a phase ii study evaluating sb-751689 in post-menopausal women with osteoporosis.

Conditions: Osteoporosis

Summary: this is a 12 month study designed to evaluate the safety and effectiveness of sb-751689 in the treatment of osteoporosis in post-menopausal women, in comparison with 2 active comparators and placebo.


Eligibility criteria:
inclusion: * informed consent: subject is willing and able to provide written informed consent. * menopausal status: ambulatory female aged \ 5 years postmenopausal. * t-score: a subject with either no or only one prevalent vertebral fracture is eligible for inclusion if she satisfies one of the following t-score requirements: if no prevalent vertebral fracture subject must have an absolute bmd value consistent with a t-score of less than or equal to -2.5 and greater than -4.0 at either the femoral neck, total hip, trochanter, or lumbar spine, or if one prevalent vertebral fracture subject must have an absolute bmd value consistent with a t-score of less than or equal to -2.0 and greater than -4.0 at either the femoral neck, total hip, trochanter, or lumbar spine. * suitable vertebra: two or more vertebra in the range of l1 to l4 that are suitable for bmd measurement by dxa. * protocol compliance: subject who, in the opinion of the investigator, is willing and able to comply with the requirements of the protocol. exclusion: * t-score: has an absolute bmd value consistent with a t-score less than or equal to -4.0 at either the femoral neck, total hip, trochanter, or lumbar spine. * vertebral fractures: has \>1 prevalent vertebral fracture at the screening visit. * non-vertebral fractures: any previous non-vertebral osteoporosis related/fragility fracture after age 40. * spine deformity: significant spine deformity which would preclude dxa/qct assessments. * bmi: bmi ≥33kg/m2. * bone metabolic diseases: other than osteoporosis, history or concurrent diseases affecting bone metabolism (e.g., osteomalacia, hyperparathyroidism, hyperthyroidism). * gi disease: history of major upper gastrointestinal disease * malabsorption: active or history of malabsorption (e.g., history of celiac disease, irritable bowel syndrome or inflammatory bowel disease). * liver disease: past or current history of liver disease or known hepatic or biliary abnormalities, (with the exception of previously documented diagnosis of gilbert's syndrome). * rheumatoid arthritis: active disease or history of rheumatoid arthritis. * nephrolithiasis: history of or active nephrolithiasis (kidney stones). * osteosarcoma risk: subjects at increased risk of osteosarcoma such as those with paget's disease of bone or any prior external beam or implant radiation therapy involving the skeleton. * malignancy: malignant disease diagnosed within the previous 5 years (except resected basal cell cancer). * biological abnormalities: any clinically relevant biological abnormality found and/or volunteered at screening (other than those related to the disease under investigation) which, in the opinion of the investigator, is clinically significant and would preclude safe participation in this study. * surgical and medical conditions: presence of the following conditions within six months prior to screening: myocardial infarction, coronary bypass surgery, coronary artery angioplasty, unstable angina, cardiac arrhythmia, clinically evident congestive heart failure, or cerebrovascular accident. * glomerular filtration rate: glomerular filtration rate (gfr) \<35 ml/min as calculated by the modification of diet in renal disease (mdrd) equation as follows: gfr (ml/min/1.73 m2) = 186 x (serum creatinine mg/dl)-1.154 x (age)-0.203 x (0.742 if female) x (1.210 if african american) (conventional units). * qt/qtc prolongation: a marked baseline prolongation of qt/qtc interval (e.g., qtc interval ≥450 msec on the screening ecg). * torsades de pointes: a history of risk factors for torsades de pointes (e.g., heart failure, hypokalemia, family history of long qt syndrome). * liver chemistries: liver chemistries \[aspartate aminotransferase (ast), alanine aminotransferase (alt) or total bilirubin\] exceeding 2-fold the upper limit of the laboratory-specified reference range, at screening. * abnormal serum calcium: serum calcium (total or albumin-adjusted) outside the central laboratory reference