually over approxi crystallized by adding methyl acetate. In some embodi mately 10 seconds. Measurements were taken from the first ments, a disodium salt of Zoledronic acid is dissolved in observed nocifensive behavior of Vocalization, struggle or water, and then crystallized by adding acetic acid. In some withdrawal. A cut-off value of 300 g was used to prevent embodiments, a disodium salt of Zoledronic acid is dissolved injury to the animal. in water, and then crystallized by adding ethanol. In some 0245 Reversal of inflammatory pain was calculated embodiments, a disodium salt of Zoledronic acid is dissolved according to the formula: in water, and then crystallized by adding methanol. For % reversal=(Post-treatment-Post-CFA baseline) (Pre embodiments employing water and a second solvent, the CFA baseline-Post-CFA baseline)x100. ratio of water to the second solvent (water:second solvent) may be about 1:100 to about 100:1, about 1:10 to about 1:5, 0246 The experiment was carried out using 9-10 animals about 1:5 to about 1:4, about 1:4 to about 1:3, about 1:3 to per group. about 1:2, about 1:2 to about 1:1, about 1:1 to about 2:1, about 2:1 to about 3:1, about 3:1 to about 4:1, about 4:1 to Results: about 5:1, or about 1:1 to about 10:1. 0247 Oral administration of Zoledronic acid significantly 0240. In some embodiments, a combination of two meth improved inflammatory pain thresholds compared to ods recited in the paragraph above may be employed, such vehicle. Pain threshold measurements taken at various times as HPLC or TLC and crystallization. In some embodiments, are shown in FIG. 1. Paw compression thresholds in the 18 a method may be repeated, such as HPLC, preparative TLC, mg/m group were higher than for vehicle during the entire crystallization, Sublimation, or Zone purification. In some measurement period after 30 minutes from the start of embodiments, a purification method recited in the paragraph treatment. On day three, paw compression thresholds for above may be performed twice. In some embodiments, a both the 18 mg/m and 900 mg/m groups were greater than purification method recited in the paragraph above may be for vehicle. An improvement in pain threshold of 49% and performed three or four times. 83% from baseline was observed for the 18 mg/m and the 0241. Some oral dosage forms comprising Zoledronic 900 mg/m groups respectively. acid or a salt thereof may have enteric coatings or film 0248 Orally administered Zoledronic acid produced a coatings. 29% reversal of inflammatory pain at the 18 mg/m, and a 48% reversal at the 900 mg/m dose. This magnitude of 0242. In the examples below, Zoledronic acid was admin effect is comparable to that obtained with clinical doses of istered in the disodium salt form as disodium Zoledronate commercially available NSAIDs when tested in a similar tetrahydrate. No bioavailability enhancing agents were used model of inflammatory pain. Under current FDA guidelines, in the test compositions. the reference body surface area of a human adult is 1.62 m. Thus, a daily dose of 18 mg/m corresponds to a monthly EXAMPLE 1. dose of about 500-560 mg/m or a human dose of about 800-900 mg. Effect of Orally Administered Zoledronic Acid in 0249 Surprisingly, the two higher doses resulted in Rat Model of Inflammatory Pain Method thresholds that were lower than vehicle on the first two days 0243 The effect of orally administered Zoledronic acid of dosing. The 120 mg/m group was approximately equal or on inflammatory pain was examined using the rat complete inferior to vehicle at all time points during the assessment Freund's adjuvant (CFA) model. Inflammatory pain was period. While the 900 mg/m group showed effectiveness on induced by injection of 100% CFA in a 75 uL volume into day 3, this result was accompanied by significant toxicity the left hind paws of Sprague-Dawley(R) rats on day 0, necessitating euthanization of all the animals in this group followed by assessments on days 1-3. Animals were orally two days after cessation of dosing. administered vehicle (control), Zoledronic acid 18 mg/m (or 3 mg/kg), Zoledronic acid 120 mg/m (or 20 mg/kg), or EXAMPLE 2 zoledronic acid 900 mg/m (or 150 mg/kg) daily on days 1-3. Drug was dissolved in distilled water and prepared fresh Effect of Orally Administered Zoledronic Acid in daily. Animals were fasted prior to dosing. Under current Rat Model of Arthritis Pain Method FDA guidelines for extrapolating starting dosages from 0250. The effect of orally administered Zoledronic acid animals to humans, dosages expressed in mg/m are con on arthritis pain was examined in the rat complete Freund's sidered equivalent between mammalian species. Thus, for adjuvant (CFA) model of arthritis pain. In this model, example, 18 mg/m in a rat is considered equivalent to 18 injection of 100% complete Freund's adjuvant (CFA) in a 75 US 2017/01 19801 A1 May 4, 2017 27 uL volume into the left hind paws is followed by a 10-14 day 2 hours after dosing. At the end of the 28-day period, casts period to allow for the development of arthritis pain. Ani were removed, and on the following day, the rats were tested mals were orally administered vehicle (control), Zoledronic for hindpaw pain, edema, and warmth. acid 54 mg/m (or 9 mg/kg), or Zoledronic acid 360 mg/m (or 60 mg/kg), divided in three equal daily doses on the first Pain Assessments three days post CFA injection. Drug was dissolved in distilled water and prepared fresh daily. Animals were fasted 0257 Pain was assessed by measuring hyperalgesia, and prior to dosing. weight bearing. 0251 Arthritis pain (mechanical hyperalgesia) in the 0258 To measure hyperalgesia, an up-down von Frey vehicle and drug-treated animals was evaluated on day 14 testing paradigm was used. Rats were placed in a clear post CFA injection using a digital Randall-Selitto device plastic cylinder (20 cm in diameter) with a wire mesh bottom (dRS: IITC Life Sciences, Woodland Hills, Calif.). Animals and allowed to acclimate for 15 minutes. The paw was tested were placed in a restraint sling that Suspended the animal, with one of a series of eight Von Frey hairs ranging in leaving the hind limbs available for testing. Paw compres stiffness from 0.41 g to 15.14 g. The von Frey hair was sion threshold was measured by applying increasing pres applied against the hindpaw plantar skin at approximately sure to the plantar surface of the hind paw with a dome midsole, taking care to avoid the tori pads. The fiber was shaped tip placed between the 3rd and 4th metatarsus. pushed until it slightly bowed and then it was jiggled in that Pressure was applied gradually over approximately 10 sec position for 6 seconds. Stimuli were presented at an interval onds. Measurements were taken from the first observed of several seconds. Hindpaw withdrawal from the fiber was nocifensive behavior of Vocalization, struggle or with considered a positive response. The initial fiber presentation drawal. A cut-off value of 300 g was used to prevent injury was 2.1 g and the fibers were presented according to the to the animal. up-down method of Dixon to generate six responses in the 0252 Reversal of arthritis pain in the ipsilateral (CFA immediate vicinity of the 50% threshold. Stimuli were injected) paw was calculated according to the formula: presented at an interval of several seconds. % reversal=(ipsilateral drug threshold-lipsilateral 0259 An incapacitance device (IITC Inc. Life Science, vehicle threshold),(contralateral vehicle thresh Woodland, Calif., USA) was used to measure hindpaw old-ipsilateral vehicle threshold)x100. weight bearing, a postural effect of pain. The rats were 0253) The experiment was carried out using 7-10 animals manually held in a vertical position over the apparatus with per group. the hindpaws resting on separate metal scale plates and the entire weight of the rat was supported on the hindpaws. The Results: duration of each measurement was 6 seconds and 10 con 0254 Oral administration of Zoledronic acid significantly secutive measurements were taken at 60-second intervals. improved arthritis pain thresholds compared to vehicle. As Eight readings (excluding the highest and lowest ones) were shown in FIGS. 2A and 2B, orally administered Zoledronic averaged to calculate the bilateral hindpaw weight-bearing acid produced a dose-dependent reversal of arthritis pain. A values. Weight bearing data were analyzed as the ratio reversal of 33% was observed in the 54 mg/m group, and between right (fracture) and left hindpaw weight bearing reversal of 54% was observed in the 360 mg/m group. values (2R/(R+L))x100%). Under current FDA guidelines, the reference body surface area of a human adult is 1.62 m. Thus, 54 mg/m in a rat is Edema Assessment equivalent to an implied human dose of about 87 mg, and 0260 Alaser sensor technique was used to determine the 360 mg/m in a rat is equivalent to an implied human dose dorsal-ventral thickness of the hindpaw. Before baseline of about 583 mg. testing the bilateral hindpaws were tattooed with a 2 to 3 mm EXAMPLE 3 spot on the dorsal skin over the midpoint of the third metatarsal. For laser measurements each rat was briefly Treatment of Complex Regional Pain Syndrome anesthetized with isoflurane and then held vertically so the with Orally Administered Zoledronic Acid hindpaw rested on a table top below the laser. The paw was gently held flat on the table with a small metal rod applied 0255. The effect of orally administered Zoledronic acid to the top of the ankle joint. Using optical triangulation, a was examined in the rat tibia fracture model of complex laser with a distance measuring sensor was used to deter regional pain syndrome (CRPS). CRPS was induced in the mine the distance to the table top and to the top of the rats by fracturing the right distal tibias of the animals and hindpaw at the tattoo site and the difference was used to casting the fractured hindpaws for 4 weeks, as described in calculate the dorsal-ventral paw thickness. The measure Guo T Zetal. (Pain. 2004: 108: 95-107). This animal model ment sensor device used in these experiments (4381 Preci has been shown to replicate the inciting trauma (such as a cura, Limab, Goteborg, Sweden) has a measurement range fracture, a Surgery, a crushing injury, a cutting injury, a of 200 mm with a 0.01 mm resolution. scratch, or a puncture injury), natural history, signs, symp toms, and pathologic changes observed in human CRPS Hindpaw Temperature Measurement patients (Kingery WS et al., Pain. 2003: 104:75-84). 0256 Animals were orally administered either vehicle 0261 The temperature of the hindpaw was measured (control) or Zoledronic acid, in a dosage of 18 mg/m/day (3 using a fine wire thermocouple (Omega, Stanford, CT, USA) mg/kg/day) for 28 days, starting on the day of fracture and applied to the paw skin. Six sites were tested per hindpaw. casting. Drug was dissolved in distilled water and adminis The six measurements for each hindpaw were averaged for tered by gavage. Animals were fasted for 4 hours before and the mean temperature. US 2017/01 19801 A1 May 4, 2017 28

Results amounts adjusted to account for the difference in molecular 0262. As illustrated in FIG. 3, treatment with orally weights between the acid and the disodium salt. administered Zoledronic acid reversed pain, restored weight 0271 Beagle dogs were orally administered tablets con bearing, and prevented edema as compared to vehicle treated taining 150 mg Zoledronic acid equivalent either in the form animals. of disodium Zoledronate (Group 1) or pure Zoledronic acid 0263. As illustrated in FIG. 4, von Frey pain thresholds (Group 2). Each animal was given three 50 mg equivalent for the right (fracture) hindpaw were reduced by 72% versus tablets (150 mg total), which were administered together. the contralateral (normal) hindpaw in vehicle treated ani The animals oral cavity was wetted with water before mals. Zoledronate treatment reversed fracture induced pain placing the tablets on the back of the animals tongue. by 77% as compared to vehicle treatment. Animals were fasted before and after dosing. Animals were 0264. As illustrated in FIG. 5, reduction in weight bear 6 to 9 months of age and weighed 6 to 10 kg on the day of ing, a postural effect of pain, was significantly higher in the dosing. There were three dogs per group. vehicle treated group as compared to the Zoledronic acid 0272. Serial blood samples were collected from each treated group. Weight bearing on the fracture hindlimb was animal by Venipuncture of the jugular vein at various points reduced to 55% of normal in the vehicle treated group. after dosing for measurement of plasma concentrations of Zoledronate treatment significantly restored hindlimb Zoledronic acid. Blood samples were collected into chilled weight bearing as compared to vehicle treatment (86% of tubes containing KEDTA as the anticoagulant. Samples normal). were then centrifuged at approximately 3000 rpm at +4° C. 0265. As illustrated in FIG. 6, the expected increase in for 10 minutes for plasma derivation. Plasma concentrations hindpaw thickness was greater in the vehicle treated group of Zoledronic acid were measured using an LC/MS/MS as compared to the Zoledronic acid treated group, reflecting method. the development of edema. Zoledronate treatment reduced Results hindpaw edema by 60% versus vehicle treatment. 0266 Zoledronic acid reduced hindpaw warmth by 5% 0273. The average plasma concentrations of Zoledronic versus vehicle treatment. acid for each group of dogs is Summarized in Table 1 and 0267. The daily dose in the above experiment was 18 illustrated in FIG. 8. Detectable plasma levels of Zoledronic mg/m/day. Under current FDA guidelines, the reference acid were observed for the entire 48 hours that they were body surface area of a human adult is 1.62 m. Thus, a daily measured. dose of 18 mg/m corresponds to a monthly dose of about 500-560 mg/m or a human dose of about 800-900 mg. TABLE 1. EXAMPLE 4 Zoledronic Acid plasma concentrations in beagle dogs Plasma Solubility of Disodium Salt of Zoledronic Acid Time concentration 0268. The aqueous solubility of Zoledronic acid and (hour) (ng/mL) disodium Zoledronate tetrahydrate was determined. One Group 1 (N = 3) Disodium Zoledronate O O.OO Tablets O.25 1193.97 gram of the test compound was measured in to a beaker. (150 mg acid equivalent) O.S 1852.12 Demineralized water (pH 5.5) was then added in small 0.75 1776.51 increments to the test compound, and Sonication was applied 1 1626.56 to the mixture. The procedure was continued until complete 2 640.57 dissolution was achieved. Full dissolution was determined to 4 136.93 6 S3.11 have been reached when a clear solution was present with no 8 26.97 visible material. The volume of water required to reach full 12 13.74 dissolution was used to calculate a solubility value 24 6.78 expressed in grams per 100 mL. The procedure was per 48 5.39 Group 2 (N = 3) Zoledronic Acid Tablets O O.OO formed for each compound. (150 mg acid equivalent) O.25 390.92 O.S 846.19 Results 0.75 819.15 1 831.77 0269. As shown in FIG. 7, the aqueous solubility of 2 477.76 disodium Zoledronate tetrahydrate is approximately 50 times 4 90.11 6 28.22 that of Zoledronic acid. Disodium Zoledronate tetrahydrate 8 15.10 has a solubility of 12.5 g/100 mL compared to only 0.25 12 6.13 g/100 mL for Zoledronic acid. 24 3.18 48 1.84 EXAMPLE 5 0274 Disodium Zoledronate produced significantly Bioavailability of Orally Administered Zoledronic higher plasma levels of Zoledronic acid than pure Zoledronic Acid and Disodium Zoledronate acid, indicating improved oral absorption with the salt form. 0270 Tablets were manufactured containing either pure Measured using peak plasma concentrations (C), the Zoledronic acid or the disodium salt of Zoledronic acid disodium salt resulted in a 119% actual and 74% weight (disodium Zoledronate tetrahydrate). Both types of tablets adjusted increase in bioavailability as compared to pure contained 50 mg of Zoledronic acid equivalent per tablet. Zoledronic acid. Measured using area under the plasma Identical excipients were used in both types of tablets, with concentration curve (AUC), bioavailability was 84% and US 2017/01 19801 A1 May 4, 2017 29

