Clinical Trial to Assess Efficacy, Tolerability of Rising Doses of Clodronate in Painful Knee Osteoarthritis Patients

Inclusion Criteria:

• Female and male patients aged 50 up to 75 years at ICF signature.
• Diagnosis of knee OA according to the American College of Rheumatology, confirmed byRx during the screening (a Rx performed in the last 3 months before Baseline isaccepted).
• Kellgren-Lawrence radiographic score between 2 and 3 degrees in the tibiofemoraljoint.
• Symptomatic knee OA (pain) since at least 6 months with a knee pain (VAS) rangingbetween 40 and 80 mm at Screening visit (the figure should be confirmed at Baseline).
• Female patients of childbearing potential must have a negative pregnancy test beforeeach treat-ment and during the Visit 5 - Week 4 and they must use adequate methods ofcontraception throughout the course of the study.
• A signed ICF by the patient after exhaustive study discussion with the investigators.

Exclusion Criteria:

• BMI > 35 kg/m² (Class II obesity).
• Joint instability due to other reasons than knee OA, such as f.i. algo dystrophicsyndrome, either partial or complete rupture of internal / externals ligaments,kneecap instability, etc.
• Otherwise located lower limb pain, such as hip pain.
• Other musculoskeletal disorders related to the target knee.
• Any treatment with IA drugs in the last 3 months before Day 0 - Baseline (includingany formulation of corticosteroids or hyaluronic acid injections).
• Corticosteroid use by any systemic route, and hyaluronic acid injection orintraarticular corticosteroids for any other joint in the previous month will not bepermitted.
• Any treatment with systemic non-steroidal anti-inflammatory drugs (NSAIDs) in the weekbefore enrolment, or any steroid anti-inflammatory drugs and chondroprotective drugsin the thirty (30) days before month before Baseline.
• Any treatment with systemic bisphosphonates in the last twelve (12) months beforeBaseline.
• Any treatment with Glucosamine or Chondroitin sulfate, Diacerein and Matrixmetalloproteinase (MMP) inhibitors in the 4 weeks before Baseline.
• Any treatment with Denosumab in the twelve (12) months before Baseline.
• Any treatment with Paracetamol in the twelve (12) hours before Baseline.
• Any knee surgery in the past or knee arthroplasty.
• Any diagnostic or surgical arthroscopy of the knee in the six (6) months beforeBaseline.
• Any jaw osteonecrosis in the last twenty-four (24) months before Baseline or at a riskof jaw osteonecrosis.
• Any known hypersensitivity to the drug in the study to its excipients or otherbisphosphonates, and any hypersensitivity to Paracetamol (rescue drug).
• Any participation in a clinical study in which the last administration of theinvestigational medicinal product was within two (2) weeks before consenting to studyparticipation (i.e.signing ICF).
• Inadequate organ function defined by the following laboratory parameters:

1. Absolute Neutrophil Count (ANC) < 1500/μl.
2. Hemoglobin (Hb) < 9 g/dl (< Hb 5.6 mmol/L)
3. Platelet Count < 100.000/μl
4. Serum Creatinine > 1.5 x Upper limit normal (ULN) or estimated GlomerularFiltration Rate (eGFR) < 60 mL/min (as per Cockroft-Gault formula).
5. Alanine aminotransferase (ALT) or Aspartate aminotransferase (AST)> 1.5 x Upperlimit normal(ULN).
6. Serum Total Bilirubin > 1.5 x Upper limit normal (ULN).

• Pregnant or breastfeeding women, or women planning to become pregnant during thestudy.
• Any positive or suspected history of alcoholism or drug use.
• Clinically significant (i.e.) gastrointestinal, renal, hepatic, pulmonary,cardiovascular or neurological disease that could interfere with the outcome of thestudy or the patient's ability to comply with study requirements.
• Patients unwilling or unable to comply with the protocol.