range at the screening visit. * abnormal pth: pth (intact or whole) outside the normal range. * abnormal creatine phosphokinase: creatine phosphokinase (cpk) outside the normal range. * abnormal alkaline phosphatase: alkaline phosphatase outside of the normal range. * thyroid hormone replacement: subjects receiving thyroid hormone replacement therapy must have a tsh level checked. subjects will be excluded if tsh levels are \ 10.0miu/l. however, subjects will not be excluded if tsh is in the range 0.1-4.5 miu/l. if tsh is \>4.5 and ≤10.0miu/ml, measure t4 and exclude the subject only if the t4 is outside the normal range. * vitamin d deficiency: vitamin d deficiency (serum 25-hydroxy vitamin d \< 20ng/ml, equivalent to 50nmol/l) at screening. subjects can undergo vitamin d repletion as per local practice and be re-screened once only for vitamin d levels within the 6-week screening period. they will remain excluded if the re-screened value is \< 20ng/ml. * previous strontium or iv bisphosphonate: any previous treatment with strontium ranelate or intravenous bisphosphonate. * oral bisphosphonates: any previous treatment with an oral bisphosphonate as follows: any treatment within the last six months * one month cumulative treatment within the last 12 months * three months cumulative treatment within the past two years, or * two years cumulative treatment within the past five years. * fluoride: treatment with fluoride (dose greater than 10mg/day) within the previous 5 years for osteoporosis. * digoxin: current therapy with digoxin. * bone metabolism drugs: treatment with other drugs affecting bone metabolism within the last six months prior to screening: chronic systemic corticosteroid \[e.g., glucocorticoid, mineralocorticoid\] treatment of no more than 2 intra-articular injections within the past year or use of oral, parenteral, or long-term, high-dose inhaled corticosteroids. treatment with any topical corticosteroid will not exclude the subject from participating. hormones \[e.g., estrogens/"natural estrogen preparations"(except for nonsystemic vaginal treatment), 19-norprogestins, serms such as raloxifene, anabolic steroids/androgens such as dehydroepiandrosterone (dhea) or its sulfated form (dheas), nandrolone, tibolone, active vitamin d analogs/metabolites such as 1,25-dihydroxy vitamin d (calcitriol) or 1alpha-hydroxyvitamin d3 (1-alpha hydroxycholecalciferol), calcitonin\]. calcineurin inhibitors \[e.g., cyclosporine, tacrolimus\] or methotrexate. * previous anabolic agents: treatment with pth, pth analogues or similar anabolic agent for osteoporosis within the last two years. * contraindications: contraindications to therapy with calcium or vitamin d. * pregnancy: women who are pregnant are not allowed in this study. * interfering medications: vitamin a in excess of 10,000 iu per day, heparin, or lithium, or anticonvulsant medications except benzodiazepines. * investigational drug exposure: administration of any investigational drug within 90 days preceding the first dose of the study drug. * substance abuse: history or current evidence of drug or alcohol abuse within the previous 12 months. * problems swallowing: inability to swallow a tablet whole. the following exclusion criteria do not apply to subjects allocated to the open-label teriparatide group: * calcium channel blockers: current therapy with calcium channel blockers diltiazem and verapamil. * oral azole antifungals: current therapy with any oral azole antifungal. * immunosuppressants: current therapy with cyclosporine or oral tacrolimus. * ritonavir: current therapy with ritonavir. * quinidine: current therapy with quinidine. * macrolide antibiotics: subjects anticipated to require chronic use of macrolide antibiotics. * alendronate contraindications: contraindications to therapy with alendronate. additional exclusion criteria for subjects recruited at qct sites * hip surgery: history of hip surgery resulting in a metal implant on either the left or right side that would cause an artefact on a qct scan. additional exclusion criteria for teriparatide subjects * teriparatide contraindications: contraindications to therapy with teriparatide according to locally approved datasheet.

Keywords: bone mineral density, ronacaleret teriparatide alendronate, post-menopausal women, osteoporosis, sb-751689