46% greater with the disodium salt than with pure Zole Grade 1 and Grade 2). Twenty six patients were treated with dronic acid, on an actual and weight-adjusted basis respec Zoledronic acid (8, 6, and 12 with OARSI Grades 0, 1, and tively. The average AUC for the disodium salt was 4073 2, respectively). Twenty six patients received placebo (8, 8. ngh/mL and the average AUCo. for the diacid was 2217 and 10 with OARSI Grades 0, 1 and 2, respectively). ngth/mL. The AUCo. was found to be dose proportional. 0277 Pain intensity was assessed, at baseline and at three Thus, for beagle dogs similar to those tested, about 3 mg to months, using a 100 mm visual analog scale (VAS), with about 4 mg of the disodium salt would be expected to result Zero representing no pain and 100 representing extreme in an AUCo. of about 100 ngh/mL, and about 7 mg to pain. The change in pain intensity from baseline to 3 months about 8 mg of the disodium salt would be expected to result was calculated. in an AUC of about 200 ngh/mL. 0278. With Zoledronic acid treatment, pain was reduced significantly as compared to placebo in patients with no joint EXAMPLE 6 space narrowing (OARSI Grade 0), but not in patients with joint space narrowing (OARSI Grades 1-2). As shown in Hardness of Tablets Comprising Zoledronic Acid in Table 3 and FIG. 10, average VAS scores were reduced by the Free Acid and Disodium Salt Forms 15 mm as compared to placebo in the OARSI Grade O group, 0275 Tablets were prepared by blending Zoledronic acid, but only by 0.28 as compared to placebo in patients with either in the form of the free acid or the disodium salt, with OARSI Grades 1-2. identical excipients. For dosage forms with a greater amount 0279. In the Zoledronic acid group, average VAS scores at of active, the amount of the excipients was reduced propor 3 months decreased from baseline by approximately 25 mm tionally to keep the weight of the tablet at about 100 mg. and 21 mm in patients with OARSI Grades 0 and 1. After blending, the ingredients were compressed at varying respectively, but only by 9 mm in the OARSI Grade 2 pressures, followed by a film coating. The resulting tablets patients (FIG. 11). were then tested for hardness using a Dr. Schleuniger Pharmatron 8M Tablet Hardness Tester. The results are TABLE 3 shown in Table 2 and FIG. 9. Change in VAS Pain Scores at Three Months by OARSI Grade (nn TABLE 2 OARSI Grade O OARSI Grades 1-2

Hardness (kPa. Zoledronic Acid -24.6 -13.2 Placebo -9.6 -12.9 Compression Disodium Disodium Difference from Placebo -15.O -0.28 Force Diacid Salt Salt (psi) 50 mg 50 mg 71 mg 0280 With Zoledronic acid treatment, pain was reduced 800 4.0 8.7 4.8 significantly as compared to placebo in patients with base 1100 6.1 11.2 6.8 1SOO 7.7 13.7 7.4 line VAS pain intensity scores of 50 mm or greater, but not 2OOO 8.7 16.3 10.7 in patients with baseline VAS scores less than 50 mm. As 2400 8.7 11.3 shown in Table 4, average VAS scores were reduced by 9 3OOO 11.4 14.1 mm as compared to placebo in the patients with baseline 4400 12.5 14.9 5500 12.8 18.2 VAS >50 mm, but only by 0.6 as compared to placebo in 6100 13.0 patients with baseline VAS <50 mm.

TABLE 4 EXAMPLE 7 Change in VAS Pain Scores at Three Months by Baseline VAS (nn Effects of Zoledronic Acid on Patients with Baseline Baseline WAS 50 mm WAS <50 mm Osteoarthritis and BML Zoledronic Acid -26.2 -7.3 0276 Some embodiments related to joint pain, bone Placebo -17.2 -6.7 marrow lesions, and osteoarthritis were conceived as a result Difference from Placebo -9.0 -0.6 of analyzing data from a clinical study. Some of the results of this study were reported by Laslett et al. in Ann Rheum 0281. As summarized in Table 5 and illustrated in FIG. Dis 2012; 71:1322-1328. Some of the description and data 12, pain reduction was greater in patients with baseline VAS reported below was not published prior to filing the present 50 mm, greater still in patients with OARSI Grade Ojoint application. Fifty-two (52) patients with clinical knee space narrowing, and greatest in patients with both baseline osteoarthritis and knee bone marrow lesions (BML) were VAS >50 mm and OARSI Grade Ojoint space narrowing. randomized to receive either intravenous Zoledronic acid (5 mg) or placebo in a double blind fashion. All patients had to have at least one bone marrow lesion (BML) in the affected TABLE 5 knee on magnetic resonance imaging (MRI). All patients Pain Reduction Compared to Placebo at Three Months (nn had X-ray of the knee for determination of joint space narrowing (JSN), which was graded according to the VAS Change Osteoarthritis Research Society International (OARSI) atlas. All patients -4.8 Patients had either no joint space narrowing (OARSI Grade Baseline VAS e50 mm -9.0 O), or greater degrees of joint space narrowing (OARSI US 2017/01 19801 A1 May 4, 2017 30

TABLE 5-continued examination included medical history and clinical assess ment of lumbar flexibility, tendon signs, and motor and Pain Reduction Compared to Placebo at Three Months (mn sensory testing. 0286. After confirmation of eligibility patients were ran VAS Change domized to receive a single intravenous infusion of 5 mg OARSI Grade O -15.O Zoledronic acid (n=20) or 100 ml saline as placebo (n =20) Baseline VAS e50 mm + OARSI Grade O -19.4 over a 15-minute period. Information on use of the con comitant medication and hospital admissions were recorded. Blood samples were taken for the assessment of safety, 0282 BMLs were evaluated using proton density inflammatory mediators and markers of bone turnover at weighted fat saturation MR images. BMLs were scored baseline, one month and one year. using Osiris software (University of Geneva, Geneva, Swit 0287 Clinical assessments were performed 14 days zerland). The maximum size was measured in mm using before enrolment (Screening visit), and follow-up visits at Software cursors applied to the greatest area of each lesion. one month and one year after the infusion. The primary The lesion with the highest score was used if more than one outcome was the change in the intensity of LBP on VAS. was present at the same site. Each patient was given a BML Secondary outcomes included leg pain intensity, ODI, score (mm) at each of the four sites (medial tibial, medial health-related quality of life assessed with RAND-36, femoral, lateral tibial, and lateral femoral sites) and these patient-reported sick leaves and lumbar flexibility. These were summed to create a total BML score (mm). The outcome measures were assessed at baseline and at each change in the total area of BMLS from baseline to 6 months follow-up. Lumbar flexibility was evaluated using the fin was calculated. gers-to-floor and trunk side bending measures (in cm). The 0283. The size of BMLS was reduced with Zoledronic percentage of patients undergoing a 20% relative improve acid treatment. As shown in FIG. 13 and Table 6, average ment, the proportion of patients reaching a VAS score of 40 BML area decreased by approximately 190 mm as com or less in the primary outcome, and patient acceptable pared to placebo in the OARSI Grade O group, but only by symptom state (PASS) were also assessed. Pain medication approximately 33 mm as compared to placebo in patients use was inquired about during the follow-up visits. with OARSI Grades 1-2. Results TABLE 6 0288 Zoledronic acid treatment resulted in a greater Change in BML Size (mm. improvement in LBP intensity at one month as compared to placebo treatment. Furthermore, the patients receiving Zole OARSI Grade O OARSI Grades 1-2 dronic acid reported NSAID use at one year significantly Zoledronic Acid -244 -117 less often than those in the placebo group. Overall, the Placebo -SS -84 improvements in most of the evaluated parameters were Difference from Placebo -190 -33 greater in the Zoledronic acid group throughout the follow up period. 0289. The clinical characteristics of study participants at baseline are displayed in Table 6. The mean LBP duration EXAMPLE 8 was 293 days, initial LBP intensity on VAS 6.7, leg pain on VAS 2.9 and the ODI score was 32%. Altogether 19 patients Methods in the ZA group and 18 in the placebo group had a M1/2 lesion. Modic changes were most commonly (70%) situated 0284. A study was performed to evaluate the efficacy of at L4/5 or L5/S1. The Zoledronic acid and placebo groups a single intravenous infusion of 5 mg ZA in comparison with were similar as regards the demographic and background intravenous placebo infusion among patients with chronic characteristics of all patients at baseline (Table 6). low back pain (LBP) and Modic changes on MRI. This study 0290. The mean difference (MD) between the treatment was a double-blinded, randomized, placebo-controlled clini groups in the primary outcome, intensity of LBP signifi cal trial in patients with low back pain (LBP). Patients were cantly favored Zoledronic acid at one month (MD 1.4: 95% included in the study if they had low back symptoms for at Cl 0.01 to 2.9) while at one year no significant difference least three months, a LBP of at least six (6) on a 10-cm was observed (MD 0.7; 95% CI -1.0 to 2.4: Table 7). The Visual Analog Scale (VAS) or an Oswestry Disability Index proportion of patients with at least 20% improvement in (ODI) of at least 30%, and an M1, mixed M1/2 or M2 type intensity of LBP and PASS both favored the Zoledronic acid change on MRI performed within six months at most prior treatment at one month: Zoledronic acid 55% vs. placebo to enrolment. 25% (p=0.105) and Zoledronic acid 50% vs. placebo 20% 0285 Patients were excluded from the study if they had (p=0.096), respectively. renal impairment with reduced creatinine clearance defined 0291 For the patients who were treated with Zoledronic as an estimated glomerular filtration rate (eGFR) below acid, the reduction in pain intensity was greater in those with ml/min, hypocalcemia, known hypersensitivity to Zole greater baseline pain intensity as shown in Table 9. The dronic acid or other bisphosphonates or ingredients of the mean reduction in pain from baseline was 3.4 for patients infusion product, the presence of red flags, nerve root with baseline pain intensity >7, as compared to a reduction entrapment or willingness for early retirement. Premeno of only 0.1 for patients with a baseline pain intensity <6. pausal women of childbearing potential were also excluded. 0292. Of the secondary outcomes, the improvement in Blood samples were taken prior to the infusion to assess the ODI, favored Zoledronic acid at 1 month, the adjusted serum concentration of calcium and creatinine. The clinical between-group difference being 6.0% (95% CI -0.6 to 13), US 2017/01 19801 A1 May 4, 2017 31 but not at one year (Table 7). Similarly, side bending (to right 0293 At baseline, there were no differences in self and left) favored the Zoledronic acid treatment at one month reported use of non-steroidal anti-inflammatory drugs but not at one year (Table 7). Changes in total RAND-36, (NSAIDs) between the treatment groups, whereas at one and in the physical and mental components of RAND-36 are year, only 20% of patients in the ZA group used NSAIDs shown in Table 8. versus 60% in the placebo group. TABLE 6 Baseline characteristics of study population according to treatment group Zoledronic Acid Pacebo Characteristics n = 20 n = 20 Sex, n (%) men 15 (75) 11 (55) Age, mean (SD) years 49 (9.3) 51 (7.3) Smoking, n (%) regular Smokers* 5 (25) 6 (30) BMI, mean (SD) kg/m 26 (3.3) 27 (3.2) Workload, n (%) Sedentary work with limited walking 4 (20) 4 (22) Fairly light work with considerable walking but 4 (20) 3 (17) no lifting or carrying heavy objects Fairly strenuous work with walking and lifting 8 (40) 6 (33) heaving objects or climbing stairs or uphill Very strenuous work with lifting or carrying 4 (20) 5 (28) heaving objects such as shoveling, digging, or hammering Type of worst MC-lesion**, n Type I 1 1 Type I/II 19 18 Type II O 1 MC at two or more levels, n (%) 7 (3.5) 4 (20) Levels of MC, in

L2.3 4 O L3f4 3 5 L4.5 6 5 LSFS1 7 10 Duration of LBP, median (IQ range) days 330 (200, 365) 315 (270, 365) intensity of LBP, mean (SD)*** 6.6 (1.4) 6.8 (1.6) Duration of leg pain, median (IQ range) days 50 (0, 100) 36 (0, 160) intensity of leg pain, mean (SD)*** 3.0 (3.1) 2.9 (2.3) Oswestry Disability Index, %, Mean (SD) 30 (11) 35 (10) Duration of sick leave during the past year, 14 (0, 48) 18 (1, 181) median (IQ range) days RAND-36, mean (SD) 50 (8) 50 (7) RAND-36 physical component, mean (SD) 51 (8) 49 (8) RAND-36 mental component, mean (SD) 51 (8) 49 (9) BMI = Body Mass Index, MC = Modic Change, LBP = low back pain, SD = standard deviation, Q = inter-quartile, Smoking at least one cigarette per day, **If different types of MC at two or more levels, classification is based on the assumed severity of the type, i.e., Type I is mixed Type III is Type II. *** Assessed using a 10 cm Visual Analogue Scale (VAS). TABLE 7 Low back symptoms and lumbar flexibility at baseline, one month and 12 months according to treatment group and between group comparisons of difference from baseline to one month and 12 months Mean (SD) original Unadjusted Adjusted values Mean (SD) analyses analyses ZA Placebo change Difference Difference

n = 20 n = 20 ZA Placebo (95% CI) P (95% CI) P* Intensity of LBP Baseline 6.6 (1.4) 6.8 (1.6) 1 mo. 4.3 (2.3) 5.8 (2.2) -2.2 -0.9 1.3 O.097 1.4 O.049 (2.7) (2.1) (-0.2 to (0.01 to 2.8) 2.9) US 2017/01 19801 A1 May 4, 2017 32

TABLE 7-continued Low back symptoms and lumbar flexibility at baseline, one month and 12 months according to treatment group and between group comparisons of difference from baseline to one month and 12 months

Mean (SD) original Unadjusted Adjusted values Mean (SD) analyses analyses

ZA Placebo change Difference Difference

n = 20 n = 20 ZA Placebo (95% CI) (95% CI)

12 mos. 3.8 (2.5) 4.6 (2.9) -2.8 -2.2 O.6 O.474 0.7 O.387 (2.9) (2.5) (-1.1 to (-1.0 to 2.4) 2.4) Intensity of leg pain

Baseline 3.0 (3.1) 2.9 (2.3) 1 mo. 2.0 (2.3) 3.0 (2.4) -0.6 O.1 O.8 O.367 O. 8 0.237 (2.4) (2.6) (-0.9 to (-0.6 to 2.4) 2.2) 12 mos. 2.1 (2.8) 2.7 (2.6) -0.9 -0.3 O.6 0.573 O.S 0.573 (3.4) (3.0) (-1.5 to (-1.3 to 2.7) 2.2) Oswestry disability index, %

Baseline 30 (11) 35 (10) 1 mo. 24 (10) 33 (13) -59 -1.7 4.3 O.212 6.0 (11) (9.7) (-2.5 to (-0.6 to 11) 13) 12 mos. 25 (13) 33 (15) -5.0 -1.9 3.1 O.475 S.1 O.231 (15) (12) (-5.6 to (-3.4 to 12) 14) Fingers-to-floor, cm

Baseline 23 (19) 19 (18) 1 mo. 17 (17) 19 (17) -5.1 -0.1 S.O O.306 3.6 O.403 (20) (8.3) (-4.8 to -(5.0 to 15) 12) 12 mos. 16 (16) 20 (19) –6.3 0.9 (11) 7.1 O.215 5.3 0.277 (23) (-4.3 to (-4.5 to 18) 15) Sidebending to right, cm

Baseline 14.1 13.8 (4.9) (7.2) 1 mo. 15.7 13.3 1.5 -O.S -2.0 O.101 -2.0 (5.9) (6.9) (4.7) (2.2) (-4.3 to (-4.4 to 0.4) 0.3) 12 mos. 15.7 13.8 1.6 -0.1 -1.6 O.227 -1.7 (5.6) (6.5) (4.8) (3.5) (-4.3 to (-4.2 to 1.1) 0.8) Sidebending to left, cm

Baseline 1S.O 13.3 (5.4) (5.5) 1 mo. 16.1 12.8 1.1 -O.S -1.5 -1.7 (5.3) (5.9) (3.0) (2.2) (-3.2 to (-3.4 to 0.1) 0.0) 12 mos. 16.2 13.7 1.2 O.S -O.7 -1.0 O.458 (6.7) (5.7) (5.3) (3.2) (-3.5 to (-3.8 to 2.1) 1.8)

SD = standard deviation, C1 = confidence interval, ZA = zoledronic acid, LBP = low back pain. *ANCOVA: Difference between follow-up and baseline, treatment effect adjusted for baseline value. One subject missing at baseline in placebo group and in ZA group, and one subject at 1 month in ZA group, US 2017/01 19801 A1 May 4, 2017 33

TABLE 8 Health-related quality of life assessed using RAND-36 at baseline, one month, and 12 months according to treatment group and between group comparisons of difference from baseline to one month and 12 months Mean (SD) Unadjusted Adjusted Original values Mean (SD) analyses analyses ZA Placebo change Difference Difference

n = 20 n = 20 ZA Placebo (95% CI) P (95% CI) P* Total RAND-36 Baseline 50 (8) 50 (7) O. 51 (8) 49 (8) O6 -0.6 1.2 (-3 to O.S30 1.3 (-3 to 0.477 (6.4) (5.0) 5) 5) 2 mos. 51 (8) 49 (9) 1.O -1.0 2.1 (-3 to O.378 2.2 (-2 to O314 (8.7) (5.9) 7) 7) Physical component Baseline 52 (8) 48 (8) O. 52 (9) 48 (8) O.1 -0.1 0.3 (-4 to O.897 1.3 (-3 to O.SS4 (8.6) (5.5) 5) 6) 2 mos. 52 (8) 48 (2) O.3 -0.3 0.7 (-5 to O.808 2.1 (-3 to O4OS (10) (6.5) 6) 7) Mental component Baseline 49 (9) 51 (8) O. 50 (9) 50 (9) 1.O -1.0 2.0 (-2 to O.286 1.6 (-2 to O.396 (6.1) (5.6) 6) 5) 2 mos. 51 (9) 49 (9) 1.8 -1.8 3.5 (-2 to O.167 2.7 (-2 to O.261 (9.0) (6.7) 9) 7) SD = standard deviation, C1 = confidence interval, ZA = zoledronic acid. *ANCOVA: Difference between follow-up and baseline, treatment effect adjusted for baseline value.

TABLE 9 Zoledronic acid, a dose of 21 mg/kg on the first day and 3 mg/kg/day daily thereafter, or distilled water for 3 weeks Pain Reduction in Patients Treated Zoledronic Acid (cm (weeks 4-7 post-fracture). Drug was dissolved in distilled VAS Change from water and administered by gavage. Animals were fasted for Baseline 4 hours before and 2 hours after dosing. At the end of the Baseline WAS <6 -0.1 21-day period, casts were removed, and on the following Baseline VAS e6 and <7 -2.3 day, the rats were tested for hindpaw pain, edema, and Baseline WAS 7 -3.4 warmth.

Results EXAMPLE 9 0297. As illustrated in FIGS. 14-15, treatment with orally Methods: administered Zoledronic acid reversed pain and restored 0294. A study was performed to evaluate the efficacy of weight bearing as compared to the vehicle treated animals. bisphosphonates such as oral Zoledronic acid in inhibiting 0298 As illustrated in FIG. 14, von Frey pain thresholds immune responses and pain behavior in a rat fracture model for the right (fracture) hindpaw were reduced by over 100% of CRPS. as compared to baseline when oral Zoledronic acid was 0295 The effect of orally administered Zoledronic acid administered. was examined in the rat tibia fracture model of complex 0299. As illustrated in FIG. 15, reduction in weight regional pain syndrome (CRPS). CRPS was induced in the bearing, a postural effect of pain, was significantly higher in rats by fracturing the right distal tibias of the animals and the vehicle treated group as compared to the Zoledronic acid casting the fractured hindpaws for 4 weeks, as described in treated group. Weight bearing on the fracture hindlimb was Guo T Zetal. (Pain. 2004: 108: 95-107). This animal model reduced to about 80% of normal in the vehicle treated group. has been shown to replicate the inciting trauma (such as a Zoledronate treatment significantly restored hindlimb fracture, a Surgery, a crushing injury, a cutting injury, a weight bearing as compared to vehicle treatment (over 90% scratch, or a puncture injury), natural history, signs, symp of normal). toms, and pathologic changes observed in human CRPS 0300. As can be seen in FIG. 16, orally administering patients (Kingery WS et al., Pain. 2003: 104:75-84). Zoledronic acid four weeks after the fracture resulted in 0296 Starting four weeks after fracture and casting, significantly greater improvement of pain relief as compared animals were orally administered either vehicle (control) or to administration at the time of injury. US 2017/01 19801 A1 May 4, 2017 34

EXAMPLE 10 0301

e O ce C O

\ /s N C O 1. O e GE / HCl, water -Si-N He- \ O e O e Uso / e 99.7% n lu-/ 87.7% O O HO 8 9 10

H3PO3, PCl3, H2O

i. HPO3, 10 eq. O ?—\ PO,H, T toluene, 70°C., 20 min N N C ii. PC1,959 C., 2h -- N1 n-ts POH iii. HCl, H2O, 100° C., 7 h, rt, 2d OH Compound 1

POH o PO2 Ns -N 4 Na NaOH HOP Na POH to HO OH Nasalt of Compound 2 Compound 2

0302) 1,3-Bis(2-methoxy-2-oxoethyl)-1H-imidazol-3- added within 45 min to absolute EtOH (90 mL). The ium chloride (9). Methyl chloroacetate (29.8 mL, 338.6 resulting turbid solution was stirred for 1 h at room tem mmol. 2.0 eq) was added drop-wise to 1-(trimethylsilyl)- perature before the solid was filtered off. The filter cake 1H-imidazole (8; 25.0 mL, 169.3 mmol). The mixture was (Compound 2) was isolated and analyzed by 2D-NMR heated at 60° C. for 24 hours. The mixture was cooled to spectroscopy and mass spectrometry (m/z. 477). The filtrate room temperature, washed with EtO (3x500 mL) and dried was concentrated in vacuo to give a residue. This residue in vacuo yielding 9 (41.97g, 168.8 mmol. 99.7%) as a white (500mg) was treated with aq. NaOH (150 mg in 3.5 mL of solid. HO) and EtOH (7 mL). After standing overnight the liquid 0303) 1,3-Bis(carboxymethyl)1H-imidazol-3-ium chlo was decanted and the resulting solid (Nasalt of Compound ride (10). To 1,3-bis(2-methoxy-2-oxoethyl)-1H-imidazol 2) was obtained and analyzed by NMR and mass spectrom 3-ium chloride (9: 41.00 g, 164.88 mmol. 1 eq.) was added etry (m/z. 477). 37% aq. HCl (30.03 mL, 362.74 mmol. 2.2 eq.). The mixture 0306 The following embodiments are specifically con was stirred under reflux for 0.5 hour. The mixture was templated: concentrated and the remaining solid was washed with 0307 Embodiment 1. A method of relieving inflamma acetone (2x200 mL) and EtO (3x200 mL). Drying in vacuo tory pain comprising administering an oral dosage form gave 10 (31.89 g, 144.55 mmol, 87.7%) as a white solid. containing Zoledronic acid to a mammal in need thereof, 0304 Compound 1: Compound 10 is reacted with an wherein the mammal receives a total monthly dose of equimolar amount of phosphorous acid, followed by an zoledronic acid that is about 800 mg/m or less based upon equimolar amount of phosphorous trichloride, and an excess the body Surface area of the mammal. of water to form Compound 1, which is precipitated from 0308 Embodiment 2. The method of embodiment 1, ethanol. wherein the mammal is a human being that receives a total 0305 Compound 2: 1,3-Bis(carboxymethyl)-1H-imida monthly dose of Zoledronic acid that is about 30 mg/m to Zol-3-ium chloride (10, 2.00 g, 9 mmol. 1.0 eq) and HPO. about 700 mg/m. (7.37 g. 90 mmol. 10 eq) were dissolved in toluene (10 mL) 0309 Embodiment 3. The method of embodiment 2, and heated to 70° C. The reaction mixture was stirred at this wherein the total monthly dose is administered in 4 or 5 temperature for 20 min before PC1 (16 mL, 180 mmol. 20 weekly doses. eq) was added within 30 min. The reaction mixture was then 0310 Embodiment 4. The method of embodiment 2, heated to 95°C. and stirred at this temperature for 2 h. Then, wherein the total monthly dose is administered in 28 to 31 aq. HCl (30 mL, 37% HCl and 5 mL HO) was added. The daily doses. reaction mixture was heated to 100° C. and stirred at this 0311 Embodiment 5. The method of embodiment 2, temperature for 7 h, then stirred at room temperature for 2 wherein the total monthly dose is administered in 5 to 10 days and filtered. The filtrate was cooled in an ice bath and individual doses during the month. US 2017/01 19801 A1 May 4, 2017

0312 Embodiment 6. The method of embodiment 1, 0329 Embodiment 23. The method of embodiment 21, wherein the mammal is a human being that receives a total wherein the total monthly dose is administered in 28 to 31 weekly dose of Zoledronic acid that is about 10 mg to about daily doses. 300 mg. 0330 Embodiment 24. The method of embodiment 21, 0313 Embodiment 7. The method of embodiment 6, wherein the total monthly dose is administered in 5 to 10 wherein the total weekly dose is a single dose, administered individual doses during the month. once a week. 0331 Embodiment 25. The method of embodiment 20, 0314 Embodiment 8. The method of embodiment 6, wherein the human being receives a total weekly dose of wherein the total weekly dose is administered in 2 to 7 Zoledronic acid that is about 100 mg to about 300 mg. individual doses during the week. 0315 Embodiment 9. The method of embodiment 1, 0332 Embodiment 26. The method of embodiment 25, wherein the mammal is a human being that receives a total wherein the total weekly dose is a single dose, administered weekly dose of Zoledronic acid that is about 10 mg to about once a week. 150 mg. 0333 Embodiment 27. The method of embodiment 25, 0316 Embodiment 10. The method of any preceding wherein the total weekly dose is administered in 2 to 7 embodiment, wherein the mammal experiences significant individual doses during the week. pain relief more than 3 hours after administration of the 0334 Embodiment 28. The method of embodiment 20, dosage form. wherein the human being receives a total weekly dose of 0317 Embodiment 11. The method of embodiment 10, Zoledronic acid that is about 10 mg to about 100 mg. wherein the mammal experiences significant pain relief 0335 Embodiment 29. The method of any of embodi during at least a part of a time from about 3 hours to about ments 20-28, wherein the human being experiences signifi 24 hours after administration of the dosage form. cant pain relief more than 3 hours after administration of the 0318 Embodiment 12. The method of embodiment 10, dosage form. wherein the mammal experiences significant pain relief 0336 Embodiment 30. The method of embodiment 29, during at least a part of a time from about 3 hours to about wherein the human being experiences significant pain relief 3 weeks after administration of the dosage form. during at least a part of a time from about 3 hours to about 0319 Embodiment 13. A method of relieving inflamma 24 hours after administration of the dosage form. tory pain comprising administering an oral dosage form 0337 Embodiment 31. The method of embodiment 29, containing Zoledronic acid to a mammal in need thereof, wherein the human being experiences significant pain relief wherein the oral dosage form contains about 10 mg/m to during at least a part of a time from about 3 hours to about about 20 mg/m of Zoledronic acid based upon the body 3 weeks after administration of the dosage form. Surface area of the mammal. 0338 Embodiment 32. The method of any of embodi 0320 Embodiment 14. The method of embodiment 13, ments 20-31, wherein the dosage form contains about 10 wherein the oral dosage form contains about 15 mg/m to mg/m to about 20 mg/m of Zoledronic acid based upon the about 20 mg/m of Zoledronic acid based upon the body body Surface area of the human being. Surface area of the mammal. 0339 Embodiment 33. The method of embodiment 32, 0321 Embodiment 15. A method of relieving inflamma wherein the dosage form contains about 15 mg/m to about tory pain comprising orally administering to a mammal in 20 mg/m of Zoledronic acid based upon the body surface need thereof, about 300 mg/m to about 600 mg/m of area of the human being. Zoledronic acid per month to the mammal, based upon the 0340 Embodiment 34. The method of any of embodi body Surface area of the mammal. ments 20-33, wherein about 50 mg/m to about 200 mg/m 0322 Embodiment 16. The method of embodiment 15, comprising orally administering about 450 mg/m to about of Zoledronic acid is orally administered per month, based 600 mg/m of Zoledronic acid per month to the mammal, upon the body Surface area of the human being. based upon the body Surface area of the mammal. 0341 Embodiment 35. The method of any of embodi 0323 Embodiment 17. The method of any preceding ments 20-31, wherein the dosage form contains about 80 embodiment, wherein the mammal is not suffering from mg/m to about 150 mg/m of Zoledronic acid based upon bone metastasis. the body Surface area of the human being. 0324 Embodiment 18. The method of any preceding 0342 Embodiment 36. The method of embodiment 35, embodiment, wherein the mammal is not suffering from wherein about 300 mg/m to about 1000 mg/m of Zole CaCC. dronic acid is orally administered per month, based upon the 0325 Embodiment 19. The method of any preceding body Surface area of the human being. embodiment, wherein the Zoledronic acid is administered as (0343 Embodiment 37. The method of any of embodi a salt of a dianion of Zoledronic acid. ments 20-36, wherein the human being is not suffering from 0326 Embodiment 20. A method of relieving pain asso bone metastasis. ciated with an arthritis comprising administering an oral 0344) Embodiment 38. The method of any of embodi dosage form containing Zoledronic acid to a human being in ments 20-37, wherein the human being is not suffering from need thereof. CaCC. 0327 Embodiment 21. The method of embodiment 20, 0345 Embodiment 39. The method of any preceding wherein the human being receives a total monthly dose of embodiment, wherein the Zoledronic acid is in the disodium Zoledronic acid that is about 40 mg to about 2000 mg. salt form. 0328 Embodiment 22. The method of embodiment 21, 0346 Embodiment 40. An oral dosage form comprising wherein the total monthly dose is administered in 4 or 5 Zoledronic acid, wherein the oral bioavailability of Zole weekly doses. dronic acid in the dosage form is about 0.01% to about 4%. US 2017/01 19801 A1 May 4, 2017 36

0347 Embodiment 41. The oral dosage form of embodi 03.64 Embodiment 58. The oral dosage form of any ment 40, wherein the oral dosage form contains about 10 mg preceding embodiment, wherein the Zoledronic acid is in a to about 300 mg of Zoledronic acid. form that has an aqueous solubility greater than 1% (w/v). 0348 Embodiment 42. The oral dosage form of embodi 0365 Embodiment 59. The oral dosage form of any ment 40, wherein the oral dosage form contains about 10 mg preceding embodiment, wherein the Zoledronic acid is in a to about 50 mg of Zoledronic acid. form that has an aqueous solubility of about 5% (w/v) to 0349 Embodiment 43. The oral dosage form of any of about 50% (w/v). embodiments 40-42, wherein the oral bioavailability of 0366 Embodiment 60. An oral dosage form comprising Zoledronic acid in the dosage form is about 0.1% to about Zoledronic acid and an excipient, wherein the Zoledronic 2%. acid is in a form that has an aqueous solubility greater than 0350 Embodiment 44. A pharmaceutical product com 1% (w/v). prising more than one unit of an oral dosage form of 0367 Embodiment 61. The oral dosage form of embodi embodiment 40. ment 60, wherein the Zoledronic acid is in a form that has an 0351. Embodiment 45. The pharmaceutical product of aqueous solubility of about 5% (w/v) to about 50% (w/v). embodiment 44, wherein each unit of the oral dosage form 0368 Embodiment 62. A method of treating complex contains about 1 mg to about 50 mg of Zoledronic acid. regional pain syndrome comprising administering an oral 0352 Embodiment 46. The pharmaceutical product of dosage form containing Zoledronic acid to a mammal in embodiment 45, comprising 28, 29, 30, or 31 units of the need thereof. oral dosage form, for a total of about 28 mg to about 1600 0369 Embodiment 63. The method of embodiment 62, mg of Zoledronic acid to be administered in about 1 month. wherein the mammal is a human being that receives an 0353 Embodiment 47. The pharmaceutical product of amount of Zoledronic acid that is about 30 mg/m to about embodiment 45, comprising 85 to 95 units of the oral dosage 700 mg/m in a period of one month or less. form, for a total of about 85 mg to about 4800 mg of 0370 Embodiment 64. The method of embodiment 63, Zoledronic acid to be administered in about 3 months. wherein 4 or 5 weekly doses are administered in a period of 0354 Embodiment 48. The pharmaceutical product of one month or less. embodiment 45, comprising 170 to 200 units of the oral 0371 Embodiment 65. The method of embodiment 63, dosage form, for a total of about 170 mg to about 10,000 mg wherein 28 to 31 daily doses are administered in a period of of Zoledronic acid to be administered in about 6 months. one month or less. 0355 Embodiment 49. The pharmaceutical product of 0372 Embodiment 66. The method of embodiment 63, embodiment 45, comprising 350 to 380 units of the oral wherein 5 to 10 individual doses are administered during a dosage form, for a total of about 350 mg to about 19,000 mg period of one month or less. of Zoledronic acid to be administered in about 1 year. 0373 Embodiment 67. The method of embodiment 63, 0356. Embodiment 50. The pharmaceutical product of wherein about 30 mg/m to about 700 mg/m of Zoledronic embodiment 44, wherein each unit of the oral dosage form acid is administered during only one month. contains about 10 mg to about 300 mg. 0374 Embodiment 68. The method of embodiment 63, 0357 Embodiment 51. The pharmaceutical product of wherein about 30 mg/m to about 700 mg/m of Zoledronic embodiment 50, comprising 4 or 5 units of the oral dosage acid is administered in a period of one month or less for 2 form, for a total of about 40 mg to about 1500 mg of or more consecutive months. Zoledronic acid to be administered within a period of about 0375 Embodiment 69. The method of embodiment 62, 1 month. wherein the mammal receives about 10 mg/m to about 30 0358 Embodiment 52. The pharmaceutical product of mg/m of Zoledronic acid daily. embodiment 50, comprising 8 or 9 units of the oral dosage 0376 Embodiment 70. The method of embodiment 62, form, for a total of about 80 mg to about 2700 mg of wherein the mammal is a human being that receives a total Zoledronic acid to be administered in about 2 months. weekly dose of Zoledronic acid that is about 10 mg to about 0359 Embodiment 53. The pharmaceutical product of 300 mg. embodiment 50, comprising 12, 13 or 14 units of the oral 0377 Embodiment 71. The method of embodiment 70, dosage form, for a total of about 120 mg to about 4200 mg wherein the total weekly dose is a single dose, administered of Zoledronic acid to be administered in about 3 months. once a week. 0360 Embodiment 54. The pharmaceutical product of 0378 Embodiment 72. The method of embodiment 70, embodiment 50, comprising 22 to 30 units of the oral dosage wherein the total weekly dose is administered in 2 to 7 form, for a total of about 220 mg to about 9000 mg of individual doses during the week. Zoledronic acid to be administered in about 6 months. 0379 Embodiment 73. The method of any of embodi 0361 Embodiment 55. The pharmaceutical product of ments 62-72, wherein the complex regional pain syndrome embodiment 50, comprising 45 to 60 units of the oral dosage is complex regional pain syndrome type I. form, for a total of about 450 mg to about 18000 mg of (0380 Embodiment 74. The method of any of embodi Zoledronic acid to be administered in about 1 year. ments 62-72, wherein the complex regional pain syndrome 0362 Embodiment 56. The pharmaceutical product of is complex regional pain syndrome type II. embodiment 44, comprising 1 to 10 units of the oral dosage 0381 Embodiment 75. The method of any preceding form, wherein the product contains about 200 mg to about embodiment, wherein the Zoledronic acid is in a salt form. 2000 mg of Zoledronic acid. (0382 Embodiment 76. The method of any of embodi 0363 Embodiment 57. The oral dosage form of any ments 62-75, wherein the dosage form contains about 10 preceding embodiment, wherein the Zoledronic acid is in the mg/m to about 20 mg/m of Zoledronic acid based upon the form of a sodium salt. body Surface area of the mammal. US 2017/01 19801 A1 May 4, 2017 37

0383 Embodiment 77. The method of embodiment 76, 04.04 Embodiment 98. A method of treating arthritis wherein the dosage form contains about 15 mg/m to about pain, comprising administering risedronic acid to a human 20 mg/m of Zoledronic acid based upon the body surface being in need thereof. area of the mammal. 04.05 Embodiment 99. A method of treating inflamma 0384 Embodiment 78. A method of treating complex tory pain, comprising administering pamidronic acid to a regional pain syndrome, comprising administering human being in need thereof. pamidronic acid to a human being in need thereof. 04.06 Embodiment 100. A method of treating inflamma 0385 Embodiment 79. A method of treating complex tory pain, comprising administering neridronic acid to a regional pain syndrome, comprising administering human being in need thereof. neridronic acid to a human being in need thereof. 04.07 Embodiment 101. A method of treating inflamma 0386 Embodiment 80. A method of treating complex tory pain, comprising administering olpadronic acid to a regional pain syndrome, comprising administering olpad human being in need thereof. ronic acid to a human being in need thereof. 04.08 Embodiment 102. A method of treating inflamma 0387 Embodiment 81. A method of treating complex tory pain, comprising administering alendronic acid to a regional pain syndrome, comprising administering alen human being in need thereof. dronic acid to a human being in need thereof. 04.09 Embodiment 103. A method of treating inflamma 0388 Embodiment 82. A method of treating complex tory pain, comprising administering incadronic acid to a regional pain syndrome, comprising administering incad human being in need thereof. ronic acid to a human being in need thereof. 0410 Embodiment 104. A method of treating inflamma 0389 Embodiment 83. A method of treating complex tory pain, comprising administering ibandronic acid to a regional pain syndrome, comprising administering iban human being in need thereof. dronic acid to a human being in need thereof. 0411 Embodiment 105. A method of treating inflamma 0390 Embodiment 84. A method of treating complex tory pain, comprising administering risedronic acid to a regional pain syndrome, comprising administering rise human being in need thereof. dronic acid to a human being in need thereof. 0412 Embodiment 106. A method of treating complex 0391) Embodiment 85. A method of treating pain, com regional pain syndrome, comprising administering etidronic prising administering pamidronic acid to a human being in acid to a human being in need thereof. need thereof. 0413 Embodiment 107. A method of treating pain, com 0392 Embodiment 86. A method of treating pain, com prising administering etidronic acid to a human being in prising administering neridronic acid to a human being in need thereof. need thereof. 0393 Embodiment 87. A method of treating pain, com 0414 Embodiment 108. A method of treating arthritis prising administering olpadronic acid to a human being in pain, comprising administering etidronic acid to a human need thereof. being in need thereof. 0394 Embodiment 88. A method of treating pain, com 0415 Embodiment 109. A method of treating inflamma prising administering alendronic acid to a human being in tory pain, comprising administering etidronic acid to a need thereof. human being in need thereof. 0395 Embodiment 89. A method of treating pain, com 0416 Embodiment 110. A method of treating complex prising administering incadronic acid to a human being in regional pain syndrome, comprising administering clodronic need thereof. acid to a human being in need thereof. 0396 Embodiment 90. A method of treating pain, com 0417 Embodiment 111. A method of treating pain, com prising administering ibandronic acid to a human being in prising administering clodronic acid to a human being in need thereof. need thereof. 0397 Embodiment 91. A method of treating pain, com 0418 Embodiment 112. A method of treating arthritis prising administering risedronic acid to a human being in pain, comprising administering clodronic acid to a human need thereof. being in need thereof. 0398 Embodiment 92. A method of treating arthritis 0419 Embodiment 113. A method of treating inflamma pain, comprising administering pamidronic acid to a human tory pain, comprising administering clodronic acid to a being in need thereof. human being in need thereof. 0399 Embodiment 93. A method of treating arthritis 0420 Embodiment 114. A method of treating complex pain, comprising administering neridronic acid to a human regional pain syndrome, comprising administering being in need thereof. tiludronic acid to a human being in need thereof. 04.00 Embodiment 94. A method of treating arthritis 0421 Embodiment 115. A method of treating pain, com pain, comprising administering olpadronic acid to a human prising administering tiludronic acid to a human being in being in need thereof. need thereof. 04.01 Embodiment 95. A method of treating arthritis 0422 Embodiment 116. A method of treating arthritis pain, comprising administering alendronic acid to a human pain, comprising administering tiludronic acid to a human being in need thereof. being in need thereof. 04.02 Embodiment 96. A method of treating arthritis 0423 Embodiment 117. A method of treating inflamma pain, comprising administering incadronic acid to a human tory pain, comprising administering tiludronic acid to a being in need thereof. human being in need thereof. 0403 Embodiment 97. A method of treating arthritis 0424. Embodiment 118. The method of any of embodi pain, comprising administering ibandronic acid to a human ments 78-117, wherein the active compound is orally admin being in need thereof. istered. US 2017/01 19801 A1 May 4, 2017

0425 Embodiment 119. The method of any of embodi 0437. Embodiment 131. The method of embodiment 129, ments 78-117, wherein the active compound is parenterally wherein the disodium salt form is administered in an administered. amount, on a molar basis, that has a value of about 0.8 n to 0426 Embodiment 120. A method of enhancing the oral about 1.2 n, wherein: bioavailability of Zoledronic acid comprising orally admin ni (b/b)(n) istering a dosage form containing Zoledronic acid in the disodium salt form. wherein b is the bioavailability of the diacid form, b is the 0427 Embodiment 121. The method of embodiment 120, bioavailability of the disodium salt form, and n is the wherein the Zoledronic acid in the disodium salt form number of moles of Zoledronic acid in the diacid form that provides an enhancement to bioavailability, as compared to would be administered in order to achieve the same plasma Zoledronic acid in the diacid form, which adds to any levels of Zoledronic acid. enhancement to bioavailability provided by any bioavail 0438 Embodiment 132. The method of embodiment 131, ability-enhancing agents in the dosage form. wherein the disodium salt is administered in an amount that 0428 Embodiment 122. The method of embodiment 120, has a value of about n. wherein the dosage form is substantially free of bioavail 0439 Embodiment 133. The method of any of embodi ability-enhancing agents. ments 120-132, wherein the Zoledronic acid is used to treat 0429 Embodiment 123. The method of embodiment 120, an inflammatory condition. wherein the Zoledronic acid in the disodium salt form is 0440 Embodiment 134. The method of embodiment 133, administered to a mammal in an amount that provides an wherein the Zoledronic acid is used to treat arthritis. area under the plasma concentration curve of Zoledronic acid of about 4 ngh/mL to about 2000 ngh/mL to the mammal 0441 Embodiment 135. The method of embodiment 133, each time the Zoledronic acid in the disodium salt is admin wherein the Zoledronic acid is used to treat complex regional istered. pain syndrome. 0430 Embodiment 124. The method of embodiment 123, 0442 Embodiment 136. The method of any of embodi wherein the Zoledronic acid in the disodium salt form is ments 1-39, 62-77, and 120-135, wherein: administered at an interval of about 3 to about 4 weeks in an 0443) a first oral dosage form is administered; and amount that provides an area under the plasma concentration curve of Zoledronic acid of about 100 ngh/mL to about 2000 0444 a second oral dosage form is administered; ngth/mL to the mammal each time the Zoledronic acid in the 0445 wherein, with respect to the first oral dosage form, disodium salt form is administered. the second oral dosage form is administered at 10xT or 0431. Embodiment 125. The method of embodiment 123, greater, wherein T is the time of maximum plasma wherein the Zoledronic acid in the disodium salt form is concentration for the first oral dosage form. administered weekly, or 3 to 5 times in a month, in an 0446. Embodiment 137. A dosage form comprising Zole amount that provides an area under the plasma concentration dronic acid in the disodium salt form, wherein the bioavail curve of Zoledronic acid of about 20 ngh/mL to about 700 ability, in a mammal, of Zoledronic acid in the disodium salt ngth/mL to the mammal each time the Zoledronic acid in the form is greater than the bioavailability of Zoledronic acid in disodium salt form is administered. the diacid form would be in the same dosage form. 0432 Embodiment 126. The method of embodiment 123, 0447 Embodiment 138. A dosage form comprising Zole wherein the Zoledronic acid in the disodium salt form is dronic acid in the disodium salt form, wherein the dosage administered daily in an amount that provides an area under form contains an amount of Zoledronic acid in the disodium the plasma concentration curve of Zoledronic acid of about salt form that provides an area under the plasma concentra 4 ngh/mL to about 100 ngh/mL to the mammal each time tion curve of Zoledronic acid of about 4 ngh/mL to about the Zoledronic acid in the disodium salt form is adminis 2000 ngh/mL to a human being to which the dosage form tered. is administered. 0433 Embodiment 127. The method of embodiment 120, 0448 Embodiment 139. The dosage form of embodiment wherein the dosage form is a solid. 138, wherein the dosage form contains an amount of Zole 0434 Embodiment 128. The method of embodiment 120, dronic acid in the disodium salt form that provides an area 121, 122, 123, 124, 125, 126, or 127, wherein the bioavail under the plasma concentration curve of Zoledronic acid of ability of Zoledronic acid is improved by at least about 20% about 100 ngh/mL to about 2000 ngh/mL to a human being as compared to administration of Zoledronic acid in the to which the dosage form is administered. diacid form. 0449 Embodiment 140. The dosage form of embodiment 0435 Embodiment 129. The method of embodiment 120, 138, wherein the dosage form contains an amount of Zole 121, 122, 123, 124, 125, 126, 127, or 128, further compris dronic acid in the disodium salt form that provides an area ing administering, on a molar basis, less of the Zoledronic under the plasma concentration curve of Zoledronic acid of acid in the disodium salt form than would be administered about 20 ngh/mL to about 700 ngh/mL to a human being to of Zoledronic acid in the diacid form in order to achieve the which the dosage form is administered. same plasma levels of Zoledronic acid. 0450 Embodiment 141. The dosage form of embodiment 0436 Embodiment 130. The method of embodiment 129, 138, wherein the dosage form contains an amount of Zole wherein at least about 10 mole % less of the disodium salt dronic acid in the disodium salt form that provides an area form is administered as compared the amount of Zoledronic under the plasma concentration curve of Zoledronic acid of acid in the diacid form that would be administered in order about 4 ngh/mL to about 100 ngh/mL to a human being to to achieve the same plasma levels of Zoledronic acid. which the dosage form is administered. US 2017/01 19801 A1 May 4, 2017 39

0451 Embodiment 142. A dosage form comprising Zole 0466 Embodiment 152. The method of any of embodi dronic acid in the disodium salt form, ments 20-39, wherein the human being is about 30 years old 0452 wherein the disodium salt form is present in a to about 75 years old. lower molar amount than would be present if the Zoledronic 0467 Embodiment 153. The method of any of embodi acid were in the diacid form; and ments 20-39, wherein the human being is about 1 year old 0453 wherein the Zoledronic acid in the disodium salt to about 16 years old. form has an improved bioavailability as compared to the 0468 Embodiment 154. The method of any of embodi Zoledronic acid in the diacid form to the extent that the lower ments 20-39, wherein the human being is about 80 years old molar amount of the disodium salt in the dosage form does to about 95 years old. not reduce the amount of Zoledronic acid delivered to the 0469 Embodiment 155. The method of any of embodi plasma of a mammal. ments 20-39, wherein the human being has suffered from the 0454. Embodiment 143. The dosage form of embodiment arthritis for at least 2 months. 137, 138, 139, 140, 141, or 142, wherein the dosage form is 0470 Embodiment 156. The method of any of embodi a solid. ments 20-39, wherein the arthritis affects, a knee, an elbow, 0455 Embodiment 144. The dosage form of embodiment a wrist, a shoulder, or a hip. 142 or 143, wherein the bioavailability of Zoledronic acid in 0471 Embodiment 157. The method of any of embodi the disodium salt form is improved by at least about 10% as ments 1-44, 62-133, and 144-156, wherein the mammal or compared to an otherwise identical dosage form containing human being to which the Zoledronic acid is administered Zoledronic acid in the diacid form. does not eat food or drink beverage for at least 1 hour before 0456. Embodiment 145. The dosage form of embodiment the Zoledronic acid is administered. 142, 143, or 144, containing at least about 20 mole % less 0472. Embodiment 158. The method of embodiment 157, of the disodium salt form as compared to the amount of the wherein the mammal or human being to which the Zole Zoledronic acid in the diacid form that would be present if dronic acid is administered does not eat food or drink the Zoledronic acid were in the diacid form. beverage for at least 2 hours before the Zoledronic acid is administered. 0457 Embodiment 146. The dosage form of embodiment 0473 Embodiment 159. The method of embodiment 158, 142, wherein the disodium salt form is present in an amount, wherein the mammal or human being to which the Zole on a molar basis, that has a value of about 0.9 nd to about dronic acid is administered does not eat food or drink 1.1 nd, wherein: beverage for at least 4 hours before the Zoledronic acid is ni (b./b)(n) administered. 0458 wherein b is the bioavailability of the diacid form, 0474 Embodiment 160. The method of embodiment 159, b is the bioavailability of the disodium salt form, and n is wherein the mammal or human being to which the Zole the number of moles of the diacid form that would be present dronic acid is administered does not eat food or drink if the Zoledronic acid were in the diacid form. beverage for at least 6 hours before the Zoledronic acid is administered. 0459 Embodiment 147. The dosage form of embodiment 0475 Embodiment 161. The method of any of embodi 146, wherein the disodium salt is administered in an amount ments 157-160, wherein the mammal or human being to that has a value of about n. which the Zoledronic acid is administered does not eat food 0460 Embodiment 148. The method of any of embodi or drink beverage for at least 30 minutes after the Zoledronic ments 1-39, 62-77, and 120-136, wherein: acid is administered. 0461) only a single oral dosage form is administered; or 0476 Embodiment 162. The method of embodiment 161, 0462 a first oral dosage form is administered, and a wherein the mammal or human being to which the Zole second oral dosage form is administered after the first oral dronic acid is administered does not eat food or drink dosage form, wherein the second oral dosage form is admin beverage for at least 1 hour after the Zoledronic acid is istered before the maximum pain relieving effect of the first administered. oral dosage form is achieved, or the second oral dosage form 0477 Embodiment 163. The method of embodiment 161, is administered before an observable pain relieving effect is where in the mammal or human being to which the Zole achieved. dronic acid is administered does not eat food or drink 0463 Embodiment 149. The method of embodiment 148, beverage for at least 2 hours after the Zoledronic acid is wherein the second oral dosage form is administered before administered. an observable pain relieving effect is achieved. 0478 Embodiment 164. The method, dosage form, or 0464 Embodiment 150. The method of any of embodi product, of any preceding embodiment, wherein the Zole ments 1-39, 62-77, and 120-132, wherein a first dosage form dronic acid in the oral dosage form has a 24 hour Sustained is administered, followed by administration of a second plasma level factor of about 1 or higher. dosage form, wherein the second dosage form is adminis 0479 Embodiment 165. The method, dosage form, or tered after the maximum pain relieving effect of the first oral product, of any preceding embodiment, wherein the Zole dosage form is achieved, and the second oral dosage form is dronic acid in the oral dosage form has a 24 hour Sustained administered while a pain relieving effect from the first oral plasma level factor that is higher than that of intravenously dosage form is observable. administered Zoledronic acid. 0465 Embodiment 151. The method of embodiment 148, 0480 Embodiment 166. The method, dosage form, or 149, or 150, wherein the second oral dosage form is admin product, of any preceding embodiment, wherein the oral istered about 24 hours to about 28 days after the first oral dosage form is a solid that has a hardness of about 5 kPa to dosage form is administered. about 20 kPa. US 2017/01 19801 A1 May 4, 2017 40

0481 Embodiment 167. A method of treating bone mar activity comprises Zoledronic acid, and the weekly dose is row lesions comprising: selecting a patient having a bone between about 25 mg and about 75 mg. marrow lesion and OARSI grade 0 of joint space narrowing, 0500 Embodiment 186. A method of treating knee pain and administering an inhibitor of osteoclast activity to the comprising: selecting a patient having knee pain and OARSI patient for the treatment of the bone marrow lesion. grade 0 of joint space narrowing, and administering an 0482 Embodiment 168. The method of embodiment 167, inhibitor of osteoclast activity to the patient for the treatment wherein the inhibitor of osteoclast activity is administered at of the knee pain. least twice. 0501 Embodiment 187. The method of embodiment 186, 0483 Embodiment 169. The method of embodiment 167, wherein the inhibitor of osteoclast activity is administered at wherein the inhibitor of osteoclast activity is administered least twice. about every three months, or more frequently. (0502. Embodiment 188. The method of any one of 0484 Embodiment 170. The method of embodiment 167, embodiments 186-187, wherein the inhibitor of osteoclast wherein the inhibitor of osteoclast activity comprises a activity is administered about every three months, or more nitrogen-containing bisphosphonate. frequently. 0485 Embodiment 171. The method of any one of embodiments 167-170, wherein the inhibitor of osteoclast (0503 Embodiment 189. The method of any one of activity is or comprises Zoledronic acid. embodiments 186-188, wherein the inhibitor of osteoclast 0486 Embodiment 172. The method of any one of activity comprises a nitrogen-containing bisphosphonate. embodiments 167-170, wherein the inhibitor of osteoclast (0504 Embodiment 190. The method of any one of activity is or comprises pamidronic acid. embodiments 186-189, wherein the patient experiences pain 0487. Embodiment 173. The method of any one of relief three months after administration of the inhibitor of embodiments 167-170, wherein the inhibitor of osteoclast osteoclast activity. activity is or comprises neridronic acid. (0505 Embodiment 191. The method of any one of 0488 Embodiment 174. The method of any one of embodiments 186-190, wherein the inhibitor of osteoclast embodiments 167-170, wherein the inhibitor of osteoclast activity is or comprises Zoledronic acid. activity is or comprises olpadronic acid. (0506 Embodiment 192. The method of any one of 0489 Embodiment 175. The method of any one of embodiments 186-190, wherein the inhibitor of osteoclast embodiments 167-170, wherein the inhibitor of osteoclast activity is or comprises pamidronic acid. activity is or comprises alendronic acid. 0507 Embodiment 193. The method of any one of 0490 Embodiment 176. The method of any one of embodiments 186-190, wherein the inhibitor of osteoclast embodiments 167-170, wherein the inhibitor of osteoclast activity is or comprises neridronic acid. activity is or comprises incadronic acid. (0508 Embodiment 194. The method of any one of 0491 Embodiment 177. The method of any one of embodiments 186-190, wherein the inhibitor of osteoclast embodiments 167-170, wherein the inhibitor of osteoclast activity is or comprises olpadronic acid. activity is or comprises ibandronic acid. (0509 Embodiment 195. The method of any one of 0492 Embodiment 178. The method of any one of embodiments 186-190, wherein the inhibitor of osteoclast embodiments 167-170, wherein the inhibitor of osteoclast activity is or comprises alendronic acid. activity is or comprises risedronic acid. 0510 Embodiment 196. The method of any one of 0493 Embodiment 179. The method of any one of embodiments 186-190, wherein the inhibitor of osteoclast embodiments 167-178, wherein the inhibitor of osteoclast activity is or comprises incadronic acid. activity is administered orally. 0494 Embodiment 180. The method of any one of 0511 Embodiment 197. The method of any one of embodiments 167-178, wherein the inhibitor of osteoclast embodiments 186-190, wherein the inhibitor of osteoclast activity is administered intravenously. activity is or comprises ibandronic acid. 0495 Embodiment 181. The method of any one of 0512 Embodiment 198. The method of any one of embodiments 167-180, wherein the patient experiences a embodiments 186-190, wherein the inhibitor of osteoclast reduction in bone marrow lesion size that is at least about activity is or comprises risedronic acid. 100% greater than a reduction in bone marrow lesion size 0513. Embodiment 199. The method of any one of achieved with a placebo. embodiments 186-198, wherein the patient experiences a 0496 Embodiment 182. The method of any one of reduction in pain intensity—when using a 100 mm visual embodiments 167-180, wherein the patient experiences a analog scale—of at least about 20. reduction in bone marrow lesion size that is at least about 0514 Embodiment 200. A method of treating a bone 150% greater than a reduction in bone marrow lesion size marrow lesion of the knee comprising: selecting a patient achieved with a placebo. having a bone marrow lesion of the knee and OARSI Grade 0497 Embodiment 183. The method of any one of 0 or Kellgren and Lawrence Grade 0 or Grade 1 of joint embodiments 167-182, wherein the inhibitor of osteoclast space narrowing, and administering an inhibitor of osteo activity is administered at least twice over a period of at least clast activity to the patient for the treatment of the bone four weeks. marrow lesion. 0498 Embodiment 184. The method of any one of 0515 Embodiment 201. The method of embodiment 200, embodiments 167-183, wherein the inhibitor of osteoclast wherein the inhibitor of osteoclast activity is administered at activity is administered once weekly for a period of six least twice. weeks. 0516 Embodiment 202. The method of embodiment 201, 0499 Embodiment 185. The method of any one of wherein the inhibitor of osteoclast activity is administered embodiments 167-184, wherein the inhibitor of osteoclast about every three months, or more frequently. US 2017/01 19801 A1 May 4, 2017

0517 Embodiment 203. The method of embodiment 200, 0538 b. administering an inhibitor of osteoclast activity wherein the inhibitor of osteoclast activity comprises a to the patient. nitrogen-containing bisphosphonate. 0539 Embodiment 221. The method of embodiment 220, 0518 Embodiment 204. The method of embodiment 203, comprising selecting a patient having OARSI Grade 0 or wherein the inhibitor of osteoclast activity is Zoledronic Kellgren and Lawrence Grade 0 or Grade 1 of joint space acid. narrowing. 0519 Embodiment 205. The method of embodiment 203, 0540 Embodiment 222. The method of embodiment 220 wherein the inhibitor of osteoclast activity is pamidronic or 221, comprising selecting a patient having pain intensity acid. of 5 or greater measured using the 0-10 NRS or 5 cm or 0520 Embodiment 206. The method of embodiment 203, greater using the 10 cm VAS. wherein the inhibitor of osteoclast activity is neridronic acid. 0541. Embodiment 223. The method of embodiment 220, 0521. Embodiment 207. The method of embodiment 203, wherein the inhibitor of osteoclast activity is administered at wherein the inhibitor of osteoclast activity is olpadronic least twice. acid. 0542 Embodiment 224. The method of embodiment 223, 0522. Embodiment 208. The method of embodiment 203, wherein the inhibitor of osteoclast activity is administered wherein the inhibitor of osteoclast activity is minodronic about every three months, or more frequently. acid. 0543. Embodiment 225. The method of embodiment 220, 0523 Embodiment 209. The method of embodiment 203, wherein the inhibitor of osteoclast activity comprises a wherein the inhibitor of osteoclast activity is incadronic nitrogen-containing bisphosphonate. acid. 0544 Embodiment 226. The method of embodiment 220, 0524. Embodiment 210. The method of embodiment 203, wherein the patient experiences pain relief within about wherein the inhibitor of osteoclast activity is ibandronic three months after the inhibitor of osteoclast activity is acid. administered to the patient. 0545 Embodiment 227. The method of embodiment 226, 0525 Embodiment 211. The method of embodiment 203, wherein the patient experiences pain relief at least 24 hours wherein the inhibitor of osteoclast activity is risedronic acid. after the inhibitor of osteoclast activity is administered to the 0526 Embodiment 212. The method of embodiment 203, patient. wherein the inhibitor of osteoclast activity is alendronic 0546 Embodiment 228. The method of embodiment 220, acid. wherein the inhibitor of osteoclast activity is Zoledronic 0527 Embodiment 213. The method of embodiment 200, acid. wherein the inhibitor of osteoclast activity is administered orally. (0547 Embodiment 229. The method of embodiment 220, wherein the inhibitor of osteoclast activity is minodronic 0528 Embodiment 214. The method of embodiment 200, acid. wherein the inhibitor of osteoclast activity is administered 0548 Embodiment 230. The method of embodiment 220, intravenously. wherein the inhibitor of osteoclast activity is neridronic acid. 0529 Embodiment 215. The method of embodiment 200, 0549. Embodiment 231. The method of embodiment 220, wherein the patient experiences a reduction in bone marrow wherein the inhibitor of osteoclast activity is olpadronic lesion size that is at least about 15% within about 6 months acid. after the inhibitor of osteoclast activity is administered to the patient. 0550 Embodiment 232. The method of embodiment 220, wherein the inhibitor of osteoclast activity is alendronic 0530 Embodiment 216. The method of embodiment 200, acid. wherein the patient experiences a reduction in bone marrow lesion size that is at least about 25% within about 6 months 0551 Embodiment 233. The method of embodiment 220, after the inhibitor of osteoclast activity is administered to the wherein the inhibitor of osteoclast activity is incadronic patient. acid. 0552. Embodiment 234. The method of embodiment 220, 0531. Embodiment 217. The method of embodiment 201, wherein the inhibitor of osteoclast activity is ibandronic wherein the inhibitor of osteoclast activity is administered at acid. least twice over a period of at least four weeks. 0553 Embodiment 235. The method of embodiment 220, 0532. Embodiment 218. The method of embodiment 201, wherein the inhibitor of osteoclast activity is risedronic acid. wherein the inhibitor of osteoclast activity is administered 0554. Embodiment 236. The method of embodiment 220, once weekly for a period of six weeks. wherein the patient experiences a reduction in pain inten 0533. Embodiment 219. The method of embodiment 218, sity—when using a 100 mm visual analog scale—of at least wherein the inhibitor of osteoclast activity comprises Zole about 5. dronic acid, and the weekly dose is between about 25 mg and 0555 Embodiment 237. The method of embodiment 220, about 75 mg. wherein the inhibitor of osteoclast activity is administered at 0534 Embodiment 220. A method of treating knee pain least twice over a period of at least four weeks. comprising: 0556 Embodiment 238. The method of embodiment 220, 0535 a. selecting a patient having knee pain, and: wherein the inhibitor of osteoclast activity is administered 0536) i. OARSI Grade 0 or Kellgren and Lawrence once weekly for a period of six weeks. Grade 0 or Grade 1 of joint space narrowing, or 0557 Embodiment 239. The method of embodiment 238, 0537 ii. pain intensity of 5 or greater measured using wherein the inhibitor of osteoclast activity comprises Zole the 0-10 NRS or 5 cm or greater using the 10 cm VAS: dronic acid, and the weekly dose is between about 25 mg and and about 75 mg. US 2017/01 19801 A1 May 4, 2017 42

0558 Embodiment 240. A method of treating moderate to 0578 orally administering about 0.4 mg/kg to about 4 severe knee pain comprising administering an inhibitor of mg/kg of Zoledronic acid to the mammal no more osteoclast activity to a person Suffering from moderate to frequently than once a day and more frequently than severe knee pain. once a week; or 0559 Embodiment 241. The method of embodiment 240, 0579 orally administering about 0.4 mg/kg to about 10 wherein the person suffering from moderate to severe knee mg/kg to the mammal once a week, or less frequently. pain has a normal joint space in the knee. 0580 Embodiment 260. The method of any preceding 0560 Embodiment 242. The method of embodiment 240, embodiment, such as embodiment 259, wherein about 0.5 wherein the inhibitor of osteoclast activity is administered at mg/kg to about 2 mg/kg is orally administered to the least twice. mammal daily. 0561. Embodiment 243. The method of embodiment 240, 0581 Embodiment 261. The method of any preceding wherein the inhibitor of osteoclast activity is administered embodiment, such as embodiment 260, wherein about 0.6 about every three months, or more frequently. mg/kg to about 0.9 mg/kg is orally administered to the 0562 Embodiment 244. The method of embodiment 240, mammal daily. wherein the inhibitor of osteoclast activity comprises a 0582 Embodiment 262. The method of any preceding nitrogen-containing bisphosphonate. embodiment, such as embodiment 259, wherein about 0.5 0563 Embodiment 245. The method of embodiment 240, mg/kg to about 2 mg/kg is orally administered to the wherein the patient experiences pain relief within about mammal weekly. three months after the inhibitor of osteoclast activity is 0583. Embodiment 263. The method of any preceding administered to the patient. embodiment, such as embodiment 263, wherein about 0.6 0564 Embodiment 246. The method of embodiment 245, mg/kg to about 0.9 mg/kg is orally administered to the wherein the patient experiences pain relief at least 24 hours mammal weekly. after the inhibitor of osteoclast activity is administered to the 0584) Embodiment 264. The method of any preceding patient. embodiment, such as embodiment 259, 260, 261, 262, or 0565 Embodiment 247. The method of embodiment 240, 263, wherein Zoledronic acid is orally administered about 3 wherein the inhibitor of osteoclast activity is Zoledronic to about 10 times. acid. 0585 Embodiment 265. The method of any preceding 0566. Embodiment 248. The method of embodiment 240, embodiment, such as embodiment 259, 260, 261, 262, 263, wherein the inhibitor of osteoclast activity is minodronic or 264, wherein Zoledronic acid is orally administered in a acid. dosage form comprising more than about 10%. Zoledronic 0567 Embodiment 249. The method of embodiment 240, acid by weight. wherein the inhibitor of osteoclast activity is neridronic acid. 0586 Embodiment 266. The method of any preceding 0568 Embodiment 250. The method of embodiment 240, embodiment, such as embodiment 259, 260, 261, 262, 263, wherein the inhibitor of osteoclast activity is olpadronic 264, or 265, wherein Zoledronic acid is administered in a acid. manner and amount that results in the mammal having an 0569 Embodiment 251. The method of embodiment 240, AUC of Zoledronic acid that is about 50 ngh/mL to about wherein the inhibitor of osteoclast activity is alendronic 500 ngh/mL with each administration of Zoledronic acid. acid. 0587 Embodiment 267. The method of any preceding embodiment, such as embodiment 266, wherein Zoledronic 0570 Embodiment 252. The method of embodiment 240, acid is administered in a manner and amount that results in wherein the inhibitor of osteoclast activity is incadronic the mammal having an AUC of Zoledronic acid that is acid. about 100 ngh/mL to about 500 ngh/mL with each admin 0571 Embodiment 253. The method of embodiment 240, istration of Zoledronic acid. wherein the inhibitor of osteoclast activity is ibandronic 0588 Embodiment 268. A method of preparing an oral acid. dosage form that is safe for repeated administration to a 0572 Embodiment 254. The method of embodiment 240, mammal comprising combining Zoledronic acid with an wherein the inhibitor of osteoclast activity is risedronic acid. excipient that is pharmaceutically acceptable to the mam 0573 Embodiment 255. The method of embodiment 240, mal, wherein the amount of Zoledronic acid that is combined wherein the patient experiences a reduction in pain inten with the excipient is such that Zoledronic acid is present in sity—when using a 100 mm visual analog scale—of at least the oral dosage form in an amount that is 0.4 mg/kg to about about 5. 10 mg/kg based upon the weight of the mammal. 0574 Embodiment 256. The method of embodiment 240, 0589 Embodiment 269. The method of any preceding wherein the inhibitor of osteoclast activity is administered at embodiment, such as embodiment 268, wherein the amount least twice over a period of at least four weeks. of Zoledronic acid that is combined with the excipient is such 0575 Embodiment 257. The method of embodiment 240, that the oral dosage form comprises more than about 10% wherein the inhibitor of osteoclast activity is administered Zoledronic acid by weight. once weekly for a period of six weeks. 0590 Embodiment 270. The method of any preceding 0576 Embodiment 258. The method of embodiment 257, embodiment, such as embodiment 268 or 269, wherein the wherein the inhibitor of osteoclast activity comprises Zole amount of Zoledronic acid that is combined with the excipi dronic acid, and the weekly dose is between about 25 mg and ent is such that Zoledronic acid is present in the oral dosage about 75 mg. form in an amount that is 0.4 mg/kg to about 3 mg/kg based 0577 Embodiment 259. A method of safely delivering upon the weight of the mammal. Zoledronic acid to the blood of a mammal through repeated 0591 Embodiment 271. The method of any preceding oral administration comprising: embodiment, such as embodiment 270, wherein the amount US 2017/01 19801 A1 May 4, 2017

of Zoledronic acid that is combined with the excipient is such 0607 Embodiment 284. The molecular complex of that Zoledronic acid is present in the oral dosage form in an Embodiment 283, wherein the molecular complex com amount that is 0.4 mg/kg to about 1.5 mg/kg based upon the prises ammonia in a salt form. weight of the mammal. 0608 Embodiment 285. The molecular complex of 0592 Embodiment 272. The method of any preceding Embodiment 283, wherein the amine is an amino acid. embodiment, such as embodiment 270, wherein the amount 0609 Embodiment 286. The molecular complex of of Zoledronic acid that is combined with the excipient is such Embodiment 285, wherein the amino acid is a lysine. that Zoledronic acid is present in the oral dosage form in an 0610 Embodiment 287. The molecular complex of amount that is 0.6 mg/kg to about 0.9 mg/kg based upon the Embodiment 285, wherein the amino acid is L-lysine. weight of the mammal. 0611 Embodiment 288. The molecular complex of 0593 Embodiment 273. The method of any preceding Embodiment 285, wherein the amino acid is D-lysine. embodiment, such as embodiment 268, 269, 270, 271, or 0612 Embodiment 289. The molecular complex of 272, wherein the oral dosage form is safe for once daily Embodiment 285, wherein the amino acid is DL-lysine. administration of the oral dosage form for about 3 to about 0613 Embodiment 290. The molecular complex of 10 days. Embodiment 285, wherein the amino acid is a glycine. 0594 Embodiment 274. The method of any preceding 0614 Embodiment 291. The molecular complex of embodiment, such as embodiment 268, 269, 270, 271, or Embodiment 285, wherein the amino acid is L-glycine. 272, wherein the oral dosage form is safe for once weekly administration of the oral dosage form for about 3 to about 0615 Embodiment 292. The molecular complex of 10 weeks. Embodiment 285, wherein the amino acid is D-glycine. 0595 Embodiment 275. A method of safely delivering 0616 Embodiment 293. The molecular complex of Zoledronic acid to the blood of a mammal through repeated Embodiment 285, wherein the amino acid is DL-glycine. oral administration comprising: 0.617 Embodiment 294. The molecular complex of 0596 orally administering about 0.05 mg/kg to about Embodiment 283, wherein the amide is nicotinamide. 4 mg/kg of Zoledronic acid to the mammal no more 0618 Embodiment 295. The molecular complex of frequently than once a day and more frequently than Embodiment 283, wherein the amine is adenine. once a week; or 0619 Embodiment 296. The molecular complex of 0597 orally administering about 0.1 mg/kg to about 10 Embodiment 285, wherein the amino acid (including the mg/kg to the mammal once a week, or less frequently DL-mixture, a D-enantiomer, oran L-enantiomer) is alanine. 0598 wherein Zoledronic acid is orally administered at (0620 Embodiment 297. The molecular complex of least 5 times. Embodiment 285, wherein the amino acid (including the 0599 Embodiment 276. The method of any preceding DL-mixture, a D-enantiomer, or an L-enantiomer) is argi embodiment, such as embodiment 275, wherein Zoledronic nine. acid is orally administered about 5 to about 10 times. 0621 Embodiment 298. The molecular complex of 0600 Embodiment 277. The method of any preceding Embodiment 285, wherein the amino acid (including the embodiment, such as embodiment 275 or 276, wherein DL-mixture, a D-enantiomer, or an L-enantiomer) is aspara Zoledronic acid is orally administered in a dosage form gine. comprising more than about 10%. Zoledronic acid by weight. 0622 Embodiment 299. The molecular complex of 0601 Embodiment 278. The method of any preceding Embodiment 285, wherein the amino acid (including the embodiment, such as embodiment 259, 260, 261, 262, 263, DL-mixture, a D-enantiomer, oran L-enantiomer) is aspartic 264, 265, 266, 267, 268, 269, 270, 271, 272,273, 274, 275, acid. 276, or 277, wherein the mammal is a human being. 0623 Embodiment 300. The molecular complex of 0602 Embodiment 279. The method of any preceding Embodiment 285, wherein the amino acid (including the embodiment, such as embodiment 259, 260, 261, 262, 263, DL-mixture, a D-enantiomer, or an L-enantiomer) is cyste 264, 265, 266, 267, 268, 269, 270, 271, 272,273, 274, 275, ine 276, 277, or 278, wherein about 50 mg to about 350 mg of 0624. Embodiment 301. The molecular complex of oral Zoledronic acid is administered to the mammal per Embodiment 285, wherein the amino acid (including the month. DL-mixture, a D-enantiomer, or an L-enantiomer) is gluta 0603 Embodiment 280. An oral dosage form prepared by mic acid. the method of any preceding embodiment, such as embodi 0625 Embodiment 302. The molecular complex of ment 259, 260, 261, 262, 263,264, 265, 266, 267, 268,269, Embodiment 285, wherein the amino acid (including the 270, 271, 272, 273, 274, 275, 276, 277, 278, or 279. DL-mixture, a D-enantiomer, or an L-enantiomer) is gluta 0604 Embodiment 281. An oral dosage form prepared by mine. the method of any preceding embodiment, wherein an 0626. Embodiment 303. The molecular complex of osteoclast inhibitor, including a bisphosphonate. Such as Embodiment 285, wherein the amino acid (including the Zoledronic acid, neridronic acid, etc., is in a dosage form DL-mixture, a D-enantiomer, or an L-enantiomer) is histi containing one of, or a combination of the ingredients in the dine. Table E. 0627 Embodiment 304. The molecular complex of 0605 Embodiment 282. A molecular complex compris Embodiment 285, wherein the amino acid (including the ing Zoledronic acid or neridronic acid in an acid or a salt DL-mixture, a D-enantiomer, or an L-enantiomer) is isoleu form. cine. 06.06 Embodiment 283. The molecular complex of (0628 Embodiment 305. The molecular complex of Embodiment 282, further comprising a basic or a salt form Embodiment 285, wherein the amino acid (including the of a) an amine, b) an amide, or c) ammonium. DL-mixture, a D-enantiomer, oran L-enantiomer) is leucine. US 2017/01 19801 A1 May 4, 2017 44

0629 Embodiment 306. The molecular complex of transient osteoarthritis of the hip, transient osteoporosis, Embodiment 285, wherein the amino acid (including the transient osteoporosis of the hip, trigeminal neuralgia, tumor DL-mixture, a D-enantiomer, oran L-enantiomer) is methio induced hypocalcemia, or vertebral crush fracture. nine. 0642 Embodiment 319. The method of Embodiment 316 0630 Embodiment 307. The molecular complex of or 317, comprising treating arthritis. Embodiment 285, wherein the amino acid (including the 0643 Embodiment 320. The method of Embodiment DL-mixture, a D-enantiomer, or an L-enantiomer) is phe 319, comprising relieving pain associated with arthritis. nylalanine. 0644. Embodiment 321. The method of Embodiment 0631 Embodiment 308. The molecular complex of 320, wherein the arthritis affects a knee, an elbow, a wrist, Embodiment 285, wherein the amino acid (including the a shoulder, or a hip. DL-mixture, a D-enantiomer, oran L-enantiomer) is proline. 0645 Embodiment 322. The method of Embodiment 0632 Embodiment 309. The molecular complex of 321, wherein the arthritis affects a knee. Embodiment 285, wherein the amino acid (including the 0646 Embodiment 323. The method of Embodiment 316 DL-mixture, a D-enantiomer, or an L-enantiomer) is serine. or 317, comprising treating musculoskeletal pain. 0633 Embodiment 310. The molecular complex of (0647 Embodiment 324. The method of Embodiment 316 Embodiment 285, wherein the amino acid (including the or 317, comprising treating a bone marrow lesion. DL-mixture, a D-enantiomer, or an L-enantiomer) is threo 0648 Embodiment 325. The method of Embodiment nine. 324, wherein the mammal is a human being that experiences 0634 Embodiment 311. The molecular complex of a reduction in bone marrow lesion size that is at least about Embodiment 285, wherein the amino acid (including the 15% within about 6 months after the inhibitor of osteoclast DL-mixture, a D-enantiomer, or an L-enantiomer) is tryp activity is administered to the human being. tophan. 0649 Embodiment 326. The method of Embodiment 0635 Embodiment 312. The molecular complex of 324, wherein the mammal is a human being that experiences Embodiment 285, wherein the amino acid (including the a reduction in bone marrow lesion size that is at least about DL-mixture, a D-enantiomer, or an L-enantiomer) is tyro 25% within about 6 months after the inhibitor of osteoclast S1C. activity is administered to the human being. 0636 Embodiment 313. The molecular complex of 0650 Embodiment 327. The method of Embodiment Embodiment 285, wherein the amino acid (including the 324, 325, or 326, wherein the bone marrow lesion affects a DL-mixture, a D-enantiomer, or an L-enantiomer) is valine. knee. 0637 Embodiment 314. A dosage form comprising the 0651 Embodiment 328. The method of Embodiment molecular complex of Embodiment 282,283, 284, 285, 286, 324, 325, 326, or 327, comprising treating a bone marrow 287, 288, 289, 290, 291, 292, 293, 294, 295, 296,297, 298, lesion of the knee by selecting a patient having a bone 299, 300, 301,302,303, 304,305,306, 307, 308,309, 310, marrow lesion of the knee and OARSI Grade 0 or Kellgren 311, 312, or 313. and Lawrence Grade 0 or Grade 1 of joint space narrowing, 0638 Embodiment 315. The dosage form of Embodi and administering the dosage form to the patient for the ment 314, which is an oral dosage form. treatment of the bone marrow lesion. 06.39 Embodiment 316. A method of treating pain, a 0652 Embodiment 329. The method of Embodiment 316 musculoskeletal condition, or a condition related to bone or or 317, comprising treating osteoarthritis. joint comprising administering a dosage form of Embodi 0653 Embodiment 330. The method of Embodiment ment 314 or 315 to a mammal in need thereof. 329, wherein the osteoarthritis affects a knee. 0640 Embodiment 317. The method of Embodiment 0654 Embodiment 331. The method of Embodiment 329 316, wherein the mammal is a human being. or 330, comprising treating an osteolytic lesion associated 0641 Embodiment 318. The method of Embodiment 316 with osteoarthritis. or 317, comprising treating acute pain, central pain, radio 0655 Embodiment 332. The method of Embodiment therapy or chemo-therapy associated neuropathy, ankylos 316, 317, 318, 319, 320, 321, 322, 323,324, 325, 326, 327, ing spondylitis, arthritis, axial spondyloarthritis, blood can 328, 329, 330, or 331, comprising treating knee pain. cers, bone fracture, bone metastases from Solid tumors, bone 0656. Embodiment 333. The method of Embodiment metastasis, breast cancer, cancer, central multiple Sclerosis 332, comprising treating moderate to severe knee pain. pain, Charcot's foot, chronic pain, complex regional pain 0657 Embodiment 334. The method of Embodiment 332 syndrome, diabetic peripheral neuropathy, erosive osteoar or 333, wherein the mammal is a human being that has a thritis, excessive bone resorption, fibrous dysplasia, giant normal joint space in the knee. cell tumor of bone, HIV-associated neuropathy, hypercalce 0658 Embodiment 335. The method of Embodiment mia of malignancy, inflammatory pain, juvenile rheumatoid 332, comprising treating knee pain by: arthritis, leukemias, low back pain, lumbar nerve root com 0659 1) selecting a patient having knee pain, and: pression, lumbosacral pain, lung cancer, metastatic bone 0660 a. OARSI Grade 0 or Kellgren and Lawrence cancer, monoradiculopathies, multiple myeloma, musculo Grade 0 or Grade 1 of joint space narrowing, or skeletal pain, neuropathic arthropaties, neuropathic pain, 0661 b. pain intensity of 5 or greater measured non-articular rheumatism, osteoarthritis, osteogenesis using the 0-10 NRS, or 5 cm or greater using the 10 imperfecta, osteoporosis, Paget’s disease, Paget’s disease of cm VAS, and bone, peri-articular disorders, phantom limb pain, post 0662. 2) administering the dosage form to the patient. herpetic neuralgia, postoperative pain, post-stroke pain, 0663 Embodiment 336. The method of Embodiment prostate cancer, rheumatoid arthritis, SAPHO syndrome, 335, comprising selecting a patient having OARSI Grade 0 sero-negative (non-rheumatoid) arthropathies, Solid tumors or Kellgren and Lawrence Grade 0 or Grade 1 of joint space or cancers, spinal cord injury, systemic lupus erythematosus, narrowing. US 2017/01 19801 A1 May 4, 2017

0664 Embodiment 337. The method of Embodiment 352, 353, 354, 355, 356, 357, or 358, wherein the mammal 335, comprising selecting a patient having pain intensity of experiences pain relief at least 24 hours after the dosage 5 or greater measured using the 0-10 NRS, or 5 cm or greater form is administered to the mammal. using the 10 cm VAS. 0687 Embodiment 360. The method of Embodiment 0665 Embodiment 338. The method of Embodiment 316, 317, 318, 319, 320, 321, 322, 323,324, 325, 326, 327, 335, 336, or 337, wherein the patient experiences a reduction 328,329, 330, 331, 332, 333,334, 335, 336,337,338,339, in pain intensity—when using a 100 mm visual analog 340, 341, 342, 343, 344, 345, 346, 347, 348, 349, 350, 351, scale—of at least about 5 mm. 352, 353, 354, 355, 356, 357, 358, or 359, wherein the 0666. Embodiment 339. The method of Embodiment 316 mammal experiences pain relief three months after the or 317, comprising treating musculoskeletal pain. dosage form is administered. 0667 Embodiment 340. The method of Embodiment 316 0688 Embodiment 361. The method of Embodiment or 317, comprising treating inflammatory pain. 316, 317, 318, 319, 320, 321, 322, 323,324, 325, 326, 327, 0668 Embodiment 341. The method of Embodiment 316 328,329, 330, 331, 332, 333,334, 335, 336,337,338,339, or 317, comprising treating back pain. 340, 341, 342, 343, 344, 345, 346, 347, 348, 349, 350, 351, 0669 Embodiment 342. The method of Embodiment 352, 353, 354, 355, 356, 357, 358, 359, or 360, wherein the 341, wherein the back pain comprises low back pain. human being experiences pain relief that lasts for a duration 0670 Embodiment 343. The method of Embodiment342, of at least 48 hours after administration of the dosage form. wherein the low back pain is related to a vertebral change. 0671 Embodiment 344. The method of Embodiment 316 0689 Embodiment 362. The method of Embodiment or 317, comprising treating type 1 Modic changes, or type 1 316, 317, 318, 319, 320, 321, 322, 323,324, 325, 326, 327, and type 2 Modic changes. 328,329, 330, 331, 332, 333,334, 335, 336,337,338,339, 0672 Embodiment 345. The method of Embodiment 340, 341, 342, 343, 344, 345, 346, 347, 348, 349, 350, 351, 344, wherein the Modic change is located at C1/2, C2/3, 352, 353,354, 355, 356, 357, 358, 359,360, or 361, wherein C3/4, C4/5, C5/6, or C6/7. the human being receives the dosage form no more often 0673 Embodiment 346. The method of Embodiment than once daily. 344, wherein the Modic change is located at C7/T1, T1/2, 0690 Embodiment 363. The method of Embodiment T2/3, T3/4, T4/5, T5/6, T6/7, T7/8, T8/9, T9/10, T10/11, or 316, 317, 318, 319, 320, 321, 322, 323,324, 325, 326, 327, T11 12. 328,329, 330, 331, 332, 333,334, 335, 336,337,338,339, 0674) Embodiment 347. The method of Embodiment 340, 341, 342, 343, 344, 345, 346, 347, 348, 349, 350, 351, 344, wherein the Modic change is located at T12/L1, L1/2, 352,353,354,355, 356,357,358, 359,360, or 361, wherein L2/3, L3/4, L4/5, or L5/S1. there is a period of about 24 hours to about 7 days between 0675 Embodiment 348. The method of Embodiment 316 administration of dosage forms. or 317, comprising treating pain in an extremity. 0691 Embodiment 364. The method of Embodiment 0676 Embodiment 349. The method of Embodiment 316 363, wherein the dosage form is administered weekly. or 317, comprising treating joint pain. 0692 Embodiment 365. The method of Embodiment 0677 Embodiment 350. The method of Embodiment 316 316, 317, 318, 319, 320, 321, 322, 323,324, 325, 326, 327, or 317, comprising treating muscle pain. 328,329, 330, 331, 332, 333,334, 335, 336,337,338,339, 0678 Embodiment 351. The method of Embodiment 316 340, 341, 342, 343, 344, 345, 346, 347, 348, 349, 350, 351, or 317, comprising treating neuropathic pain. 352, 353,354, 355, 356, 357, 358, 359,360, or 361, wherein 0679 Embodiment 352. The method of Embodiment 316 there is a period of about 14 days to about 28 days between or 317, comprising treating complex regional pain Syn administration of dosage forms. drome. 0693 Embodiment 366. The method of Embodiment 0680 Embodiment 353. The method of Embodiment 316, 317, 318, 319, 320, 321, 322, 323,324, 325, 326, 327, 352, wherein the complex regional pain syndrome is com 328,329, 330, 331, 332, 333,334, 335, 336,337,338,339, plex regional pain syndrome type I. 340, 341, 342, 343, 344, 345, 346, 347, 348, 349, 350, 351, 0681 Embodiment 354. The method of Embodiment 352, 353,354, 355, 356, 357, 358, 359,360, or 361, wherein 352, wherein the complex regional pain syndrome is com there is a period of at least one month between administra plex regional pain syndrome type II. tion of dosage forms. 0682 Embodiment 355. The method of Embodiment 316 0694 Embodiment 367. The method of Embodiment or 317, comprising treating Paget’s disease of bone. 316, 317, 318, 319, 320, 321, 322, 323,324, 325, 326, 327, 0683. Embodiment 356. The method of Embodiment 316 328,329, 330, 331, 332, 333,334, 335, 336,337,338,339, or 317, comprising treating multiple myeloma. 340, 341, 342, 343, 344, 345, 346, 347, 348, 349, 350, 351, 0684. Embodiment 357. The method of Embodiment 316 352, 353,354, 355, 356, 357, 358, 359,360, or 361, wherein or 317, comprising treating ankylosing spondylitis. there is a period of about 7 days to about 14 days between 0685 Embodiment 358. The method of Embodiment administration of dosage forms. 316, 317, 318, 319, 320, 321,322, 323, 324, 325, 326, 327, 0695 Embodiment 368. The method of Embodiment 328,329, 330, 331, 332, 333,334, 335, 336,337,338,339, 316, 317, 318, 319, 320, 321, 322, 323,324, 325, 326, 327, 340, 341, 342, 343, 344, 345,346, 347, 348, 349, 350, 351, 328,329, 330, 331, 332, 333,334, 335, 336,337,338,339, 352, 353, 354, 355, 356, or 357, wherein the dosage form is 340, 341, 342, 343, 344, 345, 346, 347, 348, 349, 350, 351, administered about every three months, or more frequently. 352, 353,354, 355, 356,357,358, 359, 360, 361, 362,363, 0686 Embodiment 359. The method of Embodiment 364, 365, 366, or 367, wherein the compound is adminis 316, 317, 318, 319, 320, 321,322, 323, 324, 325, 326, 327, tered more than once. 328,329, 330, 331, 332, 333,334, 335, 336,337,338,339, 0696 Embodiment 369. The method, composition, 340, 341, 342, 343, 344, 345,346, 347, 348, 349, 350, 351, molecular complex, dosage form, or product, of any pre US 2017/01 19801 A1 May 4, 2017 46 ceding embodiment, wherein Zoledronic acid or neridronic ceding embodiment, wherein Zoledronic acid or neridronic acid decreases osteoclast activity and/or CTX serum levels. acid decreases osteoclast activity by at about 75%. (0697 Embodiment 370. The method, composition, 0713 Embodiment 386. The method, composition, molecular complex, dosage form, or product, of any pre molecular complex, dosage form, or product, of any pre ceding embodiment, wherein Zoledronic acid or neridronic ceding embodiment, wherein Zoledronic acid or neridronic acid decreases osteoclast activity by at least about 5%. acid decreases osteoclast activity by about 80%-90%. 0698 Embodiment 371. The method, composition, 0714 Embodiment 387. The method, composition, molecular complex, dosage form, or product, of any pre molecular complex, dosage form, or product, of any pre ceding embodiment, wherein Zoledronic acid or neridronic ceding embodiment, wherein Zoledronic acid or neridronic acid decreases osteoclast activity by at least about 10%. acid decreases osteoclast activity by at least about 80%. (0699 Embodiment 372. The method, composition, 0715 Embodiment 388. The method, composition, molecular complex, dosage form, or product, of any pre molecular complex, dosage form, or product, of any pre ceding embodiment, wherein Zoledronic acid or neridronic ceding embodiment, wherein Zoledronic acid or neridronic acid decreases osteoclast activity by at least about 15%. acid decreases osteoclast activity by at least about 85%. (0700 Embodiment 373. The method, composition, 0716 Embodiment 389. The method, composition, molecular complex, dosage form, or product, of any pre molecular complex, dosage form, or product, of any pre ceding embodiment, wherein Zoledronic acid or neridronic ceding embodiment, wherein Zoledronic acid or neridronic acid decreases osteoclast activity by at least about 20%. acid decreases osteoclast activity by about 80%-85%. 0701 Embodiment 374. The method, composition, 07.17 Embodiment 390. The method, composition, molecular complex, dosage form, or product, of any pre molecular complex, dosage form, or product, of any pre ceding embodiment, wherein Zoledronic acid or neridronic ceding embodiment, wherein Zoledronic acid or neridronic acid decreases osteoclast activity by at least about 25%. acid decreases osteoclast activity by at least about 90%. 0702 Embodiment 375. The method, composition, 07.18 Embodiment 391. The method, composition, molecular complex, dosage form, or product, of any pre molecular complex, dosage form, or product, of any pre ceding embodiment, wherein Zoledronic acid or neridronic ceding embodiment, wherein Zoledronic acid or neridronic acid decreases osteoclast activity by at least about 30%. acid decreases osteoclast activity by about 85%-90%. (0703 Embodiment 376. The method, composition, 0719 Embodiment 392. The method, composition, molecular complex, dosage form, or product, of any pre molecular complex, dosage form, or product, of any pre ceding embodiment, wherein Zoledronic acid or neridronic ceding embodiment, wherein Zoledronic acid or neridronic acid decreases osteoclast activity by at least about 35%. acid decreases osteoclast activity by about 85%-95%. 0704. Embodiment 377. The method, composition, 0720 Embodiment 393. The method, composition, molecular complex, dosage form, or product, of any pre molecular complex, dosage form, or product, of any pre ceding embodiment, wherein Zoledronic acid or neridronic ceding embodiment, wherein Zoledronic acid or neridronic acid decreases osteoclast activity by at least about 40%. acid decreases osteoclast activity by about 90%-95%. (0705 Embodiment 378. The method, composition, 0721 Embodiment 394. The method, composition, molecular complex, dosage form, or product, of any pre molecular complex, dosage form, or product, of any pre ceding embodiment, wherein Zoledronic acid or neridronic ceding embodiment, wherein Zoledronic acid or neridronic acid decreases osteoclast activity by at least about 45%. acid decreases osteoclast activity by at least about 95%. (0706 Embodiment 379. The method, composition, 0722. Embodiment 395. The method, composition, molecular complex, dosage form, or product, of any pre molecular complex, dosage form, or product, of any pre ceding embodiment, wherein Zoledronic acid or neridronic ceding embodiment, wherein Zoledronic acid or neridronic acid decreases osteoclast activity by at least about 50%. acid decreases osteoclast activity by at least about 99%. (0707 Embodiment 380. The method, composition, 0723 Embodiment 396. The method, composition, molecular complex, dosage form, or product, of any pre molecular complex, dosage form, or product, of any pre ceding embodiment, wherein Zoledronic acid or neridronic ceding embodiment, wherein Zoledronic acid or neridronic acid decreases osteoclast activity by at least about 55%. acid decreases osteoclast activity by at least about 100%. 0708 Embodiment 381. The method, composition, 0724. Embodiment 397. The method, composition, molecular complex, dosage form, or product, of any pre molecular complex, dosage form, or product, of any pre ceding embodiment, wherein Zoledronic acid or neridronic ceding embodiment, wherein Zoledronic acid or neridronic acid decreases osteoclast activity by at least about 60%. acid decreases CTX serum levels by at least about 5%. (0709 Embodiment 382. The method, composition, 0725 Embodiment 398. The method, composition, molecular complex, dosage form, or product, of any pre molecular complex, dosage form, or product, of any pre ceding embodiment, wherein Zoledronic acid or neridronic ceding embodiment, wherein Zoledronic acid or neridronic acid decreases osteoclast activity by at about 60%–70%. acid decreases CTX serum levels by at least about 10%. 07.10 Embodiment 383. The method, composition, 0726 Embodiment 399. The method, composition, molecular complex, dosage form, or product, of any pre molecular complex, dosage form, or product, of any pre ceding embodiment, wherein Zoledronic acid or neridronic ceding embodiment, wherein Zoledronic acid or neridronic acid decreases osteoclast activity by about 70%–80%. acid decreases CTX serum levels by at least about 15%. 0711 Embodiment 384. The method, composition, 0727 Embodiment 400. The method, composition, molecular complex, dosage form, or product, of any pre molecular complex, dosage form, or product, of any pre ceding embodiment, wherein Zoledronic acid or neridronic ceding embodiment, wherein Zoledronic acid or neridronic acid decreases osteoclast activity by at least about 70%. acid decreases CTX serum levels by at least about 20%. 0712 Embodiment 385. The method, composition, 0728 Embodiment 401. The method, composition, molecular complex, dosage form, or product, of any pre molecular complex, dosage form, or product, of any pre US 2017/01 19801 A1 May 4, 2017 47 ceding embodiment, wherein Zoledronic acid or neridronic ceding embodiment, wherein Zoledronic acid or neridronic acid decreases CTX serum levels by at least about 25%. acid decreases CTX serum levels by about 80%-90%. 0729 Embodiment 402. The method, composition, 0745 Embodiment 418. The method, composition, molecular complex, dosage form, or product, of any pre molecular complex, dosage form, or product, of any pre ceding embodiment, wherein Zoledronic acid or neridronic ceding embodiment, wherein Zoledronic acid or neridronic acid decreases CTX serum levels by at least about 30%. acid decreases CTX serum levels by about 85%-90%. 0730 Embodiment 403. The method, composition, 0746 Embodiment 419. The method, composition, molecular complex, dosage form, or product, of any pre molecular complex, dosage form, or product, of any pre ceding embodiment, wherein Zoledronic acid or neridronic ceding embodiment, wherein Zoledronic acid or neridronic acid decreases CTX serum levels by at least about 35%. acid decreases CTX serum levels by about 85%-95%. 0731 Embodiment 404. The method, composition, 0747 Embodiment 420. The method, composition, molecular complex, dosage form, or product, of any pre molecular complex, dosage form, or product, of any pre ceding embodiment, wherein Zoledronic acid or neridronic ceding embodiment, wherein Zoledronic acid or neridronic acid decreases CTX serum levels by at least about 40%. acid decreases CTX serum levels by about 90%-95%. 0732 Embodiment 405. The method, composition, 0748 Embodiment 421. The method, composition, molecular complex, dosage form, or product, of any pre molecular complex, dosage form, or product, of any pre ceding embodiment, wherein Zoledronic acid or neridronic ceding embodiment, wherein Zoledronic acid or neridronic acid decreases CTX serum levels by at least about 45%. acid decreases CTX serum levels by at least about 95%. 0733 Embodiment 406. The method, composition, 0749 Embodiment 422. The method, composition, molecular complex, dosage form, or product, of any pre molecular complex, dosage form, or product, of any pre ceding embodiment, wherein Zoledronic acid or neridronic ceding embodiment, wherein Zoledronic acid or neridronic acid decreases CTX serum levels by at least about 50%. acid decreases CTX serum levels by at least about 99%. 0734 Embodiment 407. The method, composition, 0750 Embodiment 423. The method, composition, molecular complex, dosage form, or product, of any pre molecular complex, dosage form, or product, of any pre ceding embodiment, wherein Zoledronic acid or neridronic ceding embodiment, wherein Zoledronic acid or neridronic acid decreases CTX serum levels by at least about 55%. acid decreases CTX serum levels by at least about 100%. 0735 Embodiment 408. The method, composition, 0751. Embodiment 424. The method, dosage form, or molecular complex, dosage form, or product, of any pre product, of any preceding embodiment, wherein the Zole ceding embodiment, wherein Zoledronic acid or neridronic dronic acid is orally administered in a manner that results in acid decreases CTX serum levels by at least about 60%. a 24 hour sustained plasma level factor that is at least 1.5 0736. Embodiment 409. The method, composition, times that of 4 mg of Zoledronic acid administered intrave molecular complex, dosage form, or product, of any pre nously. ceding embodiment, wherein Zoledronic acid or neridronic 0752 Unless otherwise indicated, all numbers expressing acid decreases CTX serum levels by about 60%–70%. quantities of ingredients, properties such as molecular 0737 Embodiment 410. The method, composition, weight, reaction conditions, and so forth used in the speci molecular complex, dosage form, or product, of any pre fication and claims are to be understood in all instances as ceding embodiment, wherein Zoledronic acid or neridronic indicating both the exact values as shown and as being acid decreases CTX serum levels by about 70%–80%. modified by the term “about.” Accordingly, unless indicated 0738 Embodiment 411. The method, composition, to the contrary, the numerical parameters set forth in the molecular complex, dosage form, or product, of any pre specification and attached claims are approximations that ceding embodiment, wherein Zoledronic acid or neridronic may vary depending upon the desired properties sought to be acid decreases CTX serum levels by least about 70%. obtained. At the very least, and not as an attempt to limit the 0739 Embodiment 412. The method, composition, application of the doctrine of equivalents to the scope of the molecular complex, dosage form, or product, of any pre claims, each numerical parameter should at least be con ceding embodiment, wherein Zoledronic acid or neridronic Strued in light of the number of reported significant digits acid decreases CTX serum levels by at least about 75%. and by applying ordinary rounding techniques. 0740 Embodiment 413. The method, composition, 0753. The terms “a,” “an,” “the and similar referents molecular complex, dosage form, or product, of any pre used in the context of describing the invention (especially in ceding embodiment, wherein Zoledronic acid or neridronic the context of the following claims) are to be construed to acid decreases CTX serum levels by at least about 80%. cover both the singular and the plural, unless otherwise 0741. Embodiment 414. The method, composition, indicated herein or clearly contradicted by context. All molecular complex, dosage form, or product, of any pre methods described herein can be performed in any suitable ceding embodiment, wherein Zoledronic acid or neridronic order unless otherwise indicated herein or otherwise clearly acid decreases CTX serum levels by at least about 85%. contradicted by context. The use of any and all examples, or 0742 Embodiment 415. The method, composition, exemplary language (e.g., “such as') provided herein is molecular complex, dosage form, or product, of any pre intended merely to better illuminate the invention and does ceding embodiment, wherein Zoledronic acid or neridronic not pose a limitation on the scope of any claim. No language acid decreases CTX serum levels by about 80%-85%. in the specification should be construed as indicating any 0743 Embodiment 416. The method, composition, non-claimed element essential to the practice of the inven molecular complex, dosage form, or product, of any pre tion. ceding embodiment, wherein Zoledronic acid or neridronic 0754 Groupings of alternative elements or embodiments acid decreases CTX serum levels by at least about 90%. disclosed herein are not to be construed as limitations. Each 0744. Embodiment 417. The method, composition, group member may be referred to and claimed individually molecular complex, dosage form, or product, of any pre or in any combination with other members of the group or US 2017/01 19801 A1 May 4, 2017 48 other elements found herein. It is anticipated that one or 14. The method of claim 1, wherein at least some of the more members of a group may be included in, or deleted Zoledronic acid is in a salt form. from, a group for reasons of convenience and/or patentabil 15. The method of claim 1, wherein the Zoledronic acid is ity. When any such inclusion or deletion occurs, the speci administered in a dosage form and the dosage form further fication is deemed to contain the group as modified thus comprises water. fulfilling the written description of all Markush groups used 16. The method of claim 1, wherein the Zoledronic acid is in the appended claims. administered in a dosage form and the dosage form further 0755 Certain embodiments are described herein, includ comprises magnesium Stearate. ing the best mode known to the inventors for carrying out the 17. The method of claim 1, wherein the Zoledronic acid invention. Of course, variations on these described embodi and the lysine are present in a solid having X-ray powder ments will become apparent to those of ordinary skill in the diffraction peaks at about 9.1° 2, about 14.7° 20, about art upon reading the foregoing description. The inventor 18.0° 20, about 21.2° 20, and about 26.0° 20. expects skilled artisans to employ such variations as appro 18. The method of claim 1, wherein the Zoledronic acid priate, and the inventors intend for the invention to be and the lysine are present in a solid having X-ray powder practiced otherwise than specifically described herein. diffraction peaks at about 8.8° 20, about 9.720, about 17.6° Accordingly, the claims include all modifications and 20, about 23.1° 20, and about 26.5° 20. equivalents of the Subject matter recited in the claims as 19. The method of claim 1, wherein the Zoledronic acid permitted by applicable law. Moreover, any combination of and the lysine are present in a solid having X-ray powder the above-described elements in all possible variations thereof is contemplated unless otherwise indicated herein or diffraction peaks at about 8.3° 20, about 11.8° 20, about otherwise clearly contradicted by context. 12.3° 20, about 15.8° 20, and about 20.8° 20. 0756. In closing, it is to be understood that the embodi 20. The method of claim 1, wherein the Zoledronic acid ments disclosed herein are illustrative of the principles of the and the lysine are present in a solid having X-ray powder claims. Other modifications that may be employed are diffraction peaks at about 9.7° 20, about 10.8° 20, about within the scope of the claims. Thus, by way of example, but 14.4° 20, about 18.9° 20, and about 21.4° 20. not of limitation, alternative embodiments may be utilized in 21. The method of claim 1, wherein the Zoledronic acid accordance with the teachings herein. Accordingly, the and the lysine are present in a solid having X-ray powder claims are not limited to embodiments precisely as shown diffraction peaks at 7.2° 20, about 14.0° 20, about 18.3° 20, and described. about 19.1° 20, about 20.7° 20, about 24.6° 20, and about 34.49 29. What is claimed is: 22. The method of claim 1, wherein the Zoledronic acid 1. A method of treating complex regional pain syndrome and the lysine are present in a solid having X-ray powder comprising orally administering a dosage form comprising diffraction peaks at 6.6° 20, about 11.0° 20, about 14.2° 20, Zoledronic acid in an acid or a salt form, and a lysine, to a about 18.3° 20, about 19.7° 20, about 22.7° 20, and about human being in need thereof, wherein the human being 27.6° 20. receives about 400 to about 500 mg of Zoledronic acid or a 23. The method of claim 1, wherein the Zoledronic acid salt thereof within a period of six months. and the lysine are present in a solid having X-ray powder 2. The method of claim 1, wherein the lysine is DL-lysine. diffraction peaks at about 9.0° 20, about 14.4° 20, about 3. The method of claim 1, wherein the dosage form 18.1° 20, about 26.0° 20, and about 29.6° 20. contains about 150 mg to about 170 mg of Zoledronic acid. 24. The method of claim 1, wherein the Zoledronic acid 4. The method of claim 2, wherein the dosage form and the lysine are present in a solid having X-ray powder contains about 150 mg to about 170 mg of Zoledronic acid. diffraction peaks at about 9.6° 20, about 10.7° 20, about 5. The method of claim 1, wherein the Zoledronic acid is 14.3° 20, about 21.4° 20, and about 23.5° 20. orally administered 2 to 5 times in a month. 25. The method of claim 8, wherein the Zoledronic acid 6. The method of claim 4, wherein the Zoledronic acid is and the lysine are present in a solid having X-ray powder orally administered 2 to 5 times in a month. diffraction peaks at about 9.1° 20, about 14.7° 20, about 7. The method of claim 1, wherein a total of about 450 mg 18.0° 20, about 21.2° 20, and about 26.0° 20. to about 500 mg of the Zoledronic acid is administered. 26. The method of claim 8, wherein the Zoledronic acid 8. The method of claim 6, wherein a total of about 450 mg and the lysine are present in a solid having X-ray powder to about 500 mg of the Zoledronic acid is administered. diffraction peaks at about 8.8° 20, about 9.720, about 17.6° 9. The method of claim 1, wherein two or three doses of 20, about 23.1° 20, and about 26.5° 20. about 100 mg to about 150 mg of the Zoledronic acid are 27. The method of claim 8, wherein the Zoledronic acid orally administered within a period of two months. and the lysine are present in a solid having X-ray powder 10. The method of claim 2, wherein two or three doses of diffraction peaks at about 8.3° 20, about 11.8° 20, about about 100 mg to about 150 mg of the Zoledronic acid are 12.3° 20, about 15.8° 20, and about 20.8° 20. orally administered within a period of two months. 28. The method of claim 8, wherein the Zoledronic acid 11. The method of claim 1, wherein two doses of about and the lysine are present in a solid having X-ray powder 200 mg to about 250 mg of the Zoledronic acid are orally diffraction peaks at about 9.7° 20, about 10.8° 20, about administered within a period of two months. 14.4° 20, about 18.9° 20, and about 21.4° 20. 12. The method of claim 2, wherein two doses of about 29. The method of claim 8, wherein the Zoledronic acid 200 mg to about 250 mg of the Zoledronic acid are orally and the lysine are present in a solid having X-ray powder administered within a period of two months. diffraction peaks at 7.2° 20, about 14.0° 20, about 18.3° 20, 13. The method of claim 1, wherein the human being about 19.1° 20, about 20.7° 20, about 24.6° 20, and about experiences pain relief for at least 48 hours. 34.4° 20. US 2017/01 19801 A1 May 4, 2017 49

30. The method of claim 8, wherein the Zoledronic acid and the lysine are present in a Solid having X-ray powder diffraction peaks at 6.6° 20, about 11.0° 20, about 14.2° 20, about 18.3° 20, about 19.7° 20, about 22.7° 20, and about 27.6° 20.